DEPOD - human DEPhOsphorylation Database

Basic Information
Phosphatases
Pathway
Interacting Proteins
Phosphorylating Kinases

Gene Name	PIK3R1 (QuickGO)	Interactive visualization of PIK3R1 structures (A quick tutorial to explore the interctive visulaization) Representative structure: 1PIC
Synonyms	PIK3R1, GRB1
Protein Name	PIK3R1
Alternative Name(s)	Phosphatidylinositol 3-kinase regulatory subunit alpha;PI3-kinase regulatory subunit alpha;PI3K regulatory subunit alpha;PtdIns-3-kinase regulatory subunit alpha;Phosphatidylinositol 3-kinase 85 kDa regulatory subunit alpha;PI3-kinase subunit p85-alpha;PtdIns-3-kinase regulatory subunit p85-alpha;
Protein Family	Belongs to the PI3K p85 subunit family
EntrezGene ID	5295 (Comparitive Toxicogenomics)
UniProt AC (Human)	P27986 (protein sequence)
Enzyme Class	N/A
Molecular Weight	83598 Dalton
Protein Length	724 amino acids (AA)
Genome Browsers	NCBI \| ENSG00000145675 (Ensembl) \| UCSC
Crosslinking annotations	Query our ID-mapping table
Orthologues	Quest For Orthologues (QFO) \| GeneTree \| eggNOG - KOG4637 \| eggNOG - ENOG410XP6R
Phosphorylation Network	Visualize

Domain organization, Expression, Diseases

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Localization, Function, Catalytic activity and Sequence

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Motif information from Eukaryotic Linear Motif atlas (ELM)

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Gene Ontology (P: Process; F: Function and C: Component terms)

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GO:0001678	P:cellular glucose homeostasis
GO:0001784	F:phosphotyrosine residue binding
GO:0001953	P:negative regulation of cell-matrix adhesion
GO:0005068	F:transmembrane receptor protein tyrosine kinase adaptor activity
GO:0005158	F:insulin receptor binding
GO:0005159	F:insulin-like growth factor receptor binding
GO:0005168	F:neurotrophin TRKA receptor binding
GO:0005634	C:nucleus
GO:0005737	C:cytoplasm
GO:0005801	C:cis-Golgi network
GO:0005829	C:cytosol
GO:0005886	C:plasma membrane
GO:0005911	C:cell-cell junction
GO:0005942	C:phosphatidylinositol 3-kinase complex
GO:0005943	C:phosphatidylinositol 3-kinase complex
GO:0006468	class IA
GO:0006606	P:protein phosphorylation
GO:0007173	P:protein import into nucleus
GO:0007186	P:epidermal growth factor receptor signaling pathway
GO:0007411	P:G-protein coupled receptor signaling pathway
GO:0008134	P:axon guidance
GO:0008286	F:transcription factor binding
GO:0008625	P:insulin receptor signaling pathway
GO:0008630	P:extrinsic apoptotic signaling pathway via death domain receptors
GO:0014065	P:intrinsic apoptotic signaling pathway in response to DNA damage
GO:0016020	P:phosphatidylinositol 3-kinase signaling
GO:0016032	C:membrane
GO:0016303	P:viral process
GO:0019221	F:1-phosphatidylinositol-3-kinase activity
GO:0019903	P:cytokine-mediated signaling pathway
GO:0030168	F:protein phosphatase binding
GO:0030183	P:platelet activation
GO:0030335	P:B cell differentiation
GO:0031295	P:positive regulation of cell migration
GO:0032760	P:T cell costimulation
GO:0032869	P:positive regulation of tumor necrosis factor production
GO:0033120	P:cellular response to insulin stimulus
GO:0034644	P:positive regulation of RNA splicing
GO:0034976	P:cellular response to UV
GO:0035014	P:response to endoplasmic reticulum stress
GO:0036312	F:phosphatidylinositol 3-kinase regulator activity
GO:0038095	F:phosphatidylinositol 3-kinase regulatory subunit binding
GO:0038096	P:Fc-epsilon receptor signaling pathway
GO:0038128	P:Fc-gamma receptor signaling pathway involved in phagocytosis
GO:0042307	P:ERBB2 signaling pathway
GO:0043066	P:positive regulation of protein import into nucleus
GO:0043125	P:negative regulation of apoptotic process
GO:0043548	F:ErbB-3 class receptor binding
GO:0043551	F:phosphatidylinositol 3-kinase binding
GO:0043559	P:regulation of phosphatidylinositol 3-kinase activity
GO:0043560	F:insulin binding
GO:0045671	F:insulin receptor substrate binding
GO:0045944	P:negative regulation of osteoclast differentiation
GO:0046326	P:positive regulation of transcription by RNA polymerase II
GO:0046626	P:positive regulation of glucose import
GO:0046854	P:regulation of insulin receptor signaling pathway
GO:0046934	P:phosphatidylinositol phosphorylation
GO:0046935	F:phosphatidylinositol-4,5-bisphosphate 3-kinase activity
GO:0046982	F:1-phosphatidylinositol-3-kinase regulator activity
GO:0048009	F:protein heterodimerization activity
GO:0048010	P:insulin-like growth factor receptor signaling pathway
GO:0048015	P:vascular endothelial growth factor receptor signaling pathway
GO:0050821	P:phosphatidylinositol-mediated signaling
GO:0050852	P:protein stabilization
GO:0050900	P:T cell receptor signaling pathway
GO:0051492	P:leukocyte migration
GO:0051897	P:regulation of stress fiber assembly
GO:0060396	P:positive regulation of protein kinase B signaling
GO:1900103	P:growth hormone receptor signaling pathway
GO:1903078	P:positive regulation of endoplasmic reticulum unfolded protein response
GO:1990578	P:positive regulation of protein localization to plasma membrane
GO:2001275	C:perinuclear endoplasmic reticulum membrane

KEGG Pathway
Reactome Pathway

Pathway ID	Pathway Name	Pathway Description (KEGG)
hsa01521	EGFR tyrosine kinase inhibitor resistance	EGFR is a tyrosine kinase that participates in the regulation of cellular homeostasis. EGFR also serves as a stimulus for cancer growth. EGFR gene mutations and protein overexpression, both of which activate down- stream pathways, are associated with cancers, especially lung cancer. Several tyrosine kinase inhibitor (TKI) therapies against EGFR are currently administered and are initially effective in cancer patients who have EGFR mutations or aberrant activation of EGFR. However, the development of TKI resistance is common and results in the recurrence of tumors. Studies over the last decade have identified mechanisms that drive resistance to EGFR TKI treatment. Most outstanding mechanisms are: the secondary EGFR mutation (T790M), activation of alternative pathways (c-Met, HGF, AXL), aberrance of the downstream pathways (K-RAS mutations, loss of PTEN), impairment of the EGFR-TKIs-mediated apoptosis pathway (BCL2-like 11/BIM deletion polymorphism), histologic transformation, etc.
hsa01522	Endocrine resistance	Endocrine therapy is a key treatment strategy to control or eradicate hormone-responsive breast cancer. The most commonly used endocrine therapy agents are selective estrogen receptor modulators (SERMs, e.g. tamoxifen), estrogen synthesis inhibitors (e.g. aromatase inhibitors (AIs) such as anastrozole, letrozole, and exemestane), and selective estrogen receptor down-regulators (SERDs, e.g. fulvestrant). However, resistance to these agents has become a major clinical obstacle. Mechanisms of endocrine resistance include loss of ER-alpha expression, altered expression of coactivators or coregulators that play a critical role in ER-mediated gene transcription, ligand-independent growth factor signaling cascades that activate kinases and ER-phosphorylation, altered availability of active tamoxifen metabolites regulated by drug-metabolizing enzymes, such as CYP2D6, and deregulation of the cell cycle and apoptotic machinery.
hsa01524	Platinum drug resistance	Platinum-based drugs cisplatin, carboplatin and oxaliplatin are widely used in the therapy of solid malignancies, including testicular, ovarian, head and neck, colorectal, bladder and lung cancers. The mechanism of action of Platinum-based drugs involves covalent binding to purine DNA bases, which primarily leads to cellular apoptosis. Their clinical success is, however, limited due to severe side effects and intrinsic or acquired resistance to the treatment. Platinum resistance could arise from decreased drug influx, increased drug efflux, intracellular detoxification by glutathione, etc., decreased binding (e.g., due to high intracellular pH), increased DNA repair, decreased mismatch repair, defective apoptosis, and altered oncogene expression.
hsa04012	ErbB signaling pathway	The ErbB family of receptor tyrosine kinases (RTKs) couples binding of extracellular growth factor ligands to intracellular signaling pathways regulating diverse biologic responses, including proliferation, differentiation, cell motility, and survival. Ligand binding to the four closely related members of this RTK family -epidermal growth factor receptor (EGFR, also known as ErbB-1 or HER1), ErbB-2 (HER2), ErbB-3 (HER3), and ErbB-4 (HER4)-induces the formation of receptor homo- and heterodimers and the activation of the intrinsic kinase domain, resulting in phosphorylation on specific tyrosine residues (pY) within the cytoplasmic tail. Signaling effectors containing binding pockets for pY-containing peptides are recruited to activated receptors and induce the various signaling pathways. The Shc- and/or Grb2-activated mitogen-activated protein kinase (MAPK) pathway is a common target downstream of all ErbB receptors. Similarly, the phosphatidylinositol-3-kinase (PI-3K) pathway is directly or indirectly activated by most ErbBs. Several cytoplasmic docking proteins appear to be recruited by specific ErbB receptors and less exploited by others. These include the adaptors Crk, Nck, the phospholipase C gamma (PLCgamma), the intracellular tyrosine kinase Src, or the Cbl E3 ubiquitin protein ligase.
hsa04014	Ras signaling pathway	The Ras proteins are GTPases that function as molecular switches for signaling pathways regulating cell proliferation, survival, growth, migration, differentiation or cytoskeletal dynamism. Ras proteins transduce signals from extracellular growth factors by cycling between inactive GDP-bound and active GTP-bound states. The exchange of GTP for GDP on RAS is regulated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). Activated RAS (RAS-GTP) regulates multiple cellular functions through effectors including Raf, phosphatidylinositol 3-kinase (PI3K) and Ral guanine nucleotide-dissociation stimulator (RALGDS).
hsa04015	Rap1 signaling pathway	Rap1 is a small GTPase that controls diverse processes, such as cell adhesion, cell-cell junction formation and cell polarity. Like all G proteins, Rap1 cycles between an inactive GDP-bound and an active GTP-bound conformation. A variety of extracellular signals control this cycle through the regulation of several unique guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs). Rap1 plays a dominant role in the control of cell-cell and cell-matrix interactions by regulating the function of integrins and other adhesion molecules in various cell types. Rap1 also regulates MAP kinase (MAPK) activity in a manner highly dependent on the context of cell types.
hsa04024	cAMP signaling pathway	cAMP is one of the most common and universal second messengers, and its formation is promoted by adenylyl cyclase (AC) activation after ligation of G protein-coupled receptors (GPCRs) by ligands including hormones, neurotransmitters, and other signaling molecules. cAMP regulates pivotal physiologic processes including metabolism, secretion, calcium homeostasis, muscle contraction, cell fate, and gene transcription. cAMP acts directly on three main targets: protein kinase A (PKA), the exchange protein activated by cAMP (Epac), and cyclic nucleotide-gated ion channels (CNGCs). PKA modulates, via phosphorylation, a number of cellular substrates, including transcription factors, ion channels, transporters, exchangers, intracellular Ca2+ -handling proteins, and the contractile machinery. Epac proteins function as guanine nucleotide exchange factors (GEFs) for both Rap1 and Rap2. Various effector proteins, including adaptor proteins implicated in modulation of the actin cytoskeleton, regulators of G proteins of the Rho family, and phospholipases, relay signaling downstream from Rap.
hsa04062	Chemokine signaling pathway	Inflammatory immune response requires the recruitment of leukocytes to the site of inflammation upon foreign insult. Chemokines are small chemoattractant peptides that provide directional cues for the cell trafficking and thus are vital for protective host response. In addition, chemokines regulate plethora of biological processes of hematopoietic cells to lead cellular activation, differentiation and survival.The chemokine signal is transduced by chemokine receptors (G-protein coupled receptors) expressed on the immune cells. After receptor activation, the alpha- and beta-gamma-subunits of G protein dissociate to activate diverse downstream pathways resulting in cellular polarization and actin reorganization. Various members of small GTPases are involved in this process. Induction of nitric oxide and production of reactive oxygen species are as well regulated by chemokine signal via calcium mobilization and diacylglycerol production.
hsa04066	HIF-1 signaling pathway	Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that functions as a master regulator of oxygen homeostasis. It consists of two subunits: an inducibly-expressed HIF-1alpha subunit and a constitutively-expressed HIF-1beta subunit. Under normoxia, HIF-1 alpha undergoes hydroxylation at specific prolyl residues which leads to an immediate ubiquitination and subsequent proteasomal degradation of the subunit. In contrast, under hypoxia, HIF-1 alpha subunit becomes stable and interacts with coactivators such as p300/CBP to modulate its transcriptional activity. Eventually, HIF-1 acts as a master regulator of numerous hypoxia-inducible genes under hypoxic conditions. The target genes of HIF-1 encode proteins that increase O2 delivery and mediate adaptive responses to O2 deprivation. Despite its name, HIF-1 is induced not only in response to reduced oxygen availability but also by other stimulants, such as nitric oxide, or various growth factors.
hsa04068	FoxO signaling pathway	The forkhead box O (FOXO) family of transcription factors regulates the expression of genes in cellular physiological events including apoptosis, cell-cycle control, glucose metabolism, oxidative stress resistance, and longevity. A central regulatory mechanism of FOXO proteins is phosphorylation by the serine-threonine kinase Akt/protein kinase B (Akt/PKB), downstream of phosphatidylinositol 3-kinase (PI3K), in response to insulin or several growth factors. Phosphorylation at three conserved residues results in the export of FOXO proteins from the nucleus to the cytoplasm, thereby decreasing expression of FOXO target genes. In contrast, the stress-activated c-Jun N-terminal kinase (JNK) and the energy sensing AMP-activated protein kinase (AMPK), upon oxidative and nutrient stress stimuli phosphorylate and activate FoxOs. Aside from PKB, JNK and AMPK, FOXOs are regulated by multiple players through several post-translational modifications, including phosphorylation, but also acetylation, methylation and ubiquitylation.
hsa04070	Phosphatidylinositol signaling system
hsa04071	Sphingolipid signaling pathway	Sphingomyelin (SM) and its metabolic products are now known to have second messenger functions in a variety of cellular signaling pathways. Particularly, the sphingolipid metabolites, ceramide (Cer) and sphingosine-1-phosphate (S1P), have emerged as a new class of potent bioactive molecules. Ceramide can be generated de novo or by hydrolysis of membrane sphingomyelin by sphingomyelinase (SMase). Ceramide is subsequently metabolized by ceramidase to generate sphingosine (Sph) which in turn produces S1P through phosphorylation by sphingosine kinases 1 and 2 (SphK1, 2). Both ceramide and S1P regulate cellular responses to stress, with generally opposing effects. S1P functions as a growth and survival factor, acting as a ligand for a family of G protein-coupled receptors, whereas ceramide activates intrinsic and extrinsic apoptotic pathways through receptor-independent mechanisms.
hsa04072	Phospholipase D signaling pathway	Phospholipase D (PLD) is an essential enzyme responsible for the production of the lipid second messenger phosphatidic acid (PA), which is involved in fundamental cellular processes, including membrane trafficking, actin cytoskeleton remodeling, cell proliferation and cell survival. PLD activity can be stimulated by a large number of cell surface receptors and is elaborately regulated by intracellular factors, including protein kinase C isoforms, small GTPases of the ARF, Rho and Ras families and the phosphoinositide, phosphatidylinositol 4,5-bisphosphate (PIP2). The PLD-produced PA activates signaling proteins and acts as a node within the membrane to which signaling proteins translocate. Several signaling proteins, including Raf-1 and mTOR, directly bind PA to mediate translocation or activation, respectively.
hsa04140	Autophagy - animal	Autophagy (or macroautophagy) is a cellular catabolic pathway involving in protein degradation, organelle turnover, and non-selective breakdown of cytoplasmic components, which is evolutionarily conserved among eukaryotes and exquisitely regulated. This progress initiates with production of the autophagosome, a double-membrane intracellular structure of reticular origin that engulfs cytoplasmic contents and ultimately fuses with lysosomes for cargo degradation. Autophagy is regulated in response to extra- or intracellular stress and signals such as starvation, growth factor deprivation and ER stress. Constitutive level of autophagy plays an important role in cellular homeostasis and maintains quality control of essential cellular components.
hsa04150	mTOR signaling pathway	The mammalian (mechanistic) target of rapamycin (mTOR) is a highly conserved serine/threonine protein kinase, which exists in two complexes termed mTOR complex 1 (mTORC1) and 2 (mTORC2). mTORC1 contains mTOR, Raptor, PRAS40, Deptor, mLST8, Tel2 and Tti1. mTORC1 is activated by the presence of growth factors, amino acids, energy status, stress and oxygen levels to regulate several biological processes, including lipid metabolism, autophagy, protein synthesis and ribosome biogenesis. On the other hand, mTORC2, which consists of mTOR, mSin1, Rictor, Protor, Deptor, mLST8, Tel2 and Tti1, responds to growth factors and controls cytoskeletal organization, metabolism and survival.
hsa04151	PI3K-Akt signaling pathway	The phosphatidylinositol 3' -kinase(PI3K)-Akt signaling pathway is activated by many types of cellular stimuli or toxic insults and regulates fundamental cellular functions such as transcription, translation, proliferation, growth, and survival. The binding of growth factors to their receptor tyrosine kinase (RTK) or G protein-coupled receptors (GPCR) stimulates class Ia and Ib PI3K isoforms, respectively. PI3K catalyzes the production of phosphatidylinositol-3,4,5-triphosphate (PIP3) at the cell membrane. PIP3 in turn serves as a second messenger that helps to activate Akt. Once active, Akt can control key cellular processes by phosphorylating substrates involved in apoptosis, protein synthesis, metabolism, and cell cycle.
hsa04152	AMPK signaling pathway	AMP-activated protein kinase (AMPK) is a serine threonine kinase that is highly conserved through evolution. AMPK system acts as a sensor of cellular energy status. It is activated by increases in the cellular AMP:ATP ratio caused by metabolic stresses that either interfere with ATP production (eg, deprivation for glucose or oxygen) or that accelerate ATP consumption (eg, muscle contraction). Several upstream kinases, including liver kinase B1 (LKB1), calcium/calmodulin kinase kinase-beta (CaMKK beta), and TGF-beta-activated kinase-1 (TAK-1), can activate AMPK by phosphorylating a threonine residue on its catalytic alpha-subunit. Once activated, AMPK leads to a concomitant inhibition of energy-consuming biosynthetic pathways, such as protein, fatty acid and glycogen synthesis, and activation of ATP-producing catabolic pathways, such as fatty acid oxidation and glycolysis.
hsa04210	Apoptosis	Apoptosis is a genetically programmed process for the elimination of damaged or redundant cells by activation of caspases (aspartate-specific cysteine proteases). The onset of apoptosis is controlled by numerous interrelating processes. The 'extrinsic' pathway involves stimulation of members of the tumor necrosis factor (TNF) receptor subfamily, such as TNFRI, CD95/Fas or TRAILR (death receptors), located at the cell surface, by their specific ligands, such as TNF-alpha, FasL or TRAIL, respectively. The 'intrinsic' pathway is activated mainly by non-receptor stimuli, such as DNA damage, ER stress, metabolic stress, UV radiation or growth-factor deprivation. The central event in the 'intrinsic' pathway is the mitochondrial outer membrane permeabilization (MOMP), which leads to the release of cytochrome c. These two pathways converge at the level of effector caspases, such as caspase-3 and caspase-7. The third major pathway is initiated by the constituents of cytotoxic granules (e.g. Perforin and Granzyme B) that are released by CTLs (cytotoxic T-cells) and NK (natural killer) cells. Granzyme B, similarly to the caspases, cleaves its substrates after aspartic acid residues, suggesting that this protease has the ability to activate members of the caspase family directly. It is the balance between the pro-apoptotic and anti-apoptotic signals that eventually determines whether cells will undergo apoptosis, survive or proliferate. TNF family of ligands activates anti-apoptotic or cell-survival signals as well as apoptotic signals. NGF and Interleukin-3 promotes the survival, proliferation and differentiation of neurons or hematopoietic cells, respectively. Withdrawal of these growth factors leads to cell death, as described above.
hsa04211	Longevity regulating pathway	Regulation of longevity depends on genetic and environmental factors. Caloric restriction (CR), that is limiting food intake, is recognized in mammals as the best characterized and most reproducible strategy for extending lifespan. Four pathways have been implicated in mediating the CR effect. These are the insulin like growth factor (IGF-1)/insulin signaling pathway, the sirtuin pathway, the adenosine monophosphate (AMP) activated protein kinase (AMPK) pathway and the target of rapamycin (TOR) pathway. The collective response of these pathways to CR is believed to promote cellular fitness and ultimately longevity via activation of autophagy, stress defense mechanisms, and survival pathways while attenuating proinflammatory mediators and cellular growth. Furthermore, there is evidence supporting that life span extension can be achieved with pharmacologic agents that mimic the effects of caloric restriction, such as rapamycin, via mTOR signaling blockade, resveratrol, by activating SIRT1 activity, and metformin, which seems to be a robust stimulator of AMPK activity. As an aging suppressor, Klotho is an important molecule in aging processes and its overexpression results in longevity.
hsa04213	Longevity regulating pathway - multiple species	Aging is a complex process of accumulation of molecular, cellular, and organ damage, leading to loss of function and increased vulnerability to disease and death. Despite the complexity of aging, recent work has shown that dietary restriction (DR) and genetic down-regulation of nutrient-sensing pathways, namely IIS (insulin/insulin-like growth factor signalling) and TOR (target-of- rapamycin) can substantially increase healthy life span of laboratory model organisms. These nutrient signaling pathways are conserved in various organisms. In worms, flies, and mammals, DR reduces signalling through IIS/TOR pathways, deactivating the PI3K/Akt/TOR intracellular signalling cascade and consequently activating the antiaging FOXO family transcription factor(s). In yeast, the effects of DR on life- span extension are associated with reduced activities of the TOR/Sch9 and Ras/PKA pathways and require the serine-threonine kinase Rim15 and transcription factors Gis1 and Msn2/4. These transcription factors (FOXO, DAF-16, Gis1, and Msn2/4) transactivate genes involved in resistance to oxidative stress, energy metabolism, DNA damage repair, glucose metabolism, autophagy and protection of proteins by chaperones.
hsa04218	Cellular senescence	Cellular senescence is a state of irreversible cellular arrest and can be triggered by a number of factors, such as telomere shortening, oncogene activation, irradiation, DNA damage and oxidative stress. It is characterized by enlarged flattened morphology, senescence-associated beta-galactosidase (SA-b-gal) activity, secretion of inflammatory cytokines, growth factors and matrix metalloproteinases, as part of the senescence-associated secretory phenotype (SASP). Cellular senescence is functionally associated with many biological processes including aging, tumor suppression, placental biology, embryonic development, and wound healing.
hsa04360	Axon guidance	Axon guidance represents a key stage in the formation of neuronal network. Axons are guided by a variety of guidance factors, such as netrins, ephrins, Slits, and semaphorins. These guidance cues are read by growth cone receptors, and signal transduction pathways downstream of these receptors converge onto the Rho GTPases to elicit changes in cytoskeletal organization that determine which way the growth cone will turn.
hsa04370	VEGF signaling pathway	There is now much evidence that VEGFR-2 is the major mediator of VEGF-driven responses in endothelial cells and it is considered to be a crucial signal transducer in both physiologic and pathologic angiogenesis. The binding of VEGF to VEGFR-2 leads to a cascade of different signaling pathways, resulting in the up-regulation of genes involved in mediating the proliferation and migration of endothelial cells and promoting their survival and vascular permeability. For example, the binding of VEGF to VEGFR-2 leads to dimerization of the receptor, followed by intracellular activation of the PLCgamma;PKC-Raf kinase-MEK-mitogen-activated protein kinase (MAPK) pathway and subsequent initiation of DNA synthesis and cell growth, whereas activation of the phosphatidylinositol 3' -kinase (PI3K)-Akt pathway leads to increased endothelial-cell survival. Activation of PI3K, FAK, and p38 MAPK is implicated in cell migration signaling.
hsa04380	Osteoclast differentiation	The osteoclasts, multinucleared cells originating from the hematopoietic monocyte-macrophage lineage, are responsible for bone resorption. Osteoclastogenesis is mainly regulated by signaling pathways activated by RANK and immune receptors, whose ligands are expressed on the surface of osteoblasts. Signaling from RANK changes gene expression patterns through transcription factors like NFATc1 and characterizes the active osteoclast.
hsa04510	Focal adhesion	Cell-matrix adhesions play essential roles in important biological processes including cell motility, cell proliferation, cell differentiation, regulation of gene expression and cell survival. At the cell-extracellular matrix contact points, specialized structures are formed and termed focal adhesions, where bundles of actin filaments are anchored to transmembrane receptors of the integrin family through a multi-molecular complex of junctional plaque proteins. Some of the constituents of focal adhesions participate in the structural link between membrane receptors and the actin cytoskeleton, while others are signalling molecules, including different protein kinases and phosphatases, their substrates, and various adapter proteins. Integrin signaling is dependent upon the non-receptor tyrosine kinase activities of the FAK and src proteins as well as the adaptor protein functions of FAK, src and Shc to initiate downstream signaling events. These signalling events culminate in reorganization of the actin cytoskeleton; a prerequisite for changes in cell shape and motility, and gene expression. Similar morphological alterations and modulation of gene expression are initiated by the binding of growth factors to their respective receptors, emphasizing the considerable crosstalk between adhesion- and growth factor-mediated signalling.
hsa04550	Signaling pathways regulating pluripotency of stem cells	Pluripotent stem cells (PSCs) are basic cells with an indefinite self-renewal capacity and the potential to generate all the cell types of the three germinal layers. The types of PSCs known to date include embryonic stem (ES) and induced pluripotent stem (iPS) cells. ES cells are derived from the inner cell mass (ICM) of blastocyst-stage embryos. iPS cells are generated by reprogramming somatic cells back to pluripotent state with defined reprogramming factors, Oct4, Sox2, Klf4 and c-Myc (also known as Yamanaka factors). PSCs including ES cells and iPS cells are categorized into two groups by their morphology, gene expression profile and external signal dependence. Conventional mouse-type ES/iPS cells are called 'naive state' cells. They are mainly maintained under the control of LIF and BMP signaling. On the other hand, human-type ES/iPS cells, which are in need of Activin and FGF signaling, are termed 'primed state'. However, these signaling pathways converge towards the activation of a core transcriptional network that is similar in both groups and involves OCt4, Nanog and Sox2. The three transcription factors and their downstream target genes coordinately promote self-renewal and pluripotency.
hsa04611	Platelet activation	Platelets play a key and beneficial role for primary hemostasis on the disruption of the integrity of vessel wall. Platelet adhesion and activation at sites of vascular wall injury is initiated by adhesion to adhesive macromolecules, such as collagen and von Willebrand factor (vWF), or by soluble platelet agonists, such as ADP, thrombin, and thromboxane A2. Different receptors are stimulated by various agonists, almost converging in increasing intracellular Ca2+ concentration that stimulate platelet shape change and granule secretion and ultimately induce the inside-outsignaling process leading to activation of the ligand-binding function of integrin alpha IIb beta 3. Binding of alpha IIb beta 3 to its ligands, mainly fibrinogen, mediates platelet adhesion and aggregation and triggers outside-insignaling, resulting in platelet spreading, additional granule secretion, stabilization of platelet adhesion and aggregation, and clot retraction.
hsa04620	Toll-like receptor signaling pathway	Specific families of pattern recognition receptors are responsible for detecting microbial pathogens and generating innate immune responses. Toll-like receptors (TLRs) are membrane-bound receptors identified as homologs of Toll in Drosophila. Mammalian TLRs are expressed on innate immune cells, such as macrophages and dendritic cells, and respond to the membrane components of Gram-positive or Gram-negative bacteria. Pathogen recognition by TLRs provokes rapid activation of innate immunity by inducing production of proinflammatory cytokines and upregulation of costimulatory molecules. TLR signaling pathways are separated into two groups: a MyD88-dependent pathway that leads to the production of proinflammatory cytokines with quick activation of NF-{kappa}B and MAPK, and a MyD88-independent pathway associated with the induction of IFN-beta and IFN-inducible genes, and maturation of dendritic cells with slow activation of NF-{kappa}B and MAPK.
hsa04625	C-type lectin receptor signaling pathway	C-type lectin receptors (CLRs) are a large superfamily of proteins characterized by the presence of one or more C-type lectin-like domains (CTLDs). CLRs function as pattern-recognition receptors (PRRs) for pathogen-derived ligands in dendric cells, macrophages, neutrophils, etc., such as Dectin-1 and Dectin-2 for recognition of fungi-derived B-glucan and high mannose-type carbohydrates. Upon ligand binding, CLRs stimulate intracellular signaling cascades that induce the production of inflammatory cytokines and chemokines, consequently triggering innate and adaptive immunity to pathogens.
hsa04630	Jak-STAT signaling pathway	The Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway is one of a handful of pleiotropic cascades used to transduce a multitude of signals for development and homeostasis in animals, from humans to flies. In mammals, the JAK/STAT pathway is the principal signaling mechanism for a wide array of cytokines and growth factors. Following the binding of cytokines to their cognate receptor, STATs are activated by members of the JAK family of tyrosine kinases. Once activated, they dimerize and translocate to the nucleus and modulate the expression of target genes. In addition to the activation of STATs, JAKs mediate the recruitment of other molecules such as the MAP kinases, PI3 kinase etc. These molecules process downstream signals via the Ras-Raf-MAP kinase and PI3 kinase pathways which results in the activation of additional transcription factors.
hsa04650	Natural killer cell mediated cytotoxicity	Natural killer (NK) cells are lymphocytes of the innate immune system that are involved in early defenses against both allogeneic (nonself) cells and autologous cells undergoing various forms of stress, such as infection with viruses, bacteria, or parasites or malignant transformation. Although NK cells do not express classical antigen receptors of the immunoglobulin gene family, such as the antibodies produced by B cells or the T cell receptor expressed by T cells, they are equipped with various receptors whose engagement allows them to discriminate between target and nontarget cells. Activating receptors bind ligands on the target cell surface and trigger NK cell activation and target cell lysis. However Inhibitory receptors recognize MHC class I molecules (HLA) and inhibit killing by NK cells by overruling the actions of the activating receptors. This inhibitory signal is lost when the target cells do not express MHC class I and perhaps also in cells infected with virus, which might inhibit MHC class I exprssion or alter its conformation. The mechanism of NK cell killing is the same as that used by the cytotoxic T cells generated in an adaptive immune response; cytotoxic granules are released onto the surface of the bound target cell, and the effector proteins they contain penetrate the cell membrane and induce programmed cell death.
hsa04660	T cell receptor signaling pathway	Activation of T lymphocytes is a key event for an efficient response of the immune system. It requires the involvement of the T-cell receptor (TCR) as well as costimulatory molecules such as CD28. Engagement of these receptors through the interaction with a foreign antigen associated with major histocompatibility complex molecules and CD28 counter-receptors B7.1/B7.2, respectively, results in a series of signaling cascades. These cascades comprise an array of protein-tyrosine kinases, phosphatases, GTP-binding proteins and adaptor proteins that regulate generic and specialised functions, leading to T-cell proliferation, cytokine production and differentiation into effector cells.
hsa04662	B cell receptor signaling pathway	B cells are an important component of adaptive immunity. They produce and secrete millions of different antibody molecules, each of which recognizes a different (foreign) antigen. The B cell receptor (BCR) is an integral membrane protein complex that is composed of two immunoglobulin (Ig) heavy chains, two Ig light chains and two heterodimers of Ig-alpha and Ig-beta. After BCR ligation by antigen, three main protein tyrosine kinases (PTKs) -the SRC-family kinase LYN, SYK and the TEC-family kinase BTK- are activated. Phosphatidylinositol 3-kinase (PI3K) and phospholipase C-gamma 2 (PLC-gamma 2) are important downstream effectors of BCR signalling. This signalling ultimately results in the expression of immediate early genes that further activate the expression of other genes involved in B cell proliferation, differentiation and Ig production as well as other processes.
hsa04664	Fc epsilon RI signaling pathway	Fc epsilon RI-mediated signaling pathways in mast cells are initiated by the interaction of antigen (Ag) with IgE bound to the extracellular domain of the alpha chain of Fc epsilon RI. The activation pathways are regulated both positively and negatively by the interactions of numerous signaling molecules. Mast cells that are thus activated release preformed granules which contain biogenic amines (especially histamines) and proteoglycans (especially heparin). The activation of phospholipase A2 causes the release of membrane lipids followed by development of lipid mediators such as leukotrienes (LTC4, LTD4 and LTE4) and prostaglandins (especially PDG2). There is also secretion of cytokines, the most important of which are TNF-alpha, IL-4 and IL-5. These mediators and cytokines contribute to inflammatory responses.
hsa04666	Fc gamma R-mediated phagocytosis	Phagocytosis plays an essential role in host-defense mechanisms through the uptake and destruction of infectious pathogens. Specialized cell types including macrophages, neutrophils, and monocytes take part in this process in higher organisms. After opsonization with antibodies (IgG), foreign extracellular materials are recognized by Fc gamma receptors. Cross-linking of Fc gamma receptors initiates a variety of signals mediated by tyrosine phosphorylation of multiple proteins, which lead through the actin cytoskeleton rearrangements and membrane remodeling to the formation of phagosomes. Nascent phagosomes undergo a process of maturation that involves fusion with lysosomes. The acquisition of lysosomal proteases and release of reactive oxygen species are crucial for digestion of engulfed materials in phagosomes.
hsa04668	TNF signaling pathway	Tumor necrosis factor (TNF), as a critical cytokine, can induce a wide range of intracellular signal pathways including apoptosis and cell survival as well as inflammation and immunity. Activated TNF is assembled to a homotrimer and binds to its receptors (TNFR1, TNFR2) resulting in the trimerization of TNFR1 or TNFR2. TNFR1 is expressed by nearly all cells and is the major receptor for TNF (also called TNF-alpha). In contrast, TNFR2 is expressed in limited cells such as CD4 and CD8 T lymphocytes, endothelial cells, microglia, oligodendrocytes, neuron subtypes, cardiac myocytes, thymocytes and human mesenchymal stem cells. It is the receptor for both TNF and LTA (also called TNF-beta). Upon binding of the ligand, TNFR mediates the association of some adaptor proteins such as TRADD or TRAF2, which in turn initiate recruitment of signal transducers. TNFR1 signaling induces activation of many genes, primarily controlled by two distinct pathways, NF-kappa B pathway and the MAPK cascade, or apoptosis and necroptosis. TNFR2 signaling activates NF-kappa B pathway including PI3K-dependent NF-kappa B pathway and JNK pathway leading to survival.
hsa04670	Leukocyte transendothelial migration	Leukocyte migaration from the blood into tissues is vital for immune surveillance and inflammation. During this diapedesis of leukocytes, the leukocytes bind to endothelial cell adhesion molecules (CAM) and then migrate across the vascular endothelium. A leukocyte adherent to CAMs on the endothelial cells moves forward by leading-edge protrusion and retraction of its tail. In this process, alphaL /beta2 integrin activates through Vav1, RhoA, which subsequently activates the kinase p160ROCK. ROCK activation leads to MLC phosphorylation, resulting in retraction of the actin cytoskeleton. Moreover, Leukocytes activate endothelial cell signals that stimulate endothelial cell retraction during localized dissociation of the endothelial cell junctions. ICAM-1-mediated signals activate an endothelial cell calcium flux and PKC, which are required for ICAM-1 dependent leukocyte migration. VCAM-1 is involved in the opening of the endothelial passagethrough which leukocytes can extravasate. In this regard, VCAM-1 ligation induces NADPH oxidase activation and the production of reactive oxygen species (ROS) in a Rac-mediated manner, with subsequent activation of matrix metallopoteinases and loss of VE-cadherin-mediated adhesion.
hsa04722	Neurotrophin signaling pathway	Neurotrophins are a family of trophic factors involved in differentiation and survival of neural cells. The neurotrophin family consists of nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT-3), and neurotrophin 4 (NT-4). Neurotrophins exert their functions through engagement of Trk tyrosine kinase receptors or p75 neurotrophin receptor (p75NTR). Neurotrophin/Trk signaling is regulated by connecting a variety of intracellular signaling cascades, which include MAPK pathway, PI-3 kinase pathway, and PLC pathway, transmitting positive signals like enhanced survival and growth. On the other hand, p75NTR transmits both positive and nagative signals. These signals play an important role for neural development and additional higher-order activities such as learning and memory.
hsa04725	Cholinergic synapse	Acetylcholine (ACh) is a neurotransmitter widely distributed in the central (and also peripheral, autonomic and enteric) nervous system (CNS). In the CNS, ACh facilitates many functions, such as learning, memory, attention and motor control. When released in the synaptic cleft, ACh binds to two distinct types of receptors: Ionotropic nicotinic acetylcholine receptors (nAChR) and metabotropic muscarinic acetylcholine receptors (mAChRs). The activation of nAChR by ACh leads to the rapid influx of Na+ and Ca2+ and subsequent cellular depolarization. Activation of mAChRs is relatively slow (milliseconds to seconds) and, depending on the subtypes present (M1-M5), they directly alter cellular homeostasis of phospholipase C, inositol trisphosphate, cAMP, and free calcium. In the cleft, ACh may also be hydrolyzed by acetylcholinesterase (AChE) into choline and acetate. The choline derived from ACh hydrolysis is recovered by a presynaptic high-affinity choline transporter (CHT).
hsa04750	Inflammatory mediator regulation of TRP channels	The TRP channels that exhibit a unique response to temperature have been given the name thermo-TRPs. Among all thermo- TRP channels, TRPV1-4, TRPM8, and TRPA1 are expressed in subsets of nociceptive dorsal root ganglion (DRG) neuron cell bodies including their peripheral and central projections. These channels can be modulated indirectly by inflammatory mediators such as PGE2, bradykinin, ATP, NGF, and proinflammatory cytokines that are generated during tissue injury. While the noxious heat receptor TRPV1 is sensitized (that is, their excitability can be increased) by post-translational modifications upon activation of G-protein coupled receptors (GPCRs) or tyrosine kinase receptors, the receptors for inflammatory mediators, the same action appears to mainly desensitize TRPM8, the main somatic innocuous cold sensor. This aforementioned sensitization could allow the receptor to become active at body temperature, so it not only contributes toward thermal hypersensitivity but also is possibly a substrate for ongoing persistent pain.
hsa04810	Regulation of actin cytoskeleton
hsa04910	Insulin signaling pathway	Insulin binding to its receptor results in the tyrosine phosphorylation of insulin receptor substrates (IRS) by the insulin receptor tyrosine kinase (INSR). This allows association of IRSs with the regulatory subunit of phosphoinositide 3-kinase (PI3K). PI3K activates 3-phosphoinositide-dependent protein kinase 1 (PDK1), which activates Akt, a serine kinase. Akt in turn deactivates glycogen synthase kinase 3 (GSK-3), leading to activation of glycogen synthase (GYS) and thus glycogen synthesis. Activation of Akt also results in the translocation of GLUT4 vesicles from their intracellular pool to the plasma membrane, where they allow uptake of glucose into the cell. Akt also leads to mTOR-mediated activation of protein synthesis by eIF4 and p70S6K. The translocation of GLUT4 protein is also elicited through the CAP/Cbl/TC10 pathway, once Cbl is phosphorylated by INSR.Other signal transduction proteins interact with IRS including GRB2. GRB2 is part of the cascade including SOS, RAS, RAF and MEK that leads to activation of mitogen-activated protein kinase (MAPK) and mitogenic responses in the form of gene transcription. SHC is another substrate of INSR. When tyrosine phosphorylated, SHC associates with GRB2 and can thus activate the RAS/MAPK pathway independently of IRS-1.
hsa04914	Progesterone-mediated oocyte maturation	Xenopus oocytes are naturally arrested at G2 of meiosis I. Exposure to either insulin/IGF-1 or the steroid hormone progesterone breaks this arrest and induces resumption of the two meiotic division cycles and maturation of the oocyte into a mature, fertilizable egg. This process is termed oocyte maturation. The transition is accompanied by an increase in maturation promoting factor (MPF or Cdc2/cyclin B) which precedes germinal vesicle breakdown (GVBD). Most reports point towards the Mos-MEK1-ERK2 pathway [where ERK is an extracellular signal-related protein kinase, MEK is a MAPK/ERK kinase and Mos is a p42(MAPK) activator] and the polo-like kinase/CDC25 pathway as responsible for the activation of MPF in meiosis, most likely triggered by a decrease in cAMP.
hsa04915	Estrogen signaling pathway	Estrogens are steroid hormones that regulate a plethora of physiological processes in mammals, including reproduction, cardiovascular protection, bone integrity, cellular homeostasis, and behavior. Estrogen mediates its cellular actions through two signaling pathways classified as nuclear-initiated steroid signalingand membrane-initiated steroid signaling. In the nuclearpathway, estrogen binds either ERalpha or ERbeta, which in turn translocates to the nucleus, binds DNA at ERE elements and activates the expression of ERE-dependent genes. In membranepathway, Estrogen can exert its actions through a subpopulation of ER at the plasma membrane (mER) or novel G-protein coupled E2 receptors (GPER). Upon activation of these receptors various signaling pathways (i.e. Ca2+, cAMP, protein kinase cascades) are rapidly activated and ultimately influence downstream transcription factors.
hsa04917	Prolactin signaling pathway	Prolactin (PRL) is a polypeptide hormone known to be involved in a wide range of biological functions including osmoregulation, lactation, reproduction, growth and development, endocrinology and metabolism, brain and behavior, and immunomodulation. PRL mediates its action through PRLR, a transmembrane protein of the hematopoietin cytokine receptor superfamily. At the protein level, the long PRLR isoform (long-R) and several short PRLR isoforms (short-R) have been detected. Acting through the long-R, PRL activates many signaling cascades including Jak2/Stat, the major cascade, Src kinase, phosphatidylinositol-3-kinase (PI3K)/AKT, and mitogen-activated protein kinase (MAPK) pathways. PRL cannot activate Jak2/Stat5 through the short-R, but can activate pathways including MAPK and PI3K pathways.
hsa04919	Thyroid hormone signaling pathway	The thyroid hormones (THs) are important regulators of growth, development and metabolism. The action of TH is mainly mediated by T3 (3,5,3'-triiodo-L-thyronine). Thyroid hormones, L-thyroxine (T4) and T3 enter the cell through transporter proteins. Although the major form of TH in the blood is T4, it is converted to the more active hormone T3 within cells. T3 binds to nuclear thyroid hormone receptors (TRs), which functions as a ligand-dependent transcription factor and controls the expression of target genes (genomic action). Nongenomic mechanisms of action is initiated at the integrin receptor. The plasma membrane alpha(v)beta(3)-integrin has distinct binding sites for T3 and T4. One binding site binds only T3 and activates the phosphatidylinositol 3-kinase (PI3K) pathway. The other binding site binds both T3 and T4 and activates the ERK1/2 MAP kinase pathway.
hsa04923	Regulation of lipolysis in adipocytes	Lipolysis in adipocytes, the hydrolysis of triacylglycerol (TAG) to release fatty acids (FAs) and glycerol for use by other organs as energy substrates, is a unique function of white adipose tissue. Lipolysis is under tight hormonal control. During fasting, catecholamines, by binding to Gs-coupled-adrenergic receptors (-AR), activate adenylate cyclase (AC) to increase cAMP and activate protein kinase A (PKA). PKA phosphorylates target protein such as hormone-sensitive lipase (HSL) and perilipin 1 (PLIN). PLIN phosphorylation is a key event in the sequential activation of TAG hydrolysis involving adipose triglyceride lipase (ATGL), HSL, and monoglyceride lipase (MGL). During the fed state, insulin, through activation of phosphodiesterase-3B (PDE-3B), inhibits catecholamine-induced lipolysis via the degradation of cAMP.
hsa04926	Relaxin signaling pathway	Human relaxin-2 (relaxin), originally identified as a peptidic hormone of pregnancy, is now known to exert a range of pleiotropic effects including vasodilatory, anti-fibrotic and angiogenic effects in both males and females. It belongs to the so-called relaxin peptide family which includes the insulin-like peptides INSL3 and INSL5, and relaxin-3 (H3) as well as relaxin. INSL3 has clearly defined specialist roles in male and female reproduction, relaxin-3 is primarily a neuropeptide involved in stress and metabolic control, and INSL5 is widely distributed particularly in the gastrointestinal tract. These members of relaxin peptide family exert such effects binding to different kinds of receptors, classified as relaxin family peptide (RXFP) receptors: RXFP1, RXFP2, RXFP3, and RXFP4. These G protein-coupled receptors predominantly bind relaxin, INSL3, relaxin-3, and INSL-5, respectively. RXFP1 activates a wide spectrum of signaling pathways to generate second messengers that include cAMP and nitric oxide, whereas RXFP2 activates a subset of these pathways. Both RXFP3 and RXFP4 inhibit cAMP production, and RXFP3 activate MAP kinases.
hsa04930	Type II diabetes mellitus	Insulin resistance is strongly associated with type II diabetes. Diabetogenicfactors including FFA, TNFalpha and cellular stress induce insulin resistance through inhibition of IRS1 functions. Serine/threonine phosphorylation, interaction with SOCS, regulation of the expression, modification of the cellular localization, and degradation represent the molecular mechanisms stimulated by them. Various kinases (ERK, JNK, IKKbeta, PKCzeta, PKCtheta and mTOR) are involved in this process.The development of type II diabetes requires impaired beta-cell function. Chronic hyperglycemia has been shown to induce multiple defects in beta-cells. Hyperglycemia has been proposed to lead to large amounts of reactive oxygen species (ROS) in beta-cells, with subsequent damage to cellular components including PDX-1. Loss of PDX-1, a critical regulator of insulin promoter activity, has also been proposed as an important mechanism leading to beta-cell dysfunction.Although there is little doubt as to the importance of genetic factors in type II diabetes, genetic analysis is difficult due to complex interaction among multiple susceptibility genes and between genetic and environmental factors. Genetic studies have therefore given very diverse results. Kir6.2 and IRS are two of the candidate genes. It is known that Kir6.2 and IRS play central roles in insulin secretion and insulin signal transmission, respectively.
hsa04931	Insulin resistance	Insulin resistance is a condition where cells become resistant to the effects of insulin. It is often found in people with health disorders, including obesity, type 2 diabetes mellitus, non-alcoholic fatty liver disease, and cardiovascular diseases. In this diagram multiple mechanisms underlying insulin resistance are shown: (a) increased phosphorylation of IRS (insulin receptor substrate) protein through serine/threonine kinases, such as JNK1 and IKKB, and protein kinase C, (b) increased IRS-1 proteasome degradation via mTOR signaling pathway, (c) decreased activation of signaling molecules including PI3K and AKT, (d) increase in activity of phosphatases including PTPs, PTEN, and PP2A. Regulatory actions such as oxidative stress, mitochondrial dysfunction, accumulation of intracellular lipid derivatives (diacylglycrol and ceramides), and inflammation (via IL-6 and TNFA) contribute to these mechanisms. Consequently, insulin resistance causes reduced GLUT4 translocation, resulting in glucose takeup and glycogen synthesis in skeletal muscle as well as increased hepatic gluconeogenesis and decreased glycogen synthesis in liver. At the bottom of the diagram, interplay between O-GlcNAcylation and serine/threonine phosphorylation is shown. Studies suggested that elevated O-GlcNAc level was correlated to high glucose-induced insulin resistance. Donor UDP-GlcNAc is induced through hexosamine biosynthesis pathway and added to proteins by O-GlcNAc transferase. Elevation of O-GlcNAc modification alters phosphorylation and function of key insulin signaling proteins including IRS-1, PI3K, PDK1, Akt and other transcription factor and cofactors, resulting in the attenuation of insulin signaling cascade.
hsa04932	Non-alcoholic fatty liver disease (NAFLD)	Non-alcoholic fatty liver disease (NAFLD) represents a spectrum ranging from simple steatosis to more severe steatohepatitis with hepatic inflammation and fibrosis, known as nonalcoholic steatohepatitis (NASH). NASH may further lead to cirrhosis and hepatocellular carcinoma (HCC). This map shows a stage-dependent progression of NAFLD. In the first stage of NAFLD, excess lipid accumulation has been demonstrated. The main cause is the induction of insulin resistance, which leads to a defect in insulin suppression of free fatty acids (FAAs) disposal. In addition, two transcription factors, SREBP-1c and PPAR-alpha, activate key enzymes of lipogenesis and increase the synthesis of FAAs in liver. In the second stage, as a consequence of the progression to NASH, the production of reactive oxygen species (ROS) is enhanced due to oxidation stress through mitochondrial beta-oxidation of fatty acids and endoplamic reticulum (ER) stress, leading to lipid peroxidation. The lipid peroxidation can further cause the production of cytokines (Fas ligand, TNF-alpha, IL-8 and TGF), promoting cell death, inflammation and fibrosis. The activation of JNK, which is induced by ER stress, TNF-alpha and FAAs, is also associated with NAFLD progression. Increased JNK promotes cytokine production and initiation of HCC.
hsa04933	AGE-RAGE signaling pathway in diabetic complications	Advanced glycation end products (AGEs) are a complex group of compounds produced through the non-enzymatic glycation and oxidation of proteins, lipids and nucleic acids, primarily due to aging and under certain pathologic condition such as huperglycemia. Some of the best chemically characterized AGEs include N-epsilon-carboxy-methyl-lysine (CML), N-epsilon-carboxy-ethyl-lysine (CEL), and Imidazolone. The major receptor for AGEs, known as receptor for advanced glycation end products (RAGE or AGER), belongs to the immunoglobulin superfamily and has been described as a pattern recognition receptor. AGE/RAGE signaling elicits activation of multiple intracellular signal pathways involving NADPH oxidase, protein kinase C, and MAPKs, then resulting in NF-kappaB activity. NF-kappa B promotes the expression of pro-inflammatory cytokines such as IL-1, IL-6 and TNF-alpha and a variety of atherosclerosis-related genes, including VCAM-1, tissue factor, VEGF, and RAGE. In addition, JAK-STAT-mediated and PI3K-Akt-dependent pathways are induced via RAGE, which in turn participate in cell proliferation and apoptosis respectively. Hypoxia-mediated induction of Egr-1 was also shown to require the AGE-RAGE interaction. The results of these signal transductions have been reported to be the possible mechanism that initates diabetic complications.
hsa04960	Aldosterone-regulated sodium reabsorption	Sodium transport across the tight epithelia of Na+ reabsorbing tissues such as the distal part of the kidney nephron and colon is the major factor determining total-body Na+ levels, and thus, long-term blood pressure. Aldosterone plays a major role in sodium and potassium metabolism by binding to epithelial mineralocorticoid receptors (MR) in the renal collecting duct cells localized in the distal nephron, promoting sodium resorption and potassium excretion. Aldosterone enters a target cell and binds MR, which translocates into the nucleus and regulates gene transcription. Activation of MR leads to increased expression of Sgk-1, which phosphorylates Nedd4-2, an ubiquitin-ligase which targets ENAC to proteosomal degradation. Phosphorylated Nedd4-2 dissociates from ENAC, increasing its apical membrane abundance. Activation of MR also leads to increased expression of Na+/K+-ATPase, thus causing a net increase in sodium uptake from the renal filtrate. The specificity of MR for aldosterone is provided by 11beta-HSD2 by the rapid conversion of cortisol to cortisone in renal cortical collecting duct cells. Recently, besides genomic effects mediated by activated MR, rapid aldosterone actions that are independent of translation and transcription have been documented.
hsa04973	Carbohydrate digestion and absorption	Dietary carbohydrate in humans and omnivorous animals is a major nutrient. The carbohydrates that we ingest vary from the lactose in milk to complex carbohydrates. These carbohydrates are digested to monosaccharides, mostly glucose, galactose and fructose, prior to absorption in the small intestine. Glucose and galactose are initially transported into the enterocyte by SGLT1 located in the apical brush border membrane and then exit through the basolateral membrane by either GLUT2 or exocytosis. In a new model of intestinal glucose absorption, transport by SGLT1 induces rapid insertion and activation of GLUT2 in the brush border membrane by a PKC betaII-dependent mechanism. Moreover, trafficking of apical GLUT2 is rapidly up-regulated by glucose and artificial sweeteners, which act through T1R2 + T1R3/alpha-gustducin to activate PLC-beta2 and PKC-beta II. Fructose is transported separately by the brush border GLUT5 and then released out of the enterocyte into the blood by GLUT2.
hsa05100	Bacterial invasion of epithelial cells	Many pathogenic bacteria can invade phagocytic and non-phagocytic cells and colonize them intracellularly, then become disseminated to other cells. Invasive bacteria induce their own uptake by non-phagocytic host cells (e.g. epithelial cells) using two mechanisms referred to as zipper model and trigger model. Listeria, Staphylococcus, Streptococcus, and Yersinia are examples of bacteria that enter using the zipper model. These bacteria express proteins on their surfaces that interact with cellular receptors, initiating signalling cascades that result in close apposition of the cellular membrane around the entering bacteria. Shigella and Salmonella are the examples of bacteria entering cells using the trigger model. These bacteria use type III secretion systems to inject protein effectors that interact with the actin cytoskeleton.
hsa05142	Chagas disease (American trypanosomiasis)	Trypanosoma cruzi is an intracellular protozoan parasite that causes Chagas disease. The parasite life cycle involves hematophagous reduviid bugs as vectors. Once parasites enter the host body, they invade diverse host cells including cardiomyocytes. Establishment of infection depends on various parasite molecules such as cruzipain, oligopeptidase B, and trans-sialidase that activate Ca2+ signaling. Internalized parasites escape from the parasitophorous vacuole using secreted pore-forming TcTOX molecule and replicate in the cytosol. Multiplied parasites eventually lyse infected host cells and are released in the circulation. During these events, the parasites manipulate host innate immunity and elicit cardiomyocyte hypertrophy. T lymphocyte responses are also disturbed.
hsa05146	Amoebiasis	Entamoeba histolytica, an extracellular protozoan parasite is a human pathogen that invades the intestinal epithelium. Infection occurs on ingestion of contaminated water and food. The pathogenesis of amoebiasis begins with parasite attachment and disruption of the intestinal mucus layer, followed by apoptosis of host epithelial cells. Intestinal tissue destruction causes severe dysentery and ulcerations in amoebic colitis. Several amoebic proteins such as lectins, cysteine proteineases, and amoebapores are associated with the invasion process. The parasite can cause extraintestinal infection like amoebic liver abscess by evading immune response.
hsa05160	Hepatitis C	Hepatitis C virus (HCV) is a major cause of chronic liver disease. The HCV employ several strategies to perturb host cell immunity. After invasion, HCV RNA genome functions directly as an mRNA in the cytoplasm of the host cell and forms membrane-associated replication complexes along with non-structural proteins. Viral RNA can trigger the RIG-I pathway and interferon production during this process. Translated HCV protein products regulate immune response to inhibit the action of interferon. HCV core and NS5A proteins appear to be the most important molecules with regulatory functions that modulate transcription, cellular proliferation, and apoptosis.
hsa05161	Hepatitis B	Hepatitis B virus (HBV) is an enveloped virus and contains a partially double-stranded relaxed circular DNA (RC-DNA) genome. After entry into hepatocytes, HBV RC-DNA is transported to the nucleus and converted into a covalently closed circular molecule cccDNA. The cccDNA is the template for transcription of all viral RNAs including the pregenomic RNA (pgRNA), encoding for 7 viral proteins: large, middle, and small envelope proteins (LHBs, MHBs, and SHBs) that form the surface antigen (HBsAg), the core antigen (HBcAg), the e antigen (HBeAg), the HBV polymerase, and the regulatory protein X (HBx). The pgRNA interacts with the viral polymerase protein to initiate the encapsidation into the core particles. Through endoplasmic reticulum, the core particles finish assembling with the envelope proteins and are released. HBV infection leads to a wide spectrum of liver diseases raging from chronic hepatitis, cirrhosis to hepatocellular carcinoma. The mechanism of liver injury is still not clear. However, HBV proteins target host proteins, involved in a variety of functions, thus regulating transcription, cellular signaling cascades, proliferation, differentiation, and apoptosis.
hsa05162	Measles	Measles virus (MV) is highly contagious virus that leads infant death worldwide. Humans are the unique natural reservoir for this virus. It causes severe immunosuppression favouring secondary bacterial infections. Several MV proteins have been suggested to disturb host immunity. After infection of host lymphoid cells via SLAM, MV inhibits cytokine response by direct interference with host signaling systems. Three proteins (P, V, and C) associate with Jak/STAT proteins in interferon-triggered pathway and other important proteins related to apoptosis. Interaction between MV and host brings about the shift towards a Th2 response by decreasing IL-12 production and induces lymphopenia by suppressing cell proliferation.
hsa05163	Human cytomegalovirus infection	Human cytomegalovirus (HCMV) is an enveloped, double-stranded DNA virus that is a member of beta-herpesvirus family. HCMV is best known for causing significant morbidity and mortality in immunocompromised populations. As with other herpesviruses, HCMV gB and gH/gL envelope glycoproteins are essential for virus entry. HCMV gB could activate the PDGFRA, and induce activation of the oncogenic PI3-K/AKT pathway. Though it is unlikely that HCMV by itself can act as an oncogenic factor, HCMV may have an oncomodulatory role, to catalyze an oncogenic process that has already been initiated. US28, one of the four HCMV-encoded vGPCRs (US27, US28, UL33 and UL78), also has a specific role in the oncomodulatory properties. In addition, HCMV has developed numerous mechanisms for manipulating the host immune system. The virally encoded US2, US3, US6 and US11 gene products all interfere with major histocompatibility complex (MHC) class I antigen presentation. HCMV encodes several immediate early (IE) antiapoptotic proteins (IE1, IE2, vMIA and vICA). These proteins might avoid immune clearance of infected tumor cells by cytotoxic lymphocytes and NK cells.
hsa05164	Influenza A	Influenza is a contagious respiratory disease caused by influenza virus infection. Influenza A virus is responsible for both annual seasonal epidemics and periodic worldwide pandemics. Novel strains that cause pandemics arise from avian influenza virus by genetic reassortment among influenza viruses and two surface glycoproteins HA and NA form the basis of serologically distinct virus types. The innate immune system recognizes invaded virus through multiple mechanisms. Viral non-structural NS1 protein is a multifunctional virulence factor that interfere IFN-mediated antiviral response. It inhibits IFN production by blocking activation of transcription factors such as NF-kappa B, IRF3 and AP1. NS1 further inhibits the activation of IFN-induced antiviral genes. PB1-F2 protein is another virulence factor that induce apoptosis of infected cells, which results in life-threatening bronchiolitis.
hsa05165	Human papillomavirus infection	Human papillomavirus (HPV) is a non-enveloped, double-stranded DNA virus. HPV infect mucoal and cutaneous epithelium resulting in several types of pathologies, most notably, cervical cancer. All types of HPV share a common genomic structure and encode eight proteins: E1, E2, E4, E5, E6, and E7 (early) and L1 and L2 (late). It has been demonstrated that E1 and E2 are involved in viral transcription and replication. The functions of the E4 protein is not yet fully understood. E5, E6, and E7 act as oncoproteins. E5 inhibits the V-ATPase, prolonging EGFR signaling and thereby promoting cell proliferation. The expression of E6 and E7 not only inhibits the tumor suppressors p53 and Rb, but also alters additional signalling pathways. Among these pathways, PI3K/Akt signalling cascade plays a very important role in HPV-induced carcinogenesis. The L1 and L2 proteins form icosahedral capsids for progeny virion generation.
hsa05166	Human T-cell leukemia virus 1 infection	Human T-cell leukemia virus type 1 (HTLV-1) is a pathogenic retrovirus that is associated with adult T-cell leukemia/lymphoma (ATL). It is also strongly implicated in non-neoplastic chronic inflammatory diseases such as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Expression of Tax, a viral regulatory protein is critical to the pathogenesis. Tax is a transcriptional co-factor that interfere several signaling pathways related to anti-apoptosis or cell proliferation. The modulation of the signaling by Tax involve its binding to transcription factors like CREB/ATF, NF-kappa B, SRF, and NFAT.
hsa05167	Kaposi sarcoma-associated herpesvirus infection	Kaposi sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8 (HHV-8), is the most recently identified human tumor virus, and is associated with the pathogenesis of Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), and Multicentric Castleman's disease (MCD). Like all other herpesviruses, KSHV displays two modes of life cycle, latency and lytic replication, which are characterized by the patterns of viral gene expression. Genes expressed in latency (LANA, v-cyclin, v-FLIP, Kaposins A, B and C and viral miRNAs) are mainly thought to facilitate the establishment of life long latency in its host and survival against the host innate, and adaptive immune surveillance mechanisms. Among the viral proteins shown to be expressed during lytic replication are potent signaling molecules such as vGPCR, vIL6, vIRFs, vCCLs, K1 and K15, which have been implicated experimentally in the angiogenic and inflammatory phenotype observed in KS lesions. Several of these latent viral and lytic proteins are known to transform host cells, linking KSHV with the development of severe human malignancies.
hsa05169	Epstein-Barr virus infection	Epstein-Barr virus (EBV) is a gamma-herpes virus that widely infects human populations predominantly at an early age but remains mostly asymptomatic. EBV has been linked to a wide spectrum of human malignancies, including nasopharyngeal carcinoma and other hematologic cancers, like Hodgkin's lymphoma, Burkitt's lymphoma (BL), B-cell immunoblastic lymphoma in HIV patients, and posttransplant-associated lymphoproliferative diseases. EBV has the unique ability to establish life-long latent infection in primary human B lymphocytes. During latent infection, EBV expresses a small subset of genes, including 6 nuclear antigens (EBNA-1, -2, -3A, -3B, -3C, and -LP), 3 latent membrane proteins (LMP-1, -2A, and -2B), 2 small noncoding RNAs (EBER-1 and 2). On the basis of these latent gene expression, three different latency patterns associated with the types of cancers are recognized.
hsa05170	Human immunodeficiency virus 1 infection	Human immunodeficiency virus type 1 (HIV-1) , the causative agent of AIDS (acquired immunodeficiency syndrome), is a lentivirus belonging to the Retroviridae family. The primary cell surface receptor for HIV-1, the CD4 protein, and the co-receptor for HIV-1, either CCR5 or CXCR4, are found on macrophages and T lymphocytes. At the earliest step, sequential binding of virus envelope (Env) glycoprotein gp120 to CD4 and the co-receptor CCR5 or CXCR4 facilitates HIV-1 entry and has the potential to trigger critical signaling that may favor viral replication. At advanced stages of the disease, HIV-1 infection results in dramatic induction of T-cell (CD4+ T and CD8+ T cell) apoptosis both in infected and uninfected bystander T cells, a hallmark of HIV-1 pathogenesis. On the contrary, macrophages are resistant to the cytopathic effect of HIV-1 and produce virus for longer periods of time.
hsa05200	Pathways in cancer
hsa05203	Viral carcinogenesis	There is a strong association between viruses and the development of human malignancies. We now know that at least six human viruses, Epstein-Barr virus (EBV), hepatitis B virus (HBV), hepatitis C virus (HCV), human papilloma virus (HPV), human T-cell lymphotropic virus (HTLV-1) and Kaposi's associated sarcoma virus (KSHV) contribute to 10-15% of the cancers worldwide. Via expression of many potent oncoproteins, these tumor viruses promote an aberrant cell-proliferation via modulating cellular cell-signaling pathways and escape from cellular defense system such as blocking apoptosis. Human tumor virus oncoproteins can also disrupt pathways that are necessary for the maintenance of the integrity of host cellular genome. Viruses that encode such activities can contribute to initiation as well as progression of human cancers.
hsa05205	Proteoglycans in cancer	Many proteoglycans (PGs) in the tumor microenvironment have been shown to be key macromolecules that contribute to biology of various types of cancer including proliferation, adhesion, angiogenesis and metastasis, affecting tumor progress. The four main types of proteoglycans include hyaluronan (HA), which does not occur as a PG but in free form, heparan sulfate proteoglycans (HSPGs), chondroitin sulfate proteoglycans (CSPGs), dematan sulfate proteoglycans (DSPG) and keratan sulfate proteoglycans (KSPGs) [BR:00535]. Among these proteoglycans such as HA, acting with CD44, promotes tumor cell growth and migration, whereas other proteoglycans such as syndecans (-1~-4), glypican (-1, -3) and perlecan may interact with growth factors, cytokines, morphogens and enzymes through HS chains [BR: 00536], also leading to tumor growth and invasion. In contrast, some of the small leucine-rich proteolgycans, such as decorin and lumican, can function as tumor repressors, and modulate the signaling pathways by the interaction of their core proteins and multiple receptors.
hsa05210	Colorectal cancer	Colorectal cancer (CRC) is the second largest cause of cancer-related deaths in Western countries. CRC arises from the colorectal epithelium as a result of the accumulation of genetic alterations in defined oncogenes and tumour suppressor genes (TSG). Two major mechanisms of genomic instability have been identified in sporadic CRC progression. The first, known as chromosomal instability (CIN), results from a series of genetic changes that involve the activation of oncogenes such as K-ras and inactivation of TSG such as p53, DCC/Smad4, and APC. The second, known as microsatellite instability (MSI), results from inactivation of the DNA mismatch repair genes MLH1 and/or MSH2 by hypermethylation of their promoter, and secondary mutation of genes with coding microsatellites, such as transforming growth factor receptor II (TGF-RII) and BAX. Hereditary syndromes have germline mutations in specific genes (mutation in the tumour suppressor gene APC on chromosome 5q in FAP, mutated DNA mismatch repair genes in HNPCC).
hsa05211	Renal cell carcinoma	Renal cell cancer (RCC) accounts for ~3% of human malignancies and its incidence appears to be rising. Although most cases of RCC seem to occur sporadically, an inherited predisposition to renal cancer accounts for 1-4% of cases. RCC is not a single disease, it has several morphological subtypes. Conventional RCC (clear cell RCC) accounts for ~80% of cases, followed by papillary RCC (10-15%), chromophobe RCC (5%), and collecting duct RCC (<1%). Genes potentially involved in sporadic neoplasms of each particular type are VHL, MET, BHD, and FH respectively. In the absence of VHL, hypoxia-inducible factor alpha (HIF-alpha) accumulates, leading to production of several growth factors, including vascular endothelial growth factor and platelet-derived growth factor. Activated MET mediates a number of biological effects including motility, invasion of extracellular matrix, cellular transformation, prevention of apoptosis and metastasis formation. Loss of functional FH leads to accumulation of fumarate in the cell, triggering inhibition of HPH and preventing targeted pVHL-mediated degradation of HIF-alpha. BHD mutations cause the Birt-Hogg-Dube syndrome and its associated chromophobe, hybrid oncocytic, and conventional (clear cell) RCC.
hsa05212	Pancreatic cancer	Infiltrating ductal adenocarcinoma is the most common malignancy of the pancreas. When most investigators use the term 'pancreatic cancer' they are referring to pancreatic ductal adenocarcinoma (PDA). Normal duct epithelium progresses to infiltrating cancer through a series of histologically defined precursors (PanINs). The overexpression of HER-2/neu and activating point mutations in the K-ras gene occur early, inactivation of the p16 gene at an intermediate stage, and the inactivation of p53, SMAD4, and BRCA2 occur relatively late. Activated K-ras engages multiple effector pathways. Although EGF receptors are conventionally regarded as upstream activators of RAS proteins, they can also act as RAS signal transducers via RAS-induced autocrine activation of the EGFR family ligands. Moreover, PDA shows extensive genomic instability and aneuploidy. Telomere attrition and mutations in p53 and BRCA2 are likely to contribute to these phenotypes. Inactivation of the SMAD4 tumour suppressor gene leads to loss of the inhibitory influence of the transforming growth factor-beta signalling pathway.
hsa05213	Endometrial cancer	Endometrial cancer (EC) is the most common gynaecological malignancy and the fourth most common malignancy in women in the developed world after breast, colorectal and lung cancer. Two types of endometrial carcinoma are distinguished with respect to biology and clinical course. Type-I carcinoma is related to hyperestrogenism by association with endometrial hyperplasia, frequent expression of estrogen and progesterone receptors and younger age, whereas type-II carcinoma is unrelated to estrogen, associated with atrophic endometrium, frequent lack of estrogen and progesterone receptors and older age. The morphologic differences in these cancers are mirrored in their molecular genetic profile with type I showing defects in DNA-mismatch repair and mutations in PTEN, K-ras, and beta-catenin, and type II showing aneuploidy, p53 mutations, and her2/neu amplification.
hsa05214	Glioma	Gliomas are the most common of the primary brain tumors and account for more than 40% of all central nervous system neoplasms. Gliomas include tumours that are composed predominantly of astrocytes (astrocytomas), oligodendrocytes (oligodendrogliomas), mixtures of various glial cells (for example,oligoastrocytomas) and ependymal cells (ependymomas). The most malignant form of infiltrating astrocytoma - glioblastoma multiforme (GBM) - is one of the most aggressive human cancers. GBM may develop de novo (primary glioblastoma) or by progression from low-grade or anaplastic astrocytoma (secondary glioblastoma). Primary glioblastomas develop in older patients and typically show genetic alterations (EGFR amplification, p16/INK4a deletion, and PTEN mutations) at frequencies of 24-34%. Secondary glioblastomas develop in younger patients and frequently show overexpression of PDGF and CDK4 as well as p53 mutations (65%) and loss of Rb playing major roles in such transformations. Loss of PTEN has been implicated in both pathways, although it is much more common in the pathogenesis of primary GBM.
hsa05215	Prostate cancer	Prostate cancer constitutes a major health problem in Western countries. It is the most frequently diagnosed cancer among men and the second leading cause of male cancer deaths. The identification of key molecular alterations in prostate-cancer cells implicates carcinogen defenses (GSTP1), growth-factor-signaling pathways (NKX3.1, PTEN, and p27), and androgens (AR) as critical determinants of the phenotype of prostate-cancer cells. Glutathione S-transferases (GSTP1) are detoxifying enzymes. Cells of prostatic intraepithelial neoplasia, devoid of GSTP1, undergo genomic damage mediated by carcinogens. NKX3.1, PTEN, and p27 regulate the growth and survival of prostate cells in the normal prostate. Inadequate levels of PTEN and NKX3.1 lead to a reduction in p27 levels and to increased proliferation and decreased apoptosis. Androgen receptor (AR) is a transcription factor that is normally activated by its androgen ligand. During androgen withdrawal therapy, the AR signal transduction pathway also could be activated by amplification of the AR gene, by AR gene mutations, or by altered activity of AR coactivators. Through these mechanisms, tumor cells lead to the emergence of androgen-independent prostate cancer.
hsa05218	Melanoma	Melanoma is a form of skin cancer that has a poor prognosis and which is on the rise in Western populations. Melanoma arises from the malignant transformation of pigment-producing cells, melanocytes. The only known environmental risk factor is exposure to ultraviolet (UV) light and in people with fair skin the risk is greatly increased. Melanoma pathogenesis is also driven by genetic factors. Oncogenic NRAS mutations activate both effector pathways Raf-MEK-ERK and PI3K-Akt. The Raf-MEK-ERK pathway may also be activated via mutations in the BRAF gene. The PI3K-Akt pathway may be activated through loss or mutation of the inhibitory tumor suppressor gene PTEN. These mutations arise early during melanoma pathogenesis and are preserved throughout tumor progression. Melanoma development has been shown to be strongly associated with inactivation of the p16INK4a/cyclin dependent kinases 4 and 6/retinoblastoma protein (p16INK4a/CDK4,6/pRb) and p14ARF/human double minute 2/p53 (p14ARF/HMD2/p53) tumor suppressor pathways. MITF and TP53 are implicated in further melanoma progression.
hsa05220	Chronic myeloid leukemia	Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder of a pluripotent stem cell. The natural history of CML has a triphasic clinical course comprising of an initial chronic phase (CP), which is characterized by expansion of functionally normal myeloid cells, followed by an accelerated phase (AP) and finally a more aggressive blast phase (BP), with loss of terminal differentiation capacity. On the cellular level, CML is associated with a specific chromosome abnormality, the t(9; 22) reciprocal translocation that forms the Philadelphia (Ph) chromosome. The Ph chromosome is the result of a molecular rearrangement between the c-ABL proto-oncogene on chromosome 9 and the BCR (breakpoint cluster region) gene on chromosome 22. The BCR/ABL fusion gene encodes p210 BCR/ABL, an oncoprotein, which, unlike the normal p145 c-Abl, has constitutive tyrosine kinase activity and is predominantly localized in the cytoplasm. While fusion of c-ABL and BCR is believed to be the primary cause of the chronic phase of CML, progression to blast crisis requires other molecular changes. Common secondary abnormalities include mutations in TP53, RB, and p16/INK4A, or overexpression of genes such as EVI1. Additional chromosome translocations are also observed,such as t(3;21)(q26;q22), which generates AML1-EVI1.
hsa05221	Acute myeloid leukemia	Acute myeloid leukemia (AML) is a disease that is characterized by uncontrolled proliferation of clonal neoplastic cells and accumulation in the bone marrow of blasts with an impaired differentiation program. AML accounts for approximately 80% of all adult leukemias and remains the most common cause of leukemia death. Two major types of genetic events have been described that are crucial for leukemic transformation. A proposed necessary first event is disordered cell growth and upregulation of cell survival genes. The most common of these activating events were observed in the RTK Flt3, in N-Ras and K-Ras, in Kit, and sporadically in other RTKs. Alterations in myeloid transcription factors governing hematopoietic differentiation provide second necessary event for leukemogenesis. Transcription factor fusion proteins such as AML-ETO, PML-RARalpha or PLZF-RARalpha block myeloid cell differentiation by repressing target genes. In other cases, the transcription factors themselves are mutated.
hsa05222	Small cell lung cancer	Lung cancer is a leading cause of cancer death among men and women in industrialized countries. Small cell lung carcinoma (SCLC) is a highly aggressive neoplasm, which accounts for approximately 25% of all lung cancer cases. Molecular mechanisms altered in SCLC include induced expression of oncogene, MYC, and loss of tumorsuppressor genes, such as p53, PTEN, RB, and FHIT. The overexpression of MYC proteins in SCLC is largely a result of gene amplification. Such overexpression leads to more rapid proliferation and loss of terminal differentiation. Mutation or deletion of p53 or PTEN can lead to more rapid proliferation and reduced apoptosis. The retinoblastoma gene RB1 encodes a nuclear phosphoprotein that helps to regulate cell-cycle progression. The fragile histidine triad gene FHIT encodes the enzyme diadenosine triphosphate hydrolase, which is thought to have an indirect role in proapoptosis and cell-cycle control.
hsa05223	Non-small cell lung cancer	Lung cancer is a leading cause of cancer death among men and women in industrialized countries. Non-small-cell lung cancer (NSCLC) accounts for approximately 85% of lung cancer and represents a heterogeneous group of cancers, consisting mainly of squamous cell (SCC), adeno (AC) and large-cell carcinoma. Molecular mechanisms altered in NSCLC include activation of oncogenes, such as K-RAS, EGFR and EML4-ALK, and inactivation of tumorsuppressor genes, such as p53, p16INK4a, RAR-beta, and RASSF1. Point mutations within the K-RAS gene inactivate GTPase activity and the p21-RAS protein continuously transmits growth signals to the nucleus. Mutations or overexpression of EGFR leads to a proliferative advantage. EML4-ALK fusion leads to constitutive ALK activation, which causes cell proliferation, invasion, and inhibition of apoptosis. Inactivating mutation of p53 can lead to more rapid proliferation and reduced apoptosis. The protein encoded by the p16INK4a inhibits formation of CDK-cyclin-D complexes by competitive binding of CDK4 and CDK6. Loss of p16INK4a expression is a common feature of NSCLC. RAR-beta is a nuclear receptor that bears vitamin-A-dependent transcriptional activity. RASSF1A is able to form heterodimers with Nore-1, an RAS effector.Therefore loss of RASSF1A might shift the balance of RAS activity towards a growth-promoting effect.
hsa05224	Breast cancer	Breast cancer is the leading cause of cancer death among women worldwide. The vast majority of breast cancers are carcinomas that originate from cells lining the milk-forming ducts of the mammary gland. The molecular subtypes of breast cancer, which are based on the presence or absence of hormone receptors (estrogen and progesterone subtypes) and human epidermal growth factor receptor-2 (HER2), include: hormone receptor positive and HER2 negative (luminal A subtype), hormone receptor positive and HER2 positive (luminal B subtype), hormone receptor negative and HER2 positive (HER2 positive), and hormone receptor negative and HER2 negative (basal-like or triple-negative breast cancers (TNBCs)). Hormone receptor positive breast cancers are largely driven by the estrogen/ER pathway. In HER2 positive breast tumours, HER2 activates the PI3K/AKT and the RAS/RAF/MAPK pathways, and stimulate cell growth, survival and differentiation. In patients suffering from TNBC, the deregulation of various signalling pathways (Notch and Wnt/beta-catenin), EGFR protein have been confirmed. In the case of breast cancer only 8% of all cancers are hereditary, a phenomenon linked to genetic changes in BRCA1 or BRCA2. Somatic mutations in only three genes (TP53, PIK3CA and GATA3) occurred at >10% incidence across all breast cancers.
hsa05225	Hepatocellular carcinoma	Hepatocellular carcinoma (HCC) is a major type of primary liver cancer and one of the rare human neoplasms etiologically linked to viral factors. It has been shown that, after HBV/HCV infection and alcohol or aflatoxin B1 exposure, genetic and epigenetic changes occur. The recurrent mutated genes were found to be highly enriched in multiple key driver signaling processes, including telomere maintenance, TP53, cell cycle regulation, the Wnt/beta-catenin pathway (CTNNB1 and AXIN1), the phosphatidylinositol-3 kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway. Recent studies using whole-exome sequencing have revealed recurrent mutations in new driver genes involved in the chromatin remodelling (ARID1A and ARID2) and the oxidative stress (NFE2L2) pathways.
hsa05226	Gastric cancer	Gastric cancer (GC) is one of the world's most common cancers. According to Lauren's histological classification gastric cancer is divided into two distinct histological groups - the intestinal and diffuse types. Several genetic changes have been identified in intestinal-type GC. The intestinal metaplasia is characterized by mutations in p53 gene, reduced expression of retinoic acid receptor beta (RAR-beta) and hTERT expression. Gastric adenomas furthermore display mutations in the APC gene, reduced p27 expression and cyclin E amplification. In addition, amplification and overexpression of c-ErbB2, reduced TGF-beta receptor type I (TGFBRI) expression and complete loss of p27 expression are commonly observed in more advanced GC. The main molecular changes observed in diffuse-type GCs include loss of E-cadherin function by mutations in CDH1 and amplification of MET and FGFR2F.
hsa05230	Central carbon metabolism in cancer	Malignant transformation of cells requires specific adaptations of cellular metabolism to support growth and survival. In the early twentieth century, Otto Warburg established that there are fundamental differences in the central metabolic pathways operating in malignant tissue. He showed that cancer cells consume a large amount of glucose, maintain high rate of glycolysis and convert a majority of glucose into lactic acid even under normal oxygen concentrations (Warburg's Effects). More recently, it has been recognized that the 'Warburg effect' encompasses a similarly increased utilization of glutamine. From the intermediate molecules provided by enhanced glycolysis and glutaminolysis, cancer cells synthesize most of the macromolecules required for the duplication of their biomass and genome. These cancer-specific alterations represent a major consequence of genetic mutations and the ensuing changes of signalling pathways in cancer cells. Three transcription factors, c-MYC, HIF-1 and p53, are key regulators and coordinate regulation of cancer metabolism in different ways, and many other oncogenes and tumor suppressor genes cluster along the signaling pathways that regulate c-MYC, HIF-1 and p53.
hsa05231	Choline metabolism in cancer	Abnormal choline metabolism is emerging as a metabolic hallmark that is associated with oncogenesis and tumour progression. Following transformation, oncogenic signalling via pathways such as the RAS and PI3K-AKT pathways, and transcription factors associated with oncogenesis such as hypoxia-inducible factor 1 (HIF1) mediate overexpression and activation of choline cycle enzymes, which causes increased levels of choline-containing precursors and breakdown products of membrane phospholipids. These products of choline phospholipid metabolism, such as phosphocholine (PCho), diacylglycerol (DAG) and phosphatidic acid, may function as second messengers that are essential for the mitogenic activity of growth factors, particularly in the activation of the ras-raf-1-MAPK cascade and protein kinase C pathway.
hsa05418	Fluid shear stress and atherosclerosis	Shear stress represents the frictional force that the flow of blood exerts at the endothelial surface of the vessel wall and plays a central role in vascular biology and contributes to the progress of atherosclerosis. Sustained laminar flow with high shear stress upregulates expressions of endothelial cell (EC) genes and proteins that are protective against atherosclerosis. The key shear stress-induced transcription factors that govern the expression of these genes are Kruppel-like factor 2 (KLF2) and nuclear factor erythroid 2-like 2 (Nrf2). On the other hand, disturbed flow with associated reciprocating, low shear stress generally upregulates the EC genes and proteins that promote oxidative and inflammatory states in the artery wall, resulting in atherogenesis. Important transcriptional events that reflect this condition of ECs in disturbed flow include the activation of activator protein 1 (AP-1) and nuclear factor kappaB (NF-kappaB).

Pathway ID	Pathway Name	Pathway Description (KEGG)
R-HSA-109704	PI3K Cascade.	The PI3K (Phosphatidlyinositol-3-kinase) - AKT signaling pathway stimulates cell growth and survival
R-HSA-112399	IRS-mediated signalling.	Release of phospho-IRS from the insulin receptor triggers a cascade of signalling events via PI3K, SOS, RAF and the MAP kinases
R-HSA-114604	GPVI-mediated activation cascade.	The GPVI receptor is a complex of the GPVI protein with Fc epsilon R1 gamma (FcR). The Src family kinases Fyn and Lyn constitutively associate with the GPVI-FcR complex in platelets and initiate platelet activation through phosphorylation of the immunoreceptor tyrosine-based activation motif (ITAM) in the FcR gamma chain, leading to binding and activation of the tyrosine kinase Syk. Downstream of Syk, a series of adapter molecules and effectors lead to platelet activation. The GPVI receptor signaling cascade is similar to that of T- and B-cell immune receptors, involving the formation of a signalosome composed of adapter and effector proteins. At the core of the T-cell receptor signalosome is the transmembrane adapter LAT and two cytosolic adapters SLP-76 and Gads. While LAT is essential for signalling to PLCgamma1 downstream of the T-cell receptor, the absence of LAT in platelets only impairs the activation of PLCgamma2, the response to collagen and GPVI receptor ligands remains sufficient to elicit a full aggregation response. In contrast, GPVI signalling is almost entirely abolished in the absence of SLP-76
R-HSA-1236382	Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants.	Signaling by EGFR is frequently activated in cancer through activating mutations in the coding sequence of the EGFR gene, resulting in expression of a constitutively active mutant protein. Epidermal growth factor receptor kinase domain mutants are present in ~16% of non-small-cell lung cancers (NSCLCs), but are also found in other cancer types, such as breast cancer, colorectal cancer, ovarian cancer and thyroid cancer. EGFR kinase domain mutants harbor activating mutations in exons 18-21 which code for the kinase domain (amino acids 712-979) . Small deletions, insertions or substitutions of amino acids within the kinase domain lock EGFR in its active conformation in which the enzyme can dimerize and undergo autophosphorylation spontaneously, without ligand binding (although ligand binding ability is preserved), and activate downstream signaling pathways that promote cell survival (Greulich et al. 2005, Zhang et al. 2006, Yun et al. 2007, Red Brewer et al. 2009). Point mutations in the extracellular domain of EGFR are frequently found in glioblastoma. Similar to kinase domain mutations, point mutations in the extracellular domain result in constitutively active EGFR proteins that signal in the absence of ligands, but ligand binding ability and responsiveness are preserved (Lee et al. 2006). EGFR kinase domain mutants need to maintain association with the chaperone heat shock protein 90 (HSP90) for proper functioning (Shimamura et al. 2005, Lavictoire et al. 2003). CDC37 is a co-chaperone of HSP90 that acts as a scaffold and regulator of interaction between HSP90 and its protein kinase clients. CDC37 is frequently over-expressed in cancers involving mutant kinases and acts as an oncogene (Roe et al. 2004, reviewed by Gray Jr. et al. 2008). Over-expression of the wild-type EGFR or EGFR cancer mutants results in aberrant activation of downstream signaling cascades, namely RAS/RAF/MAP kinase signaling and PI3K/AKT signaling, and possibly signaling by PLCG1, which leads to increased cell proliferation and survival, providing selective advantage to cancer cells that harbor activating mutations in the EGFR gene (Sordella et al. 2004, Huang et al. 2007). While growth factor activated wild-type EGFR is promptly down-regulated by internalization and degradation, cancer mutants of EGFR demonstrate prolonged activation (Lynch et al. 2004). Association of HSP90 with EGFR kinase domain mutants negatively affects CBL-mediated ubiquitination, possibly through decreasing the affinity of EGFR kinase domain mutants for phosphorylated CBL, so that CBL dissociates from the complex upon phosphorylation and cannot perform ubiquitination (Yang et al. 2006, Padron et al. 2007). Various molecular therapeutics are being developed to target aberrantly activated EGFR in cancer. Non-covalent (reversible) small tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, selectively bind kinase domain of EGFR, competitively inhibiting ATP binding and subsequent autophosphorylation of EGFR dimers. EGFR kinase domain mutants sensitive to non-covalent TKIs exhibit greater affinity for TKIs than ATP compared with the wild-type EGFR protein, and are therefore preferential targets of non-covalent TKI therapeutics (Yun et al. 2007). EGFR proteins that harbor point mutations in the extracellular domain also show sensitivity to non-covalent tyrosine kinase inhibitors (Lee et al. 2006). EGFR kinase domain mutants harboring small insertions in exon 20 or a secondary T790M mutation are resistant to reversible TKIs (Balak et al. 2006) due to increased affinity for ATP (Yun et al. 2008), and are targets of covalent (irreversible) TKIs that form a covalent bond with EGFR cysteine residue C397. However, effective concentrations of covalent TKIs also inhibit wild-type EGFR, causing severe side effects (Zhou et al. 2009). Hence, covalent TKIs have not shown much promise in clinical trials (Reviewed by Pao and Chmielecki in 2010)
R-HSA-1250342	PI3K events in ERBB4 signaling.	The CYT1 isoforms of ERBB4 possess a C-tail tyrosine residue that, upon trans-autophosphorylation, serves as a docking site for the p85 alpha subunit of PI3K - PIK3R1 (Kaushansky et al. 2008, Cohen et al. 1996). Binding of PIK3R1 to CYT1 isoforms of ERBB4 is followed by recruitment of the p110 catalytic subunit of PI3K (PIK3CA), leading to assembly of an active PI3K complex that converts PIP2 to PIP3 and activates AKT signaling (Kainulainen et al. 2000)
R-HSA-1257604	PIP3 activates AKT signaling.	Signaling by AKT is one of the key outcomes of receptor tyrosine kinase (RTK) activation. AKT is activated by the cellular second messenger PIP3, a phospholipid that is generated by PI3K. In ustimulated cells, PI3K class IA enzymes reside in the cytosol as inactive heterodimers composed of p85 regulatory subunit and p110 catalytic subunit. In this complex, p85 stabilizes p110 while inhibiting its catalytic activity. Upon binding of extracellular ligands to RTKs, receptors dimerize and undergo autophosphorylation. The regulatory subunit of PI3K, p85, is recruited to phosphorylated cytosolic RTK domains either directly or indirectly, through adaptor proteins, leading to a conformational change in the PI3K IA heterodimer that relieves inhibition of the p110 catalytic subunit. Activated PI3K IA phosphorylates PIP2, converting it to PIP3; this reaction is negatively regulated by PTEN phosphatase. PIP3 recruits AKT to the plasma membrane, allowing TORC2 to phosphorylate a conserved serine residue of AKT. Phosphorylation of this serine induces a conformation change in AKT, exposing a conserved threonine residue that is then phosphorylated by PDPK1 (PDK1). Phosphorylation of both the threonine and the serine residue is required to fully activate AKT. The active AKT then dissociates from PIP3 and phosphorylates a number of cytosolic and nuclear proteins that play important roles in cell survival and metabolism. For a recent review of AKT signaling, please refer to Manning and Cantley, 2007
R-HSA-1266695	Interleukin-7 signaling.	Interleukin-7 (IL7) is produced primarily by T zone fibroblastic reticular cells found in lymphoid organs, and also expressed by non-hematopoietic stromal cells present in other tissues including the skin, intestine and liver. It is an essential survival factor for lymphocytes, playing a key anti-apoptotic role in T-cell development, as well as mediating peripheral T-cell maintenance and proliferation. This dual function is reflected in a dose-response relationship that distinguishes the survival function from the proliferative activity; low doses of IL7 (<1 ng/ml) sustain only survival, higher doses (>1 ng/ml) promote survival and cell cycling (Kittipatarin et al. 2006, Swainson et al. 2007).The IL7 receptor is a heterodimeric complex of the the common cytokine-receptor gamma chain (IL2RG, CD132, or Gc) and the IL7-receptor alpha chain (IL7R, IL7RA, CD127). Both chains are members of the type 1 cytokine family. Neither chain is unique to the IL7 receptor as IL7R is utilized by the receptor for thymic stromal lymphopoietin (TSLP) while IL2RG is shared with the receptors for IL2, IL4, IL9, IL15 and IL21. IL2RG consists of a single transmembrane region and a 240aa extracellular region that includes a fibronectin type III (FNIII) domain thought to be involved in receptor complex formation. It is expressed on most lymphocyte populations. Null mutations of IL2RG in humans cause X-linked severe combined immunodeficiency (X-SCID), which has a phenotype of severely reduced T-cell and natural killer (NK) cell populations, but normal numbers of B cells. In addition to reduced T- and NK-cell numbers, Il2rg knockout mice also have dramatically reduced B-cell populations suggesting that Il2rg is more critical for B-cell development in mice than in humans. Patients with severe combined immunodeficiency (SCID) phenotype due to IL7R mutations (see Puel & Leonard 2000), or a partial deficiency of IL7R (Roifman et al. 2000) have markedly reduced circulating T cells, but normal levels of peripheral blood B cells and NK cells, similar to the phenotype of IL2RG mutations, highlighting a requirement for IL7 in T cell lymphopoiesis. It has been suggested that IL7 is essential for murine, but not human B cell development, but recent studies indicate that IL7 is essential for human B cell production from adult bone marrow and that IL7-induced expansion of the progenitor B cell compartment is increasingly critical for human B cell production during later stages of development (Parrish et al. 2009).IL7 has been shown to induce rapid and dose-dependent tyrosine phosphorylation of JAKs 1 and 3, and concomitantly tyrosine phosphorylation and DNA-binding activity of STAT5a/b (Foxwell et al. 1995). IL7R was shown to directly induce the activation of JAKs and STATs by van der Plas et al. (1996). Jak1 and Jak3 knockout mice displayed severely impaired thymic development, further supporting their importance in IL7 signaling (Rodig et al. 1998, Nosaka et al. 1995).The role of STAT5 in IL7 signaling has been studied largely in mouse models. Tyr449 in the cytoplasmic domain of IL7RA is required for T-cell development in vivo and activation of JAK/STAT5 and PI3k/Akt pathways (Jiang et al. 2004, Pallard et al. 1999). T-cells from an IL7R Y449F knock-in mouse did not activate STAT5 (Osbourne et al. 2007), indicating that IL7 regulates STAT5 activity via this key tyrosine residue. STAT5 seems to enhance proliferation of multiple cell lineages in mouse models but it remains unclear whether STAT5 is required solely for survival signaling or also for the induction of proliferative activity (Kittipatarin & Khaled, 2007).The model for IL7 receptor signaling is believed to resemble that of other Gc family cytokines, based on detailed studies of the IL2 receptor, where IL2RB binds constitutively to JAK1 while JAK3 is pre-associated uniquely with the IL2RG chain. Extending this model to IL7 suggests a similar series of events: IL7R constitutively associated with JAK1 binds IL7, the resulting trimer recruits IL2RG:JAK3, bringing JAK1 and JAK3 into proximity. The association of both chains of the IL7 receptor orients the cytoplasmic domains of the receptor chains so that their associated kinases (Janus and phosphatidylinositol 3-kinases) can phosphorylate sequence elements on the cytoplasmic domains (Jiang et al. 2005). JAKs have low intrinsic enzymatic activity, but after mutual phosphorylation acquire much higher activity, leading to phosphorylation of the critical Y449 site on IL7R. This site binds STAT5 and possibly other signaling adapters, they in turn become phosphorylated by JAK1 and/or JAK3. Phosphorylated STATs translocate to the nucleus and trigger the transcriptional events of their target genes.The role of the PI3K/AKT pathway in IL7 signaling is controversial. It is a potential T-cell survival pathway because in many cell types PI3K signaling regulates diverse cellular functions such as cell cycle progression, transcription, and metabolism. The ERK/MAPK pathway does not appear to be involved in IL7 signaling (Crawley et al. 1996).It is not clear how IL7 influences cell proliferation. In the absence of a proliferative signal such as IL7 or IL3, dependent lymphocytes arrest in the G0/G1 phase of the cell cycle. To exit this phase, cells typically activate specific G1 Cyclin-dependent kinases/cyclins and down regulate cell cycle inhibitors such as Cyclin-dependent kinase inhibitor 1B (Cdkn1b or p27kip1). There is indirect evidence suggesting a possible role for IL7 stimulated activation of PI3K/AKT signaling, obtained from transformed cell lines and thymocytes, but not confirmed by observations using primary T-cells (Kittipatarin & Khaled, 2007). IL7 withdrawal results in G1/S cell cycle arrest and is correlated with loss of cdk2 activity (Geiselhart et al. 2001), both events which are known to be regulated by the dephosphorylating activity of Cdc25A. Expression of a p38 MAPK-resistant Cdc25A mutant in an IL-7-dependent T-cell line as well as in peripheral, primary T-cells was sufficient to sustain cell survival and promote cell cycling for several days in the absence of IL7 (Khaled et al. 2005). Cdkn1b is a member of the CIP/KIP family of cyclin-dependent cell cycle inhibitors (CKIs) that negatively regulates the G1/S transition. In IL7 dependent T-cells, the expression of Cdkn1b was sufficient to cause G1 arrest in the presence of IL7. Withdrawal of IL7 induced the upregulation of Cdkn1b and arrested cells in G1 while siRNA knockout of Cdkn1b enhanced cell cycle progression. However, adoptive transfer of Cdkn1b-deficient lymphocytes into IL7 deficient mice indicated that loss of Cdkn1b could only partially compensate for the IL7 signal needed by T-cells to expand in a lymphopenic environment (Li et al. 2006), so though Cdkn1b may be involved in negative regulation of the cell cycle through an effect on cdk2 activity, its absence is not sufficient to fully induce cell cycling under lymphopenic conditions
R-HSA-1433557	Signaling by SCF-KIT.	Stem cell factor (SCF) is a growth factor with membrane bound and soluble forms. It is expressed by fibroblasts and endothelial cells throughout the body, promoting proliferation, migration, survival and differentiation of hematopoetic progenitors, melanocytes and germ cells.(Linnekin 1999, Ronnstrand 2004, Lennartsson and Ronnstrand 2006). The receptor for SCF is KIT, a tyrosine kinase receptor (RTK) closely related to the receptors for platelet derived growth factor receptor, colony stimulating factor 1 (Linnekin 1999) and Flt3 (Rosnet et al. 1991). Four isoforms of c-Kit have been identified in humans. Alternative splicing results in isoforms of KIT differing in the presence or absence of four residues (GNNK) in the extracellular region. This occurs due to the use of an alternate 5' splice donor site. These GNNK+ and GNNK- variants are co-expressed in most tissues; the GNNK- form predominates and was more strongly tyrosine-phosphorylated and more rapidly internalized (Ronnstrand 2004). There are also splice variants that arise from alternative usage of splice acceptor site resulting in the presence or absence of a serine residue (Crosier et al., 1993). Finally, there is an alternative shorter transcript of KIT expressed in postmeiotic germ cells in the testis which encodes a truncated KIT consisting only of the second part of the kinase domain and thus lackig the extracellular and transmembrane domains as well as the first part of the kinase domain (Rossi et al. 1991). Binding of SCF homodimers to KIT results in KIT homodimerization followed by activation of its intrinsic tyrosine kinase activity. KIT stimulation activates a wide array of signalling pathways including MAPK, PI3K and JAK/STAT (Reber et al. 2006, Ronnstrand 2004). Defects of KIT in humans are associated with different genetic diseases and also in several types of cancers like mast cell leukaemia, germ cell tumours, certain subtypes of malignant melanoma and gastrointestinal tumours
R-HSA-1660499	Synthesis of PIPs at the plasma membrane.	At the plasma membrane, subsequent phosphorylation of phosphatidylinositol 4-phosphate (PI4P) produces phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) and phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3) while the actions of various other kinases and phosphatases produces phosphatidylinositol 3-phosphate (PI3P), phosphatidylinositol 5-phosphate (PI5P), phosphatidylinositol 3,4-bisphosphate (PI(3,4)P2), and phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) (Zhang et al. 1997, Gurung et al. 2003, Guo et al. 1999, Vanhaesebroeck et al. 1997, Tolias et al. 1998, Schaletzky et al. 2003, Kim et al. 2002, Clarke et al. 2010). Many of the phosphatidylinositol phosphatases that act at the plasma membrane belong to the myotubularin family. Enzymatically inactive myotubularin family members can heterodimerize with catalytically active mytotubularins to regulate their stability, activity and/or substrate specificity (Berger et al. 2006, Zou et al. 2012)
R-HSA-180292	GAB1 signalosome.	GAB1 is recruited to the activated EGFR indirectly, through GRB2. GAB1 acts as an adaptor protein that enables formation of an active PIK3, through recruitment of PIK3 regulatory subunit PIK3R1 (also known as PI3Kp85), which subsequently recruits PIK3 catalytic subunit PIK3CA (also known as PI3Kp110). PIK3, in complex with EGFR, GRB2 and GAB1, catalyzes phosphorylation of PIP2 and its conversion to PIP3, which leads to the activation of the AKT signaling
R-HSA-1839117	Signaling by cytosolic FGFR1 fusion mutants.	8p11 myeloproliferative syndrome (EMS) is an aggressive disorder that is associated with a translocation event at the FGFR1 gene on chromosome 8p11. Typical symptoms upon diagnosis include eosinophilia and associated T-cell lymphoblastic lymphoma; the disease rapidly advances to acute leukemia, usually of myeloid lineage. At present the only effective treatment is allogenic stem cell transplantation (reviewed in Jackson, 2010). At the molecular level, EMS appears to be caused by translocation events on chromosome 8 that create gene fusions between the intracellular domain of FGFR1 and an N-terminal partner gene that encodes a dimerization domain. The resulting fusion protein dimerizes in a ligand-independent fashion based the N-terminal domain provided by the partner protein and stimulates constititutive downstream FGFR1 signaling without altering the intrisic kinase activity of the receptor. To date, 11 partner genes have been identified: ZMYM2, FGFR1OP, FGFR1OP2, HERVK, TRIM24, CUX1, BCR, CEP110, LRRFIP1, MYO18A and CPSF6, although not all have been functionally characterized (reviewed in Jackson, 2010, Turner and Grose, 2010; Wesche, 2011). Where examined, cell lines carrying FGFR1 fusion genes have been shown to be transforming and to support IL3-independent proliferation through anti-apoptotic, prosurvival pathways(Lelievre, 2008; Ollendorff, 1999; Chase, 2007; Guasch, 2001; Wasag 2011; Roumiantsev, 2004; Demiroglu, 2001; Smedley, 1999). Signaling appears to occur predominantly through PLCgamma, PI3K and STAT signaling, with a more minor contribution from MAPK activation. Because the fusion proteins lack the FRS2-binding site, the mechanism of MAPK activation is unclear. Recruitment of GRB2:SOS1 through recruitment of SHC is one possibility (Guasch, 2001)
R-HSA-186763	Downstream signal transduction.	The role of autophosphorylation sites on PDGF receptors are to provide docking sites for downstream signal transduction molecules which contain SH2 domains. The SH2 domain is a conserved motif of around 100 amino acids that can bind a phosphorylated tyrosine residue. These downstream molecules are activated upon binding to, or phosphorylated by, the receptor kinases intrinsic to PDGF receptors.Some of the dowstream molecules are themselves enzymes, such as phosphatidylinositol 3'-kinase (PI3K), phospholipase C (PLC-gamma), the Src family of tyrosine kinases, the tyrosine phosphatase SHP2, and a GTPase activating protein (GAP) for Ras. Others such as Grb2 are adaptor molecules which link the receptor with downstream catalytic molecules
R-HSA-1963642	PI3K events in ERBB2 signaling.	ERBB2:ERBB3 and ERBB2:ERBB4cyt1 heterodimers activate PI3K signaling by direct binding of PI3K regulatory subunit p85 (Yang et al. 2007, Cohen et al. 1996, Kaushansky et al. 2008) to phosphorylated tyrosine residues in the C-tail of ERBB3 (Y1054, Y1197, Y1222, Y1224, Y1276 and Y1289) and ERBB4 CYT1 isoforms (Y1056 in JM-A CYT1 isoform and Y1046 in JM-B CYT1 isoform). Regulatory subunit p85 subsequently recruits catalytic subunit p110 of PI3K, resulting in the formation of active PI3K, conversion of PIP2 to PIP3, and PIP3-mediated activation of AKT signaling (Junttila et al. 2009, Kainulainen et al. 2000). Heterodimers of ERBB2 and EGFR recruit PI3K indirectly, through GRB2:GAB1 complex (Jackson et al. 2004), which again leads to PIP3-mediated activation of AKT signaling
R-HSA-198203	PI3K/AKT activation.	PI3K/AKT signalling is a major regulator of neuron survival. It blocks cell death by both impinging on the cytoplasmic cell death machinery and by regulating the expression of genes involved in cell death and survival. In addition, it may also use metabolic pathways to regulate cell survival.The PI3K/AKT pathway also affects axon diameter and branching (Marcus et al, 2002) and regulates small G proteins like RhoA (Vanhaesebroeck, B and Waterman, MD, 1999), which control the behaviour of the F-actin cytoskeleton. Moreover, through its connection with the TOR pathway, it promotes translation of a subset of mRNAs
R-HSA-202424	Downstream TCR signaling.	Changes in gene expression are required for the T cell to gain full proliferative competence and to produce effector cytokines. Three transcription factors in particular have been found to play a key role in TCR-stimulated changes in gene expression, namely NF-kB, NFAT and AP-1. A key step in NF-kB activation is the stimulation and translocation of PKC theta. The critical element that effects PKC theta activation is PI3K. This enzyme complex translocates to the plasma membrane by interacting with phospho-tyrosines on CD28 via its two SH2 domains located in p85 subunit. The p110 subunit of PI3K phosphorylates the inositol ring of PIP2 to generate PIP3 (steps 17-18). PIP3 may also be dephosphorylated by the phosphatase SHIP to generate PI-3,4-P2. PIP3 and PI-3,4-P2 acts as binding sites to the PH domain of PKB/Akt and PDK1 (steps 19, 21 and 22). PKB is activated in response to PI3K stimulation by PDK1 (step 23). PDK1 has an essential role in regulating the activation of PKC theta and recruitment of CBM complex to the immune synapse. PKC theta is a member of novel class (DAG dependent, Ca++ independent) of PKC and the only member known to translocate to this synapse. Prior to TCR stimulation PKC theta exists in an inactive closed conformation. Upon release of DAG, it binds to PKC theta via the C1 domain and undergoes phosphorylation on tyrosine 90 by Lck to attain an open conformation. PKC theta is further phosphorylated by PDK1 on threonine 538. This step is critical for PKC activity (steps 24-26). CARMA1 translocates to the plasma membrane following the interaction of its SH3 domain with the 'PxxP' motif on PDK1. CARMA1 is phosphorylated by PKC-theta on residue S552, leading to the oligomerization of CARMA1. This complex acts as a scaffold, recruiting Bcl10 to the synapse by interacting with their CARD domains. Bcl10 undergoes phosphorylation mediated by the enzyme RIP2. Activated Bcl10 then mediates the ubiquitination of NEMO by recruiting MALT1 and TRAF6. MALT1 binds to Bcl10 with its Ig-like domains and undergoes oligomerization. TRAF6 binds to the oligomerized MALT1 and also undergoes oligomerization. Oligomerized TRAF6 acts as a ubiquitin-protein ligase, catalyzing auto-K63-linked polyubiquitination (steps 27-33). This K-63 ubiquitinated TRAF6 activates TAK1 kinase bound to TAB2 and also ubiquitinates NEMO/IKK-gamma in the IKK complex. TAK1 undergoes autophosphorylation on residues T184 and T187 and gets activated. Activated TAK1 kinase phosphorylates IKK-beta on residues S177 and S181 in the activation loop and activates the IKK kinase activity. IKK-beta phosphorylates the IkB-alpha bound to the NF-kB heterodimer, on residues S19 and S23 and directs IkB-beta to 26S proteasome degradation (step 34-38 & 40). The NF-kB heterodimer with a free NTS sequence finally migrates to the nucleus to regulate gene transcription (step 39)
R-HSA-2029485	Role of phospholipids in phagocytosis.	Phospholipases play an integral role in phagocytosis by generating essential second messengers. An early step in phagocytic signaling is the association of PIP2 and IP3 with the phagocytic cup. These are formed by the activity of phosphoinositol kinases and phospholipases. PI3K is has been shown to accumulate at phagocytic cups and converts PI (4,5)P2 to PI (3,4,5)P3. These phosphoinositides are capable of binding and increasing the activity of proteins that regulate the actin cytoskeleton. Phospholipases are lipid modifying enzymes that produce lipid mediators such as diacylglycerol (DAG), arachidonic acid (AA) and IP3. Phopsholipases PLA, PLC and PLD have been shown to be involved in antibody (IgG) mediated phagocytosis. The PLC product IP3 stimulates release of calcium from the endoplasmic reticulum. This Ca+2 concentration increase is greatest in the cytoplasm surrounding the phagocytic cup. Calcium is involved in the various stages of phagosome formation, including phagocytic ingestion and phagosome maturation
R-HSA-210993	Tie2 Signaling.	The Tie2/Tek receptor tyrosine kinase plays a pivotal role in vascular and hematopoietic development and is expressed exclusively on endothelial lineage. Tie2 interacts with a group of ligands belonging to angiopoietin family and undergoes activation.These ligands show opposing actions, angiopoietin 1 and angiopoietin 4 stimulate the Tie2 phosphorylation and angiopoietin 2 inhibits it. Upon tyrosine phosphorylation Tie2 acts as a scaffold for various signaling proteins involved in different signal transduction cascades that can effect survival of endothelium and angiogenic sprout formation
R-HSA-2219530	Constitutive Signaling by Aberrant PI3K in Cancer.	Signaling by PI3K/AKT is frequently constitutively activated in cancer via gain-of-function mutations in one of the two PI3K subunits - PI3KCA (encoding the catalytic subunit p110alpha) or PIK3R1 (encoding the regulatory subunit p85alpha). Gain-of-function mutations activate PI3K signaling by diverse mechanisms. Mutations affecting the helical domain of PIK3CA and mutations affecting nSH2 and iSH2 domains of PIK3R1 impair inhibitory interactions between these two subunits while preserving their association. Mutations in the catalytic domain of PIK3CA enable the kinase to achieve an active conformation. PI3K complexes with gain-of-function mutations therefore produce PIP3 and activate downstream AKT in the absence of growth factors (Huang et al. 2007, Zhao et al. 2005, Miled et al. 2007, Horn et al. 2008, Sun et al. 2010, Jaiswal et al. 2009, Zhao and Vogt 2010, Urick et al. 2011)
R-HSA-2424491	DAP12 signaling.	In response to receptor ligation, the tyrosine residues in DAP12's immunoreceptor tyrosine-based activation motif (ITAM) are phosphorylated by Src family kinases. These phosphotyrosines form the docking site for the protein tyrosine kinase SYK in myeloid cells and SYK and ZAP70 in NK cells. DAP12-bound SYK autophosphorylates and phosphorylates the scaffolding molecule LAT, recruiting the proximal signaling molecules phosphatidylinositol-3-OH kinase (PI3K), phospholipase-C gamma (PLC-gamma), GADS (GRB2-related adapter downstream of SHC), SLP76 (SH2 domain-containing leukocyte protein of 76 kDa), GRB2:SOS (Growth factor receptor-bound protein 2:Son of sevenless homolog 1) and VAV. All of these intermediate signalling molecules result in the recruitment and activation of kinases AKT, CBL (Casitas B-lineage lymphoma) and ERK (extracellular signal-regulated kinase), and rearrangement of the actin cytoskeleton (actin polymerization) finally leading to cellular activation. PLC-gamma generates the secondary messengers diacylglycerol (DAG) and inositol-1,4,5-trisphosphate (InsP3), leading to activation of protein kinase C (PKC) and calcium mobilization, respectively (Turnbull & Colonna 2007, Klesney-Tait et al. 2006)
R-HSA-2730905	Role of LAT2/NTAL/LAB on calcium mobilization.	The lipid raft resident adaptor molecules LAT1 and Non-T cell activation linker (NTAL), also known as linker for activation of B cells (LAB)/LAT2 are known participants in the regulation of mast cell calcium responses. Both LAT and NTAL are expressed and phosphorylated following engagement of FCERI on mast cells. NTAL is functionally and topographically different from LAT. There is a considerable debate on the role of NTAL in mast cell. Depending on the circumstances, NTAL appears to have a dual role as positive and negative regulator of MC responses elicited via FCERI. Studies conducted in bone marrow-derived mast cells (BMMCs) of mice lacking NTAL displayed enhanced FCERI-mediated tyrosine phosphorylation of several substrates, calcium response, degranulation, and cytokine production. This indicated that NTAL negatively regulates FCERI-mediated degranulation. However, in mice lacking both LAT and NTAL showed severe block in FCERI-mediated signaling than BMMCs deficient in LAT alone, suggesting that NTAL also shares a redundant function with LAT to play a positive role (Draberova et al. 2007, Orr & McVicar. 2011, Zhu et al. 2004, Volna et al. 2004)
R-HSA-373753	Nephrin family interactions.	Nephrin (NPHS1) is a member of the Super-IgG-Molecule family and is most prominently expressed in kidney podocytes. It is a major if not the most important structural component of the slit diaphragm, a modified adherens junction inbetween these cells. NPHS1 has an extracellular domain that contains eight distal IgG like domains and one proximal fibronectin type III domain, a transmembrane domain and a short intracellular domain. NPHS1 molecules show both homophilic and heterophilic interactions. Among heterophilic interaction partners, slit diaphragm proteins such as Kin of IRRE-like protein 1 (KIRREL, Nephrin-like protein 1, NEPH1), KIRREL3 (NEPH2) and KIRREL2 (NEPH3) were shown to stabilize the slit diaphragm structure. Intracellularly Podocin (NPHS2), CD2 associated protein (CD2AP) and adherins junction associated proteins like IQGAP, MAGI, CASK and spectrins all interact with NPHS1. Hence it seems to play a major role in organizing the molecular structure of the slit diaphragm itself and via its binding partners links it to the actin cytoskeleton. NPHS1 tyrosine phosphorylation by the Src kinase FYN initiates the PI3K-AKT signaling cascade, which seems to promote antiapoptotic signals
R-HSA-388841	Costimulation by the CD28 family.	Optimal activation of T-lymphocytes requires at least two signals. A primary one is delivered by the T-cell receptor (TCR) complex after antigen recognition and additional costimulatory signals are delivered by the engagement of costimulatory receptors such as CD28. The best-characterized costimulatory pathways are mediated by a set of cosignaling molecules belonging to the CD28 superfamily, including CD28, CTLA4, ICOS, PD1 and BTLA receptors. These proteins deliver both positive and negative second signals to T-cells by interacting with B7 family ligands expressed on antigen presenting cells. Different subsets of T-cells have very different requirements for costimulation. CD28 family mediated costimulation is not required for all T-cell responses in vivo, and alternative costimulatory pathways also exist. Different receptors of the CD28 family and their ligands have different regulation of expression. CD28 is constitutively expressed on naive T cells whereas CTLA4 expression is dependent on CD28/B7 engagement and the other receptor members ICOS, PD1 and BTLA are induced after initial T-cell stimulation. The positive signals induced by CD28 and ICOS molecules are counterbalanced by other members of the CD28 family, including cytotoxic T-lymphocyte associated antigen (CTLA)4, programmed cell death (PD)1, and B and T lymphocyte attenuator (BTLA), which dampen immune responses. The balance of stimulatory and inhibitory signals is crucial to maximize protective immune responses while maintaining immunological tolerance and preventing autoimmunity. The costimulatory receptors CD28, CTLA4, ICOS and PD1 are composed of single extracellular IgV-like domains, whereas BTLA has one IgC-like domain. Receptors CTLA4, CD28 and ICOS are covalent homodimers, due to an interchain disulphide linkage. The costimulatory ligands B71, B72, B7H2, B7H1 and B7DC, have a membrane proximal IgC-like domain and a membrane distal IgV-like domain that is responsible for receptor binding and dimerization. CD28 and CTLA4 have no known intrinsic enzymatic activity. Instead, engagement by their physiologic ligands B71 and B72 leads to the physical recruitment and activation of downstream T-cell effector molecules
R-HSA-389357	CD28 dependent PI3K/Akt signaling.	PI3Ks can be activated by a number of different receptors, including the TcR (T cell receptor), co-stimulatory receptors (CD28), cytokine receptors and chemokine receptors. However, the specific roles of PI3Ks downstream of these receptors vary. CD28 contains the YMNM consensus PI3K-binding motif, and PI3K recruitment by CD28 contributes to or complements TCR-dependent PI3K signaling. Activation of PI3K promotes PIP3 production at the plasma membrane and several potential target molecules for this phospholipid have been implicated in PI3K pathways downstream of the TcR and CD28. Of these targets, at least Vav and Akt have been implicated in CD28 costimulation of T cell activation. AKT/PKB connects PI3K to signaling pathways that promote cytokine transcription, survival, cell-cycle entry and growth
R-HSA-416476	G alpha (q) signalling events.	The classic signalling route for G alpha (q) is activation of phospholipase C beta thereby triggering phosphoinositide hydrolysis, calcium mobilization and protein kinase C activation. This provides a path to calcium-regulated kinases and phosphatases, GEFs, MAP kinase cassettes and other proteins that mediate cellular responses ranging from granule secretion, integrin activation, and aggregation in platelets. Gq participates in many other signalling events including direct interaction with RhoGEFs that stimulate RhoA activity and inhibition of PI3K. Both in vitro and in vivo, the G-protein Gq seems to be the predominant mediator of the activation of platelets. Moreover, G alpha (q) can stimulate the activation of Burton tyrosine kinase (Ma Y C et al. 1998). Regulator of G-protein Signalling (RGS) proteins can regulate the activity of G alpha (z) (Soundararajan M et al. 2008)
R-HSA-416482	G alpha (12/13) signalling events.	The G12/13 family is probably the least well characterized subtype, partly because G12/13 coupling is difficult to determine when compared with the other subtypes which predominantly rely on assay technologies that measure intracellular calcium. The G12/13 family are best known for their involvement in the processes of cell proliferation and morphology, such as stress fiber and focal adhesion formation. Interactions with Rho guanine nucleotide exchange factors (RhoGEFs) are thought to mediate many of these processes. (Buhl et al.1995, Sugimoto et al. 2003). Activation of Rho or the regulation of events through Rho is often taken as evidence of G12/13 signaling. Receptors that are coupled with G12/13 invariably couple with one or more other G protein subtypes, usually Gq
R-HSA-430116	GP1b-IX-V activation signalling.	The platelet GPIb complex (GP1b-IX-V) together with GPVI are primarily responsible for regulating the initial adhesion of platelets to the damaged blood vessel and platelet activation. The importance of GPIb is demonstrated by the bleeding problems in patients with Bernard-Soulier syndrome where this receptor is either absent or defective. GP1b-IX-V binds von Willebrand Factor (vWF) to resting platelets, particularly under conditions of high shear stress. This transient interaction is the first stage of the vascular repair process. Activation of GP1b-IX-V on exposure of the fibrous matrix following atherosclerotic plaque rupture, or in occluded arteries, is a major contributory factor leading to thrombus formation leading to heart attack or stroke.\nGpIb also binds thrombin (Yamamoto et al. 1986), at a site distinct from the site of vWF binding, acting as a docking site for thrombin which then activates Proteinase Activated Receptors leading to enhanced platelet activation (Dormann et al. 2000)
R-HSA-4420097	VEGFA-VEGFR2 Pathway.	Angiogenesis is the formation of new blood vessels from preexisting vasculature. One of the most important proangiogenic factors is vascular endothelial growth factor (VEGF). VEGF exerts its biologic effect through interaction with transmembrane tyrosine kinase receptors VEGFR, selectively expressed on vascular endothelial cells. VEGFA signaling through VEGFR2 is the major pathway that activates angiogenesis by inducing the proliferation, survival, sprouting and migration of endothelial cells (ECs), and also by increasing endothelial permeability (Lohela et al. 2009, Shibuya & Claesson-Welsh 2006, Claesson-Welsh & Welsh, 2013). The critical role of VEGFR2 in vascular development is highlighted by the fact that VEGFR2-/- mice die at E8.5-9.5 due to defective development of blood islands, endothelial cells and haematopoietic cells (Shalaby et al. 1995)
R-HSA-512988	Interleukin-3, Interleukin-5 and GM-CSF signaling.	The Interleukin-3 (IL-3), IL-5 and Granulocyte-macrophage colony stimulating factor (GM-CSF) receptors form a family of heterodimeric receptors that have specific alpha chains but share a common beta subunit, often referred to as the common beta (Bc). Both subunits contain extracellular conserved motifs typical of the cytokine receptor superfamily. The cytoplasmic domains have limited similarity with other cytokine receptors and lack detectable catalytic domains such as tyrosine kinase domains. IL-3 is a 20-26 kDa product of CD4+ T cells that acts on the most immature marrow progenitors. IL-3 is capable of inducing the growth and differentiation of multi-potential hematopoietic stem cells, neutrophils, eosinophils, megakaryocytes, macrophages, lymphoid and erythroid cells. IL-3 has been used to support the proliferation of murine cell lines with properties of multi-potential progenitors, immature myeloid as well as T and pre-B lymphoid cells (Miyajima et al. 1992). IL-5 is a hematopoietic growth factor responsible for the maturation and differentiation of eosinophils. It was originally defined as a T-cell-derived cytokine that triggers activated B cells for terminal differentiation into antibody-secreting plasma cells. It also promotes the generation of cytotoxic T-cells from thymocytes. IL-5 induces the expression of IL-2 receptors (Kouro & Takatsu 2009). GM-CSF is produced by cells (T-lymphocytes, tissue macrophages, endothelial cells, mast cells) found at sites of inflammatory responses. It stimulates the growth and development of progenitors of granulocytes and macrophages, and the production and maturation of dendritic cells. It stimulates myeloblast and monoblast differentiation, synergises with Epo in the proliferation of erythroid and megakaryocytic progenitor cells, acts as an autocrine mediator of growth for some types of acute myeloid leukemia, is a strong chemoattractant for neutrophils and eosinophils. It enhances the activity of neutrophils and macrophages. Under steady-state conditions GM-CSF is not essential for the production of myeloid cells, but it is required for the proper development of alveolar macrophages, otherwise, pulmonary alvelolar proteinosis (PAP) develops. A growing body of evidence suggests that GM-CSF plays a key role in emergency hematopoiesis (predominantly myelopoiesis) in response to infection, including the production of granulocytes and macrophages in the bone marrow and their maintenance, survival, and functional activation at sites of injury or insult (Hercus et al. 2009). All three receptors have alpha chains that bind their specific ligands with low affinity (de Groot et al. 1998). Bc then associates with the alpha chain forming a high affinity receptor (Geijsen et al. 2001), though the in vivo receptor is likely be a higher order multimer as recently demonstrated for the GM-CSF receptor (Hansen et al. 2008). The receptor chains lack intrinsic kinase activity, instead they interact with and activate signaling kinases, notably Janus Kinase 2 (JAK2). These phosphorylate the common beta subunit, allowing recruitment of signaling molecules such as Shc, the phosphatidylinositol 3-kinases (PI3Ks), and the Signal Transducers and Activators of Transcription (STATs). The cytoplasmic domain of Bc has two distinct functional domains: the membrane proximal region mediates the induction of proliferation-associated genes such as c-myc, pim-1 and oncostatin M. This region binds multiple signal-transducing proteins including JAK2 (Quelle et al. 1994), STATs, c-Src and PI3 kinase (Rao and Mufson, 1995). The membrane distal domain is required for cytokine-induced growth inhibition and is necessary for the viability of hematopoietic cells (Inhorn et al. 1995). This region interacts with signal-transducing proteins such as Shc (Inhorn et al. 1995) and SHP and mediates the transcriptional activation of c-fos, c-jun, c-Raf and p70S6K (Reddy et al. 2000).Figure reproduced by permission from Macmillan Publishers Ltd: Leukemia, WL Blalock et al. 13:1109-1166, copyright 1999. Note that residue numbering in this diagram refers to the mature Common beta chain with signal peptide removed
R-HSA-5637810	Constitutive Signaling by EGFRvIII.	In glioblastoma, the most prevalent EGFR mutation, present in ~25% of tumors, is the deletion of the ligand binding domain of EGFR, accompanied with amplification of the mutated allele, which results in over-expression of the mutant protein known as EGFRvIII. EGFRvIII mutant is not able to bind a ligand, but dimerizes and autophosphorylates spontaneously and is therefore constitutively active (Fernandes et al. 2001). Point mutations in the extracellular domain of EGFR are also frequently found in glioblastoma, but ligand binding ability and responsiveness are preserved (Lee et al. 2006). Similar to EGFR kinase domain mutants, EGFRvIII mutant needs to maintain association with the chaperone heat shock protein 90 (HSP90) for proper functioning (Shimamura et al. 2005, Lavictoire et al. 2003). CDC37 is a co-chaperone of HSP90 that acts as a scaffold and regulator of interaction between HSP90 and its protein kinase clients. CDC37 is frequently over-expressed in cancers involving mutant kinases and acts as an oncogene (Roe et al. 2004, reviewed by Gray Jr. et al. 2008). Expression of EGFRvIII mutant results in aberrant activation of downstream signaling cascades, namely RAS/RAF/MAP kinase signaling and PI3K/AKT signaling, and possibly signaling by PLCG1, which leads to increased cell proliferation and survival, providing selective advantage to cancer cells that harbor EGFRvIII (Huang et al. 2007). EGFRvIII mutant does not autophosorylate on the tyrosine residue Y1045, a docking site for CBL, and is therefore unable to recruit CBL ubiquitin ligase, which enables it to escape degradation (Han et al
R-HSA-5654689	PI-3K cascade:FGFR1.	The ability of growth factors to protect from apoptosis is primarily due to the activation of the AKT survival pathway. P-I-3-kinase dependent activation of PDK leads to the activation of AKT which in turn affects the activity or expression of pro-apoptotic factors, which contribute to protection from apoptosis. AKT activation also blocks the activity of GSK-3b which could lead to additional antiapoptotic signals
R-HSA-5654695	PI-3K cascade:FGFR2.	The ability of growth factors to protect from apoptosis is primarily due to the activation of the AKT survival pathway. P-I-3-kinase dependent activation of PDK leads to the activation of AKT which in turn affects the activity or expression of pro-apoptotic factors, which contribute to protection from apoptosis. AKT activation also blocks the activity of GSK-3b which could lead to additional antiapoptotic signals
R-HSA-5654710	PI-3K cascade:FGFR3.	The ability of growth factors to protect from apoptosis is primarily due to the activation of the AKT survival pathway. P-I-3-kinase dependent activation of PDK leads to the activation of AKT which in turn affects the activity or expression of pro-apoptotic factors, which contribute to protection from apoptosis. AKT activation also blocks the activity of GSK-3b which could lead to additional antiapoptotic signals
R-HSA-5654720	PI-3K cascade:FGFR4.	The ability of growth factors to protect from apoptosis is primarily due to the activation of the AKT survival pathway. P-I-3-kinase dependent activation of PDK leads to the activation of AKT which in turn affects the activity or expression of pro-apoptotic factors, which contribute to protection from apoptosis. AKT activation also blocks the activity of GSK-3b which could lead to additional antiapoptotic signals
R-HSA-5655253	Signaling by FGFR2 in disease.	The FGFR2 gene has been shown to be subject to activating mutations and gene amplification leading to a variety of proliferative and developmental disorders depending on whether these events occur in the germline or arise somatically. Activating FGFR2 mutations in the germline give rise to a range of craniosynostotic conditions including Pfeiffer, Apert, Jackson-Weiss, Crouzon and Beare-Stevensen Cutis Gyrata syndromes. These autosomal dominant skeletal disorders are characterized by premature fusion of several sutures in the skull, and in some cases also involve syndactyly (abnormal bone fusions in the hands and feet) (reviewed in Webster and Donoghue, 1997; Burke, 1998; Cunningham, 2007). Activating FGFR2 mutations arising somatically have been linked to the development of gastric and endometrial cancers (reviewed in Greulich and Pollock, 2011; Wesche, 2011). Many of these mutations are similar or identical to those that contribute to the autosomal disorders described above. Notably, loss-of-function mutations in FGFR2 have also been recently described in melanoma (Gartside, 2009). FGFR2 may also contribute to tumorigenesis through overexpression, as FGFR2 has been identified as a target of gene amplification in gastric and breast cancers (Kunii, 2008; Takeda, 2007)
R-HSA-5655291	Signaling by FGFR4 in disease.	FGFR4 is perhaps the least well studied of the FGF receptors, and unlike the case for the other FGFR genes, mutations in FGFR4 are not known to be associated with any developmental disorders. Recently, however, somatically arising mutations in the FGFR4 coding sequence have begun to be identified in some cancers. 8% of rhabdomyosarcomas have activating mutations in the kinase domain of FGFR4. Two of these mutations - N535K (paralogous to the FGFR2 N550K allele found in endometrial cancers) and V550E - have been shown to support the oncogenic transformation of NIH 3T3 cells (Taylor, 2009). An FGFR4 Y367C mutation has also been identified in breast cancers (Ruhe, 2007; Roidl, 2010); mutations of paralogous residues in FGFR2 and FGFR3 are associated with both skeletal dysplasias and the development of diverse cancers (Pollock, 2007; Ruhe, 2007; Rousseau, 1996; Chesi, 1997, 2001).Finally, a SNP at position 388 of FGFR4 is associated with aggressive disease development. Expression of the G388R allele in breast, colorectal and prostate cancers is correlated with rapid progression times and increased rates of recurrence and metastasis (Bange, 2002; Spinola, 2005; Wang, 2004)
R-HSA-5655302	Signaling by FGFR1 in disease.	The FGFR1 gene has been shown to be subject to activating mutations, chromosomal rearrangements and gene amplification leading to a variety of proliferative and developmental disorders depending on whether these events occur in the germline or arise somatically (reviewed in Webster and Donoghue, 1997; Burke, 1998; Cunningham, 2007; Wesche, 2011; Greulich and Pollock, 2011). Activating mutation P252R in FGFR1 is associated with the development of Pfeiffer syndrome, characterized by craniosynostosis (premature fusion of several sutures in the skull) and broadened thumbs and toes (Muenke, 1994; reviewed in Cunningham, 2007). This residue falls in a highly conserved Pro-Ser dipeptide between the second and third Ig domains of the extracellular region of the receptor. The mutation is thought to increase the number of hydrogen bonds formed with the ligand and to thereby increase ligand-binding affinity (Ibrahimi, 2004a). Unlike other FGF receptors, few activating point mutations in the FGFR1 coding sequence have been identified in cancer. Point mutations in the Ig II-III linker analagous to the P252R Pfeiffer syndrome mutation have been identified in lung cancer and melanoma (Ruhe, 2007; Davies, 2005), and two kinase-domain mutations in FGFR1 have been identified in glioblastoma (Rand, 2005, Network TCGA, 2008).In contrast, FGFR1 is a target of chromosomal rearrangements in a number of cancers. FGFR1 has been shown to be recurrently translocated in the 8p11 myeloproliferative syndrome (EMS), a pre-leukemic condition also known as stem cell leukemia/lymphoma (SCLL) that rapidly progresses to leukemia. This translocation fuses the kinase domain of FGFR1 with the dimerization domain of one of 10 identified fusion partners, resulting in the constitutive dimerization and activation of the kinase (reviewed in Jackson, 2010). Amplification of the FGFR1 gene has been implicated as a oncogenic factor in a range of cancers, including breast, ovarian, bladder, lung, oral squamous carcinomas, and rhabdomyosarcoma (reviewed in Turner and Grose, 2010; Wesche, 2011; Greulich and Pollock, 2011), although there are other candidate genes in the amplified region and the definitive role of FGFR1 has not been fully established.More recently, FGFR1 fusion proteins have been identified in a number of cancers; these are thought to undergo constitutive ligand-independent dimerization and activation based on dimerization motifs found in the fusion partners (reviewed in Parker, 2014)
R-HSA-6785807	Interleukin-4 and Interleukin-13 signaling.	Interleukin-4 (IL4) is a principal regulatory cytokine during the immune response, crucially important in allergy and asthma (Nelms et al. 1999). When resting T cells are antigen-activated and expand in response to Interleukin-2 (IL2), they can differentiate as Type 1 (Th1) or Type 2 (Th2) T helper cells. The outcome is influenced by IL4. Th2 cells secrete IL4, which both stimulates Th2 in an autocrine fashion and acts as a potent B cell growth factor to promote humoral immunity (Nelms et al. 1999). Interleukin-13 (IL13) is an immunoregulatory cytokine secreted predominantly by activated Th2 cells. It is a key mediator in the pathogenesis of allergic inflammation. IL13 shares many functional properties with IL4, stemming from the fact that they share a common receptor subunit. IL13 receptors are expressed on human B cells, basophils, eosinophils, mast cells, endothelial cells, fibroblasts, monocytes, macrophages, respiratory epithelial cells, and smooth muscle cells, but unlike IL4, not T cells. Thus IL13 does not appear to be important in the initial differentiation of CD4 T cells into Th2 cells, rather it is important in the effector phase of allergic inflammation (Hershey et al. 2003).\n\nIL4 and IL13 induce “alternative activation” of macrophages, inducing an anti-inflammatory phenotype by signaling through IL4R alpha in a STAT6 dependent manner. This signaling plays an important role in the Th2 response, mediating anti-parasitic effects and aiding wound healing (Gordon & Martinez 2010, Loke et al. 2002)\n\nThere are two types of IL4 receptor complex (Andrews et al. 2006). Type I IL4R (IL4R1) is predominantly expressed on the surface of hematopoietic cells and consists of IL4R and IL2RG, the common gamma chain. Type II IL4R (IL4R2) is predominantly expressed on the surface of nonhematopoietic cells, it consists of IL4R and IL13RA1 and is also the type II receptor for IL13. (Obiri et al. 1995, Aman et al. 1996, Hilton et al. 1996, Miloux et al. 1997, Zhang et al. 1997). The second receptor for IL13 consists of IL4R and Interleukin-13 receptor alpha 2 (IL13RA2), sometimes called Interleukin-13 binding protein (IL13BP). It has a high affinity receptor for IL13 (Kd = 250 pmol/L) but is not sufficient to render cells responsive to IL13, even in the presence of IL4R (Donaldson et al. 1998). It is reported to exist in soluble form (Zhang et al. 1997) and when overexpressed reduces JAK-STAT signaling (Kawakami et al. 2001). It's function may be to prevent IL13 signalling via the functional IL4R:IL13RA1 receptor. IL13RA2 is overexpressed and enhances cell invasion in some human cancers (Joshi & Puri 2012).The first step in the formation of IL4R1 (IL4:IL4R:IL2RB) is the binding of IL4 with IL4R (Hoffman et al. 1995, Shen et al. 1996, Hage et al. 1999). This is also the first step in formation of IL4R2 (IL4:IL4R:IL13RA1). After the initial binding of IL4 and IL4R, IL2RB binds (LaPorte et al. 2008), to form IL4R1. Alternatively, IL13RA1 binds, forming IL4R2. In contrast, the type II IL13 complex (IL13R2) forms with IL13 first binding to IL13RA1 followed by recruitment of IL4R (Wang et al. 2009).Crystal structures of the IL4:IL4R:IL2RG, IL4:IL4R:IL13RA1 and IL13:IL4R:IL13RA1 complexes have been determined (LaPorte et al. 2008). Consistent with these structures, in monocytes IL4R is tyrosine phosphorylated in response to both IL4 and IL13 (Roy et al. 2002, Gordon & Martinez 2010) while IL13RA1 phosphorylation is induced only by IL13 (Roy et al. 2002, LaPorte et al. 2008) and IL2RG phosphorylation is induced only by IL4 (Roy et al. 2002).Both IL4 receptor complexes signal through Jak/STAT cascades. IL4R is constitutively-associated with JAK2 (Roy et al. 2002) and associates with JAK1 following binding of IL4 (Yin et al. 1994) or IL13 (Roy et al. 2002). IL2RG constitutively associates with JAK3 (Boussiotis et al. 1994, Russell et al. 1994). IL13RA1 constitutively associates with TYK2 (Umeshita-Suyama et al. 2000, Roy et al. 2002, LaPorte et al. 2008, Bhattacharjee et al. 2013). IL4 binding to IL4R1 leads to phosphorylation of JAK1 (but not JAK2) and STAT6 activation (Takeda et al. 1994, Ratthe et al. 2007, Bhattacharjee et al. 2013). IL13 binding increases activating tyrosine-99 phosphorylation of IL13RA1 but not that of IL2RG. IL4 binding to IL2RG leads to its tyrosine phosphorylation (Roy et al. 2002). IL13 binding to IL4R2 leads to TYK2 and JAK2 (but not JAK1) phosphorylation (Roy & Cathcart 1998, Roy et al. 2002).Phosphorylated TYK2 binds and phosphorylates STAT6 and possibly STAT1 (Bhattacharjee et al. 2013). A second mechanism of signal transduction activated by IL4 and IL13 leads to the insulin receptor substrate (IRS) family (Kelly-Welch et al. 2003). IL4R1 associates with insulin receptor substrate 2 and activates the PI3K/Akt and Ras/MEK/Erk pathways involved in cell proliferation, survival and translational control. IL4R2 does not associate with insulin receptor substrate 2 and consequently the PI3K/Akt and Ras/MEK/Erk pathways are not activated (Busch-Dienstfertig & González-Rodríguez 2013)
R-HSA-6811558	PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling.	Phosphatidylinositol-5-phosphate (PI5P) may modulate PI3K/AKT signaling in several ways. PI5P is used as a substrate for production of phosphatidylinositol-4,5-bisphosphate, PI(4,5)P2 (Rameh et al. 1997, Clarke et al. 2008, Clarke et al. 2010, Clarke and Irvine 2013, Clarke et al. 2015), which serves as a substrate for activated PI3K, resulting in the production of PIP3 (Mandelker et al. 2009, Burke et al. 2011). The majority of PI(4,5)P2 in the cell, however, is produced from the phosphatidylinositol-4-phosphate (PI4P) substrate (Zhang et al. 1997, Di Paolo et al. 2002, Oude Weernink et al. 2004, Halstead et al. 2006, Oude Weernink et al. 2007). PIP3 is necessary for the activating phosphorylation of AKT. AKT1 can be deactivated by the protein phosphatase 2A (PP2A) complex that contains a regulatory subunit B56-beta (PPP2R5B) or B56-gamma (PPP2R5C). PI5P inhibits AKT1 dephosphorylation by PP2A through an unknown mechanism (Ramel et al. 2009). Increased PI5P levels correlate with inhibitory phosphorylation(s) of the PP2A complex. MAPK1 (ERK2) and MAPK3 (ERK1) are involved in inhibitory phosphorylation of PP2A, in a process that involves IER3 (IEX-1) (Letourneux et al. 2006, Rocher et al. 2007). It is uncertain, however, whether PI5P is in any way involved in ERK-mediated phosphorylation of PP2A or if it regulates another PP2A kinase
R-HSA-8851907	MET activates PI3K/AKT signaling.	MET binds and phosphorylates the adapter protein GAB1, thus creating a docking site for the regulatory subunit PIK3R1 of the PI3K complex. Recruitment of PI3K to MET-bound phosphorylated GAB1 results in PI3K activation, production of PIP3, and stimulation of downstream AKT signaling (Rodrigues et al. 2000, Schaeper et al. 2000)
R-HSA-8853334	Signaling by FGFR3 fusions in cancer.	In recent years, recurrent fusions of FGFR3 have been identified in a number of cancers, including glioblastoma and cancers of the lung and bladder, among others (Singh et al, 2012; Parker et al, 2013; Williams et al, 2013; Wu et al, 2013; Capelletti et al, 2014; Yuan et al, 2014; Wang et al, 2014; Carneiro et al, 2015; reviewed in Parker et al, 2014). The most common fusion partner of FGFR3 is TACC3 (transforming acidic coiled coil protein 3), a protein involved in mitotic spindle assembly and chromosome segregation (Lin et al, 2010; Burgess et al, 2015). FGFR3 fusions are constitutively active and may form oligomers in a ligand-independent manner based on dimerization domains provided by the fusion partner (Singh et al, 2012; Williams et al, 2013; Parker et al, 2013; reviewed in Parker et al, 2014). Transformation and proliferation appear to be promoted through activation of the ERK and AKT signaling pathways. In contrast, PLC gamma signaling is not stimulated downstream of FGFR3 fusions, as the PLC gamma docking site is not present in the fusion. FGFR3 fusions are sensitive to protein kinase inhibitors, suggesting their potential as therapeutic targets (Singh et al, 2012; Williams et al, 2013; Wu et al, 2013; reviewed in Parker et al, 2014)
R-HSA-8853338	Signaling by FGFR3 point mutants in cancer.	The FGFR3 gene has been shown to be subject to activating mutations and gene amplification leading to a variety of proliferative and developmental disorders depending on whether these events occur in the germline or arise somatically. Activating mutations in FGFR3 are associated with the development of a range of skeletal dysplasias that result in dwarfism (reviewed in Webster and Donoghue, 1997; Burke et al, 1998; Harada et al, 2009). The most common form of human dwarfism is achondroplasia (ACH), which is caused by mutations G380R and G375C in the transmembrane domain of FGFR3 that are thought to promote ligand-independent dimerization (Rousseau et al, 1994; Shiang et al, 1994; Bellus et al, 1995a) Hypochondroplasia (HCH) is a milder form dwarfism that is the result of mutations in the tyrosine kinase domain of FGFR3 (Bellus et al, 1995b). Two neonatal lethal conditions, thanatophoric dysplasia type I and II (TDI and TDII) are also the result of mutations in FGFR3; TDI arises from a range of mutations that either result in the formation of unpaired cysteine residues in the extracellular region that promote aberrant ligand-independent dimerization or by mutations that introduce stop codons (Rousseau et al, 1995; Rousseau et al, 1996, D'Avis et al,1998). A single mutation, K650E in the second tyrosine kinase domain of FGFR3 is responsible for all identified cases of TDII (Tavormina et al, 1995a, b). Other missense mutations at the same K650 residue give rise to Severe Achondroplasia with Developmental Disorders and Acanthosis Nigricans (SADDAN) syndrome (Tavormina et al, 1999; Bellus et al, 1999). The severity of the phenotype arising from many of the activating FGFR3 mutations has recently been shown to correlate with the extent to which the mutations activate the receptor (Naski et al, 1996; Bellus et al, 2000) In addition to mutations that cause dwarfism syndromes, a Pro250Arg mutation in the conserved dipeptide between the IgII and IgIII domains has been identified in an atypical craniosynostosis condition (Bellus et al, 1996; Reardon et al, 1997). This mutation, which is paralogous to mutations seen in FGFR1 and 2 in Pfeiffer and Apert Syndrome, respectively, results in an increase in ligand-binding affinity for the receptor (Ibrahimi et al, 2004b).Of all the FGF receptors, FGFR3 has perhaps the best established link to the development in cancer. 50% of bladder cancers have somatic mutations in the coding sequence of FGFR3; of these, more than half occur in the extracellular region at a single position (S249C) (Cappellen et al, 1999; Naski et al, 1996; di Martino et al, 2009, Sibley et al, 2001). Activating mutations are also seen in the juxta- and trans-membrane domains, as well as in the kinase domain (reviewed in Weshe et al, 2011). As is the case for the other receptors, many of the activating mutations that are seen in FGFR3-related cancers mimic the germline FGFR3 mutations that give rise to autosomal skeletal disorders and include both ligand-dependent and independent mechanisms (reviewed in Webster and Donoghue, 1997; Burke et al, 1998). In addition to activating mutations, the FGFR3 gene is subject to a translocation event in 15% of multiple myelomas (Avet-Loiseau et al, 1998; Chesi et al, 1997). This chromosomal rearrangement puts the FGFR3 gene under the control of the highly active IGH promoter and promotes overexpression and constitutive activation of FGFR3. In a small proportion of multiple myelomas, the translocation event is accompanied by activating mutations in the FGFR3 coding sequence (Chesi et al, 1997).More recently, a number of fusion proteins of FGFR3 have been identified in various cancers (Singh et al, 2012; Williams et al, 2013; Parker et al, 2013; Wu et al, 2013; Wang et al, 2014; Yuan et al, 2014; reviewed in Parker et al, 2014). The most common fusion protein is TACC3, a coiled coil protein involved in mitotic spindle assembly. FGFR3 fusion proteins are constitutively active and appear to contribute to proliferation and tumorigenesis through activation of the ERK and AKT signaling pathways (reviewed in Parker et al, 2014)
R-HSA-8853659	RET signaling.	The RET proto-oncogene encodes a receptor tyrosine kinase expressed primarily in urogenital precursor cells, spermatogonocytes, dopaminergic neurons, motor neurons and neural crest progenitors and derived cells. It is essential for kidney genesis, spermatogonial self-renewal and survivial, specification, migration, axonal growth and axon guidance of developing enteric neurons, motor neurons, parasympathetic neurons and somatosensory neurons (Schuchardt et al. 1994, Enomoto et al. 2001, Naughton et al. 2006, Kramer et al. 2006, Luo et al. 2006, 2009). RET was identified as the causative gene for human papillary thyroid carcinoma (Grieco et al. 1990), multiple endocrine neoplasia (MEN) type 2A (Mulligan et al. 1993), type 2B (Hofstra et al. 1994, Carlson et al. 1994), and Hirschsprung's disease (Romeo et al. 1994, Edery et al. 1994). RET contains a cadherin-related motif and a cysteine-rich domain in the extracellular domain (Takahashi et al. 1988). It is the receptor for members of the glial cell-derived neurotrophic factor (GDNF) family of ligands, GDNF (Lin et al. 1993), neurturin (NRTN) (Kotzbauer et al. 1996), artemin (ARTN) (Baloh et al. 1998), and persephin (PSPN) (Milbrandt et al. 1998), which form a family of neurotrophic factors. To stimulate RET, these ligands need a glycosylphosphatidylinositol (GPI)-anchored co-receptor, collectively termed GDNF family receptor-alpha (GFRA) (Treanor et al. 1996, Jing et al. 1996). The four members of this family have different, overlapping ligand preferences. GFRA1, GFRA2, GFRA3, and GFRA4 preferentially bind GDNF, NRTN, ARTN and PSPN, respectively (Jing et al. 1996, 1997, Creedon et al. 1997, Baloh et al. 1997, 1998, Masure et al. 2000). The GFRA co-receptor can come from the same cell as RET, or from a different cell. When the co-receptor is produced by the same cell as RET, it is termed cis signaling. When the co-receptor is produced by another cell, it is termed trans signaling. Cis and trans activation has been proposed to diversify RET signaling, either by recruiting different downstream effectors or by changing the kinetics or efficacy of kinase activation (Tansey et al. 2000, Paratcha et al. 2001). Whether cis and trans signaling has significant differences in vivo is unresolved (Fleming et al. 2015). Different GDNF family members could activate similar downstream signaling pathways since all GFRAs bind to and activate the same tyrosine kinase and induce coordinated phosphorylation of the same four RET tyrosines (Tyr905, Tyr1015, Tyr1062, and Tyr1096) with similar kinetics (Coulpier et al. 2002). However the exact RET signaling pathways in different types of cells and neurons remain to be determined
R-HSA-9028335	Activated NTRK2 signals through PI3K.	Neurotrophin receptor NTRK2 (TRKB), activated by BDNF or NTF4, activates PI3K, resulting in formation of the PIP3 secondary messenger. PIP3 activates AKT signaling, and AKT signaling activates mTOR signaling (Yuen and Mobley 1999, Cao et al. 2013)
R-HSA-912526	Interleukin receptor SHC signaling.	Phosphorylation of Shc at three tyrosine residues, 239, 240 (Gotoh et al. 1996) and 317 (Salcini et al. 1994) involves unidentified tyrosine kinases presumed to be part of the activated receptor complex. These phosphorylated tyrosines subsequently bind SH2 signaling proteins such as Grb2, Gab2 and SHIP that are involved in the regulation of different signaling pathways. Grb2 can associate with the guanosine diphosphate-guanosine triphosphate exchange factor Sos1, leading to Ras activation and regulation of cell proliferation. Downstream signals are mediated via the Raf-MEK-Erk pathway.Grb2 can also associate through Gab2 with PI3K and with SHIP.Figure reproduced from Gu, H. et al. 2000. Mol. Cell. Biol. 20(19):7109-7120Copyright American Society for Microbiology. All Rights Reserved
R-HSA-912631	Regulation of signaling by CBL.	Cbl is an E3 ubiquitin-protein ligase that negatively regulates signaling pathways by targeting proteins for ubiquitination and proteasomal degradation (Rao et al. 2002). Cbl negatively regulates PI3K via this mechanism (Dufour et al. 2008). The binding of Cbl to the p85 subunit of PI3K is mediated at least in part by tyrosine phosphorylation at Y731 (Dufour et al. 2008). Fyn and the related kinases Hck and Lyn are known to be associated with Cbl (Anderson et al. 1997, Hunter et al. 1999). Fyn is proven capable of Cbl Y731 phosphorylation (Hunter et al. 1999).The association of Fyn and Cbl has been described as constitutive (Hunter et al. 1999). CBL further associates with the p85 subunit of PI3K (Hartley et al. 1995, Anderson et al. 1997, Hunter et al. 1997), this also described as constitutive and mediated by the SH3 domain of p85. Binding of the SH2 domain of p85 to a specific phosphorylation site in Cbl is postulated to explain the the increase in Cbl/p85 association seen in activated cells (Panchamoorthy et al 1996) which negatively regulates PI3K activity (Fang et al. 2001). The negative effect of increased Cbl-PI3K interaction is mediated by Y731 of Cbl. Cbl binding increases PI3K ubiquitination and proteasome degradation (Dufour et al. 2008).Cbl is constitutively associated with Grb in resting hematopoietic cells (Anderson et al. 1997, Odai et al. 1995, Park et al. 1998, Panchamoorthy et al. 1996). Both the SH2 and SH3 domains of Grb2 are involved. Cbl has 2 distinct C-terminal domains, proximal and distal. The proximal domain binds Grb2 in resting and stimulated cells, and in stimulated cells also binds Shc. The distal domain binds the adaptor protein CRKL. Tyrosine phosphorylation of Cbl in response to IL-3 releases the SH3 domain of Grb2 which then is free to bind other molecules (Park et al. 1998). Cbl is tyrosine phosphorylated in response to many cytokines including IL-3, IL-2 (Gesbert et al. 1998) and IL-4 (Ueno et al. 1998)
R-HSA-9603381	Activated NTRK3 signals through PI3K.	The PI3K complex, composed of PIK3R1 and PIK3CA, co-immunoprecipitates with NTRK3 (TRKC), activated by NTF3 (NT-3) treatment (Yuen and Mobley 1999). Activation of NTRK3 correlates with activating phosphorylation of AKT, the main mediator of PI3K signaling (Tognon et al. 2001, Jin et al. 2008), and is dependent on PI3K activity (Tognon et al. 2001). NTRK3-mediated activation of PI3K signaling depends on SRC activation and the adaptor protein IRS1, but the exact mechanism is not known (Morrison et al. 2002, Lannon et al. 2004, Jin et al. 2008)
R-HSA-983695	Antigen activates B Cell Receptor (BCR) leading to generation of second messengers.	Mature B cells express IgM and IgD immunoglobulins which are complexed with Ig-alpha (CD79A, MB-1) and Ig-beta (CD79B, B29) to form the B cell receptor (BCR) (Fu et al. 1974, Fu et al. 1975, Kunkel et al. 1975, Van Noesal et al. 1992, Sanchez et al. 1993, reviewed in Brezski and Monroe 2008). Binding of antigen to the immunoglobulin activates phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) in the cytoplasmic tails of Ig-alpha and Ig-beta by Src family tyrosine kinases, including LYN, FYN, and BLK (Nel et al. 1984, Yamanashi et al. 1991, Flaswinkel and Reth 1994, Saouaf et al. 1994, Hata et al. 1994, Saouaf et al. 1995, reviewed in Gauld and Cambier 2004, reviewed in Harwood and Batista 2010). The protein kinase SYK may also be involved in phosphorylating the ITAMs.The protein kinase SYK binds the phosphorylated immunoreceptor tyrosine-activated motifs (ITAMs) on the cytoplasmic tails of Ig-alpha (CD79A, MB-1) and Ig-beta (CD79B, B29) (Wienands et al. 1995, Rowley et al. 1995, Tsang et al. 2008). The binding causes the activation and autophosphorylation of SYK (Law et al. 1994, Irish et al. 2006, Baldock et al. 2008, Tsang et al. 2008, reviewed in Bradshaw 2010).Activated SYK and other kinases phosphorylate BLNK (SLP-65, BASH) and BCAP. LYN and FYN phosphorylate CD19. Phosphorylated BLNK, BCAP, and CD19 serve as scaffolds which recruit effectors to the plasma membrane and assemble large complexes, the signalosomes. BCAP and CD19 recruit phosphoinositol 3-kinase (PI3K). BLNK recruits phospholipase C gamma (predominantly PLC-gamma2 in B cells, Coggeshall et al. 1992), NCK, BAM32, BTK, VAV1, and SHC. The effectors are phosphorylated by SYK and other kinases.Phosphorylated BCAP recruits PI3K, which is phosphorylated by a SYK-dependent mechanism (Kuwahara et al. 1996) and produces phosphatidylinositol-3,4,5-trisphosphate (PIP3). Phosphorylated CD19 likewise recruits PIP3K. PIP3 recruits BAM32 (Marshall et al. 2000) and BTK (de Weers et al. 1994, Baba et al. 2001) to the plasma membrane via their PH domains. PIP3 also recruits and activates PLC-gamma1 and PLC-gamma2 (Bae et al. 1998). BTK binds phosphorylated BLNK via its SH2 domain (Baba et al. 2001). BTK phosphorylates PLC-gamma2 (Rodriguez et al. 2001), which activates phospholipase activity (Carter et al. 1991, Roifman and Wang 1992, Kim et al. 2004, Sekiya et al. 2004). Phosphorylated BLNK recruits PLC-gamma, VAV, GRB2, and NCK (Fu and Chan 1997, Fu et al. 1998, Chiu et al. 2002).PLC-gamma hydrolyzes phosphatidylinositol-4,5-bisphosphate to yield inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (Carter et al. 1991, Kim et al. 2004). IP3 binds receptors on the endoplasmic reticulum and causes release of Ca2+ ions from the ER into the cytosol. The depletion of calcium from the ER in turn activates STIM1 to interact with ORAI and TRPC1 channels (and possibly other TRP channels) in the plasma membrane, resulting in an influx of extracellular calcium ions (Mori et al. 2002, Muik et al. 2008, Luik et al. 2008, Park et al. 2009)

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Interacting partner	Detection method	Interaction type	PubMed IDs	Interaction Score	Source
ABL1	Affinity Capture-MS, Affinity Capture-Western, Reconstituted Complex, peptide array	physical, physical association	16135792, 16219545, 17474147, 19380743, 8294442, (Europe PMC)	0.40	BioGRID, IntAct
ACTA1	Affinity Capture-Western	physical	23353701, (Europe PMC)	NA	BioGRID
ADAM12	Affinity Capture-Western, Reconstituted Complex	physical	11313349, (Europe PMC)	NA	BioGRID
ADAMTS2	Two-hybrid	physical	18624398, (Europe PMC)	NA	BioGRID
AGAP2	Affinity Capture-Western, Reconstituted Complex	physical	11136977, (Europe PMC)	NA	BioGRID
AKT1	Affinity Capture-Western	physical	19117013, (Europe PMC)	NA	BioGRID
ALK	Reconstituted Complex	physical	16135792, (Europe PMC)	NA	BioGRID
ALOX5	Affinity Capture-Western	physical	21200133, (Europe PMC)	NA	BioGRID
APPL1	Affinity Capture-Western, Two-hybrid, two hybrid array, validated two hybrid	physical, physical association	12621049, 25814554, (Europe PMC)	0.49	BioGRID, IntAct
ARAF	Reconstituted Complex, coimmunoprecipitation, phage display, pull down	direct interaction, physical, physical association	10967104, 11812000, (Europe PMC)	0.61	BioGRID, IntAct, MINT
ARHGAP1	Reconstituted Complex	physical	8253717, (Europe PMC)	NA	BioGRID
ARHGAP17	Reconstituted Complex	physical	11431473, (Europe PMC)	NA	BioGRID
ARHGAP32	Affinity Capture-Western	physical	12454018, (Europe PMC)	NA	BioGRID
AXL	Affinity Capture-Western, Biochemical Activity, coimmunoprecipitation, far western blotting	association, physical	18346204, 9178760, (Europe PMC)	0.46	BioGRID, IntAct, MINT
BCAR1	Affinity Capture-Western, Reconstituted Complex	physical	10799562, (Europe PMC)	NA	BioGRID
BCR	Far Western	physical	18346204, (Europe PMC)	NA	BioGRID
BRCA1	Reconstituted Complex, peptide array	physical, physical association	16135792, 17474147, (Europe PMC)	0.40	BioGRID, IntAct
CBL	Affinity Capture-MS, Affinity Capture-Western, Biochemical Activity, Far Western, Reconstituted Complex, Two-hybrid, anti bait coimmunoprecipitation, coimmunoprecipitation, experimental interaction detection, far western blotting, pull down, tandem affinity purification, two hybrid, two hybrid array, validated two hybrid	association, physical, physical association	10025673, 10358153, 10620516, 10918571, 11030146, 11042121, 11087752, 11157475, 11418612, 11944898, 11994282, 14530346, 15107835, 15556646, 15581361, 16135792, 16219545, 16289966, 16982329, 17237826, 18374639, 19190244, 19380743, 19861161, 21203488, 24113870, 25814554, 7642581, 7791764, 8612729, 8621719, 8662998, 8695807, 8702998, 8896416, 8941725, 8995243, 9092538, 9160881, 9174058, 9259313, 9414268, 9461587, 9541596, 9890943, 9890970, 9918857, 9988765, (Europe PMC)	0.49, 0.94	BioGRID, IntAct, MINT
CBLB	Affinity Capture-Western	physical	10022120, 11526404, 19190244, 9614102, (Europe PMC)	NA	BioGRID
CCL14	Two-hybrid, two hybrid array	physical, physical association	21988832, (Europe PMC)	0.37	BioGRID, IntAct
CD244	Affinity Capture-MS	physical	26186194, (Europe PMC)	NA	BioGRID
CD247	Affinity Capture-Western	physical	11526404, (Europe PMC)	NA	BioGRID
CD28	Affinity Capture-Western, Protein-peptide, coimmunoprecipitation, competition binding, pull down	association, physical	10820259, 11526404, 19190244, 7568038, 7584133, 7807015, 8146197, 8183372, 8621607, 9417079, (Europe PMC)	0.89	BioGRID, IntAct, MINT
CD3E	Affinity Capture-Western	physical	19190244, 9312149, (Europe PMC)	NA	BioGRID
CD40	Affinity Capture-Western	physical	21200133, (Europe PMC)	NA	BioGRID
CD7	Affinity Capture-Western, Reconstituted Complex, competition binding	association, physical	12594831, 8918688, (Europe PMC)	0.35	BioGRID, IntAct, MINT
CHAF1A	Affinity Capture-MS, anti tag coimmunoprecipitation, peptide array	association, physical, physical association	17474147, 26496610, (Europe PMC)	0.56	BioGRID, IntAct
CLNK	Two-hybrid, two hybrid array, validated two hybrid	physical, physical association	25814554, (Europe PMC)	0.49	BioGRID, IntAct
CMIP	Affinity Capture-Western, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation	physical, physical association	20018188, (Europe PMC)	0.52	BioGRID, IntAct, MINT
CRK	Affinity Capture-MS, Affinity Capture-Western, Co-localization, Two-hybrid, proximity ligation assay, tandem affinity purification, two hybrid array, validated two hybrid	association, physical, physical association	10962563, 11418612, 19380743, 25241761, 25814554, (Europe PMC)	0.49, 0.56	BioGRID, IntAct
CRKL	Affinity Capture-Western, Reconstituted Complex, anti bait coimmunoprecipitation, proximity ligation assay	physical, physical association	11418612, 16135792, 16982329, 23397142, 9461587, (Europe PMC)	0.59	BioGRID, IntAct, MINT
CSF1R	Affinity Capture-Western, Co-localization, proximity ligation assay	physical, physical association	10025673, 25241761, (Europe PMC)	0.40	BioGRID, IntAct
CSF2RA	Affinity Capture-Western, peptide array	physical, physical association	12538575, 17474147, (Europe PMC)	0.40	BioGRID, IntAct
CTNNB1	Co-localization, Reconstituted Complex, proximity ligation assay	physical, physical association	10477752, 25241761, (Europe PMC)	0.40	BioGRID, IntAct
CUL3	Affinity Capture-MS, Affinity Capture-Western	physical	21145461, 27708159, (Europe PMC)	NA	BioGRID
CXCL2	Two-hybrid	physical	18624398, (Europe PMC)	NA	BioGRID
CYP4A11	Two-hybrid	physical	18624398, (Europe PMC)	NA	BioGRID
DAB2IP	Affinity Capture-Western, Reconstituted Complex	physical	19903888, (Europe PMC)	NA	BioGRID
DEFA5	Affinity Capture-MS	physical	28514442, (Europe PMC)	NA	BioGRID
DLX2	Two-hybrid, two hybrid array	physical, physical association	21988832, (Europe PMC)	0.37	BioGRID, IntAct
DNM2	Affinity Capture-Western	physical	21996738, (Europe PMC)	NA	BioGRID
DOK1	Protein-peptide, Reconstituted Complex	physical	11071635, 22974441, (Europe PMC)	NA	BioGRID
EFNB2	Affinity Capture-MS	physical	26186194, (Europe PMC)	NA	BioGRID
EGFR	Affinity Capture-MS, Affinity Capture-Western, Co-localization, Protein-peptide, coimmunoprecipitation, competition binding, protein array, proximity ligation assay	association, direct interaction, physical, physical association	16273093, 19531499, 21701776, 25241761, 7797556, 8662998, (Europe PMC)	0.78	BioGRID, IntAct, MINT
EP300	Affinity Capture-Western, anti tag coimmunoprecipitation	physical, physical association	21057544, (Europe PMC)	0.40	BioGRID, IntAct
EPHA2	Affinity Capture-Western, Reconstituted Complex, Two-hybrid	physical	7982920, (Europe PMC)	NA	BioGRID
EPN1	Affinity Capture-Western	physical	24113870, (Europe PMC)	NA	BioGRID
EPOR	Affinity Capture-Western, PCA, Reconstituted Complex	physical	15644415, 24113870, 7559499, 9162069, (Europe PMC)	NA	BioGRID
ERBB2	Affinity Capture-Western, Protein-peptide, anti bait coimmunoprecipitation, protein array, pull down	association, direct interaction, physical	16273093, 16843263, 21075308, 9756944, (Europe PMC)	0.69	BioGRID, IntAct, MINT
ERBB3	Affinity Capture-MS, Affinity Capture-Western, Protein-peptide, anti bait coimmunoprecipitation, protein array, tandem affinity purification	association, direct interaction, physical, physical association	10383151, 10572067, 11546794, 11694521, 15812817, 16273093, 18803287, 20007781, 20227043, 21075308, 21278786, 22439932, 24189400, 9130710, 9756944, (Europe PMC)	0.92	BioGRID, IntAct, MINT
ESR1	Affinity Capture-Western, anti bait coimmunoprecipitation, proximity ligation assay	association, physical, physical association	11029009, 11689445, 17043237, 23065768, (Europe PMC)	0.56	BioGRID, IntAct
EZR	Affinity Capture-Western, Reconstituted Complex, pull down	association, physical	10377409, (Europe PMC)	0.35	BioGRID, IntAct, MINT
FAS	Affinity Capture-Western	physical	18328427, (Europe PMC)	NA	BioGRID
FASLG	Co-localization, phage display, proximity ligation assay	direct interaction, physical, physical association	19807924, 25241761, (Europe PMC)	0.61	BioGRID, IntAct
FBXL2	Affinity Capture-Western	physical	23604317, (Europe PMC)	NA	BioGRID
FCGR2A	Affinity Capture-Western, Reconstituted Complex	physical	8631888, 9268059, (Europe PMC)	NA	BioGRID
FER	Two-hybrid, two hybrid array	physical, physical association	25814554, (Europe PMC)	0.37	BioGRID, IntAct
FES	Affinity Capture-Western	physical	8916957, (Europe PMC)	NA	BioGRID
FGFR1	Co-localization, Reconstituted Complex, Two-hybrid, coimmunoprecipitation, proximity ligation assay, pull down	association, physical, physical association	15117958, 18412956, 25241761, 8321198, (Europe PMC)	0.62	BioGRID, IntAct, MINT
FGFR2	Affinity Capture-Western	physical	18374639, (Europe PMC)	NA	BioGRID
FLRT1	Affinity Capture-MS	physical	28514442, (Europe PMC)	NA	BioGRID
FLT1	Affinity Capture-Western, coimmunoprecipitation, proximity ligation assay	association, physical, physical association	20805333, 23397142, 7657594, (Europe PMC)	0.56	BioGRID, IntAct, MINT
FLT3	Affinity Capture-Western, anti bait coimmunoprecipitation	physical, physical association	16982329, (Europe PMC)	0.40	BioGRID, IntAct, MINT
FYN	Reconstituted Complex, mammalian protein protein interaction trap	physical, physical association	25416956, 8294442, (Europe PMC)	0.37	BioGRID, IntAct
GAB1	Affinity Capture-Western, Far Western, Reconstituted Complex, Two-hybrid, coimmunoprecipitation, fluorescence polarization spectroscopy, pull down, two hybrid	association, direct interaction, physical, physical association	10978177, 16638574, 23612964, 24728074, 8596638, 9658397, 9804835, 9891995, (Europe PMC)	0.80	BioGRID, IntAct, MINT
GAB2	Affinity Capture-Western, Reconstituted Complex, Two-hybrid, anti tag coimmunoprecipitation, pull down	association, physical, physical association	10871282, 11334882, 11782427, 14530346, 16135792, 16219545, 16253990, (Europe PMC)	0.56	BioGRID, IntAct, MINT
GNAQ	Affinity Capture-Western	physical	12704201, (Europe PMC)	NA	BioGRID
GNB1	Affinity Capture-Western	physical	19117013, (Europe PMC)	NA	BioGRID
GRB10	Affinity Capture-Western, anti bait coimmunoprecipitation	physical, physical association	12783867, 23246379, (Europe PMC)	0.40	BioGRID, IntAct, MINT
GRB2	Affinity Capture-MS, Affinity Capture-Western, Reconstituted Complex, Two-hybrid, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, mammalian protein protein interaction trap, pull down, tandem affinity purification, two hybrid pooling approach	association, physical, physical association	11418612, 16219545, 18346204, 19380743, 20936779, 21706016, 25416956, 7642581, 7737969, 7759531, 9174058, 9541596, 9886492, (Europe PMC)	0.86	BioGRID, IntAct, MINT
GSPT1	Two-hybrid, two hybrid array	physical, physical association	21988832, (Europe PMC)	0.37	BioGRID, IntAct
HAVCR2	Affinity Capture-MS, anti bait coimmunoprecipitation, pull down	association, physical	26492563, 28514442, (Europe PMC)	0.46	BioGRID, IntAct
HCST	Protein-peptide	physical	10426994, (Europe PMC)	NA	BioGRID
HDAC3	Affinity Capture-Western	physical	22027828, (Europe PMC)	NA	BioGRID
HOXA1	Two-hybrid, two hybrid array	physical, physical association	21988832, (Europe PMC)	0.37	BioGRID, IntAct
HRAS	Affinity Capture-Western, Co-localization, Reconstituted Complex, proximity ligation assay	physical, physical association	10212255, 25241761, 9150145, (Europe PMC)	0.40	BioGRID, IntAct
HTT	Two-hybrid, two hybrid, two hybrid prey pooling approach	physical, physical association	17500595, 23275563, (Europe PMC)	0.55	BioGRID, IntAct
IFNAR1	Affinity Capture-Western	physical	10542297, (Europe PMC)	NA	BioGRID
IGF1R	Co-localization, coimmunoprecipitation, proximity ligation assay, pull down, two hybrid	association, physical, physical association	25241761, 7589433, 7642582, 8603569, (Europe PMC)	0.75	BioGRID, IntAct, MINT
IL1R1	Affinity Capture-Western	physical	9360994, (Europe PMC)	NA	BioGRID
IL20RA	Affinity Capture-MS	physical	28514442, (Europe PMC)	NA	BioGRID
IL6ST	Affinity Capture-Western	physical	10579793, (Europe PMC)	NA	BioGRID
INPP5D	Affinity Capture-Western	physical	9918857, (Europe PMC)	NA	BioGRID
INPPL1	Affinity Capture-MS, tandem affinity purification	association, physical	19380743, (Europe PMC)	0.35	BioGRID, IntAct
IRS1	Affinity Capture-Luminescence, Affinity Capture-Western, Far Western, Protein-peptide, Two-hybrid, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, coimmunoprecipitation, cross-linking study, enzymatic study, luminescence based mammalian interactome mapping, nuclear magnetic resonance, pull down, surface plasmon resonance, two hybrid, two hybrid array, validated two hybrid	association, physical, physical association	11403293, 11416002, 12107746, 12173038, 12730242, 1381348, 14511371, 14632132, 15514089, 16150444, 16230374, 16354680, 17640984, 19561084, 22974441, 23439647, 23643389, 25814554, 7680095, 7680644, 8175658, 8382612, 8628286, 9564850, (Europe PMC)	0.57, 0.92	BioGRID, IntAct, MINT
IRS2	Affinity Capture-MS, Affinity Capture-Western, Far Western, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation	association, physical, physical association	12107746, 15514089, 19561084, 21241768, 23439647, 23617393, 26496610, 8910607, 9334184, 9852124, (Europe PMC)	0.69	BioGRID, IntAct, MINT
IRS4	Affinity Capture-Luminescence, Affinity Capture-MS, anti tag coimmunoprecipitation	association, physical	25036637, (Europe PMC)	0.35	BioGRID, IntAct
ITSN1	Two-hybrid	physical	22558309, (Europe PMC)	NA	BioGRID
JAK2	Negative Genetic, Reconstituted Complex, peptide array	genetic, physical, physical association	16135792, 17474147, 28319113, (Europe PMC)	0.40	BioGRID, IntAct
KBTBD2	Affinity Capture-Western, Reconstituted Complex	physical	27708159, (Europe PMC)	NA	BioGRID
KHDRBS1	Affinity Capture-Western, FRET, Protein-peptide, Reconstituted Complex	physical	10467411, 11604231, 22745667, 8175658, (Europe PMC)	NA	BioGRID
KIT	Affinity Capture-Western, Co-localization, Reconstituted Complex, Two-hybrid, coimmunoprecipitation, fluorescence polarization spectroscopy, proximity ligation assay	association, direct interaction, physical, physical association	10022833, 11071635, 1382595, 17452978, 24728074, 25241761, 7509796, 7537096, 9233773, (Europe PMC)	0.77	BioGRID, IntAct, MINT
LAT	Affinity Capture-Western, Reconstituted Complex, coimmunoprecipitation, pull down	association, physical	10811803, 11368773, (Europe PMC)	0.46	BioGRID, IntAct, MINT
LCK	Reconstituted Complex, pull down	physical, physical association	8246987, 8294442, (Europe PMC)	0.40	BioGRID, IntAct, MINT
LCP2	Affinity Capture-Western, Two-hybrid, pull down	physical, physical association	15388330, 15929943, (Europe PMC)	0.40	BioGRID, IntAct, MINT
LTK	Affinity Capture-Western, coimmunoprecipitation	association, physical	8084603, 9223670, (Europe PMC)	0.35	BioGRID, IntAct, MINT
MAP3K5	Affinity Capture-Western	physical	19903888, (Europe PMC)	NA	BioGRID
MAPT	Affinity Capture-Western, Reconstituted Complex	physical	19681044, (Europe PMC)	NA	BioGRID
MED28	Affinity Capture-Western, peptide array	physical, physical association	16964398, (Europe PMC)	0.40	BioGRID, IntAct, MINT
MYO16	Reconstituted Complex	physical	21946561, (Europe PMC)	NA	BioGRID
NCK1	Affinity Capture-Western	physical	11418612, (Europe PMC)	NA	BioGRID
NCL	Affinity Capture-Western	physical	16571724, (Europe PMC)	NA	BioGRID
NFKBIA	Reconstituted Complex, coimmunoprecipitation, competition binding	association, physical	9892650, (Europe PMC)	0.46	BioGRID, IntAct, MINT
NISCH	Affinity Capture-MS, inference by socio-affinity scoring	physical, physical association	27173435, (Europe PMC)	0.27	BioGRID, IntAct
NLGN3	Affinity Capture-MS	physical	28514442, (Europe PMC)	NA	BioGRID
NPM1	Affinity Capture-MS	physical	14968112, (Europe PMC)	NA	BioGRID
NTRK1	Affinity Capture-MS, coimmunoprecipitation, competition binding	association, physical	25921289, 8226808, (Europe PMC)	0.46	BioGRID, IntAct, MINT
NTRK2	Two-hybrid	physical	12074588, (Europe PMC)	NA	BioGRID
NYAP1	Reconstituted Complex	physical	21946561, (Europe PMC)	NA	BioGRID
NYAP2	Affinity Capture-MS, Reconstituted Complex, anti tag coimmunoprecipitation	association, physical	21946561, 26496610, (Europe PMC)	0.35	BioGRID, IntAct
PCBP1	Affinity Capture-MS	physical	26186194, 28514442, (Europe PMC)	NA	BioGRID
PDE4D	Far Western	physical	10571082, (Europe PMC)	NA	BioGRID
PDGFRA	Affinity Capture-Western, Co-localization, proximity ligation assay	physical, physical association	17452978, 25241761, (Europe PMC)	0.40	BioGRID, IntAct
PDGFRB	Affinity Capture-MS, Affinity Capture-Western, Reconstituted Complex, biophysical, circular dichroism, classical fluorescence spectroscopy, coimmunoprecipitation, cross-linking study, isothermal titration calorimetry, nuclear magnetic resonance, proximity ligation assay, pull down, surface plasmon resonance, two hybrid	association, physical, physical association	10697503, 10752619, 11710529, 11896612, 1314164, 1330535, 15377662, 16135792, 19864249, 28514442, 7536927, 7680644, 7692233, 8382612, 8564419, 8670861, 9153411, (Europe PMC)	0.95	BioGRID, IntAct, MINT
PECAM1	Affinity Capture-Western	physical	9774384, (Europe PMC)	NA	BioGRID
PIK3CA	Affinity Capture-MS, Affinity Capture-Western, Reconstituted Complex, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, phosphotransferase assay, pull down, x-ray crystallography	association, direct interaction, phosphorylation reaction, physical, physical association	11526404, 15377662, 16043515, 16135792, 19117013, 19574958, 19805105, 20018188, 20713702, 22402981, 23643389, 25253337, 26496610, 7929193, (Europe PMC)	0.96	BioGRID, IntAct, MINT
PIK3CB	Affinity Capture-MS, Affinity Capture-Western, Co-fractionation, Co-localization, anti tag coimmunoprecipitation, barcode fusion genetics two hybrid, proximity ligation assay, two hybrid, validated two hybrid	association, physical, physical association	20713702, 22939629, 25241761, 26344197, 26496610, 27107012, 8139559, (Europe PMC)	0.56, 0.69	BioGRID, IntAct
PIK3CD	Affinity Capture-MS, Affinity Capture-Western, Reconstituted Complex, anti bait coimmunoprecipitation, confocal microscopy, mass spectrometry study of hydrogen/deuterium exchange, molecular sieving, protein kinase assay, pull down, two hybrid array, two hybrid prey pooling approach	colocalization, direct interaction, physical, physical association	21827948, 22020336, 26496610, 9113989, (Europe PMC)	0.46, 0.49, 0.74	BioGRID, IntAct
PIK3R1	Reconstituted Complex, coimmunoprecipitation	association, physical	11337495, 8294442, (Europe PMC)	0.35	BioGRID, IntAct, MINT
PIK3R2	Affinity Capture-MS	physical	19380743, 26186194, 28514442, (Europe PMC)	NA	BioGRID
PIK3R3	Affinity Capture-MS	physical	28514442, (Europe PMC)	NA	BioGRID
PLCG2	Co-localization, peptide array, proximity ligation assay	physical, physical association	17474147, 25241761, (Europe PMC)	0.59	BioGRID, IntAct
PRMT2	Affinity Capture-MS	physical	26186194, (Europe PMC)	NA	BioGRID
PROM1	Affinity Capture-Western, Reconstituted Complex	physical	23569237, (Europe PMC)	NA	BioGRID
PTGER3	Affinity Capture-MS	physical	26186194, (Europe PMC)	NA	BioGRID
PTK2	Affinity Capture-Western, Far Western	physical	10973983, 11119718, 19889638, 7537275, (Europe PMC)	NA	BioGRID
PTPN11	Affinity Capture-Western	physical	10962556, 11593409, 16371368, 9361008, 9886492, 9918857, (Europe PMC)	NA	BioGRID
PTPN6	Two-hybrid, coimmunoprecipitation, pull down	association, physical	10488096, 11160222, (Europe PMC)	0.46	BioGRID, IntAct, MINT
PTPRK	Proximity Label-MS	physical	27880917, (Europe PMC)	NA	BioGRID
PTTG1	Affinity Capture-Western	physical	15845362, (Europe PMC)	NA	BioGRID
PXK	Affinity Capture-Western	physical	20086096, (Europe PMC)	NA	BioGRID
PXN	Co-localization, proximity ligation assay	physical, physical association	23397142, 25241761, (Europe PMC)	0.59	BioGRID, IntAct
RAB5A	Affinity Capture-Western	physical	15377662, (Europe PMC)	NA	BioGRID
RASD2	Affinity Capture-Western, Reconstituted Complex	physical	22683505, (Europe PMC)	NA	BioGRID
RET	Reconstituted Complex	physical	10995764, (Europe PMC)	NA	BioGRID
RNF19B	Affinity Capture-MS	physical	28514442, (Europe PMC)	NA	BioGRID
RRAS2	Affinity Capture-Western	physical	11850823, (Europe PMC)	NA	BioGRID
RXRA	Affinity Capture-Western, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, confocal microscopy	colocalization, physical, physical association	20541701, (Europe PMC)	0.56	BioGRID, IntAct
SELPLG	Affinity Capture-Western	physical	17632516, (Europe PMC)	NA	BioGRID
SH2D2A	Affinity Capture-Luminescence, Two-hybrid, luminescence based mammalian interactome mapping, two hybrid array, validated two hybrid	physical, physical association	25814554, (Europe PMC)	0.57	BioGRID, IntAct
SH3KBP1	Affinity Capture-Western, Reconstituted Complex, Two-hybrid, peptide array	physical, physical association	10921882, 15476827, 17474147, 20457601, (Europe PMC)	0.40	BioGRID, IntAct
SHB	Affinity Capture-Western, Reconstituted Complex	physical	7537362, (Europe PMC)	NA	BioGRID
SHC1	Affinity Capture-MS, Affinity Capture-Western, Reconstituted Complex, coimmunoprecipitation, proximity ligation assay, pull down, tandem affinity purification	association, physical, physical association	16135792, 16219545, 19380743, 19889638, 23397142, 7537361, 8621719, 8662998, 9541596, (Europe PMC)	0.83	BioGRID, IntAct, MINT
SIRT1	Affinity Capture-Western, anti bait coimmunoprecipitation	physical, physical association	21241768, (Europe PMC)	0.40	BioGRID, IntAct
SNX32	Affinity Capture-MS	physical	28514442, (Europe PMC)	NA	BioGRID
SOCS1	Two-hybrid, two hybrid array, validated two hybrid	physical, physical association	25814554, (Europe PMC)	0.49	BioGRID, IntAct
SOCS6	Affinity Capture-MS	physical	12052866, (Europe PMC)	NA	BioGRID
SOS1	Co-localization, peptide array, proximity ligation assay	physical, physical association	17474147, 25241761, (Europe PMC)	0.59	BioGRID, IntAct
SQSTM1	Affinity Capture-Western, Far Western	physical	9564850, (Europe PMC)	NA	BioGRID
SRC	Affinity Capture-Western, Co-localization, anti bait coimmunoprecipitation, proximity ligation assay	association, physical, physical association	10487518, 19861161, 19903481, 23065768, 23397142, 24498420, 25241761, (Europe PMC)	0.82	BioGRID, IntAct, MINT
STAT3	Two-hybrid	physical	25814554, (Europe PMC)	NA	BioGRID
SYK	Affinity Capture-Western, Reconstituted Complex, Two-hybrid, anti bait coimmunoprecipitation, pull down, two hybrid	physical, physical association	15536084, 16921024, (Europe PMC)	0.58	BioGRID, IntAct, MINT
SYN1	Affinity Capture-Western	physical	10899172, (Europe PMC)	NA	BioGRID
SYNM	Affinity Capture-Western	physical	17437541, (Europe PMC)	NA	BioGRID
TGFBR1	Affinity Capture-Western	physical	9435577, (Europe PMC)	NA	BioGRID
TGFBR2	Affinity Capture-MS, Affinity Capture-Western	physical	26186194, 28514442, 9435577, (Europe PMC)	NA	BioGRID
TLR3	Affinity Capture-Western, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation	physical, physical association	15502848, 16858407, (Europe PMC)	0.52	BioGRID, IntAct, MINT
TMEM17	Proximity Label-MS, proximity-dependent biotin identification	association, physical	26638075, (Europe PMC)	0.35	BioGRID, IntAct
TNFRSF1A	Affinity Capture-Western	physical	18606683, (Europe PMC)	NA	BioGRID
TNIP1	Affinity Capture-Western	physical	17632516, (Europe PMC)	NA	BioGRID
TNS4	Two-hybrid, two hybrid array, validated two hybrid	physical, physical association	25814554, (Europe PMC)	0.49	BioGRID, IntAct
TTR	Two-hybrid	physical	18624398, (Europe PMC)	NA	BioGRID
TUBA1B	Affinity Capture-Western, Reconstituted Complex	physical	7592789, (Europe PMC)	NA	BioGRID
TYRO3	Affinity Capture-Western, Two-hybrid	physical	10627473, (Europe PMC)	NA	BioGRID
VAV1	Affinity Capture-Western, Reconstituted Complex, pull down	association, physical	17050525, 9162069, 9891995, (Europe PMC)	0.35	BioGRID, IntAct, MINT
VHL	Negative Genetic	genetic	28319113, (Europe PMC)	NA	BioGRID
VSIG4	Affinity Capture-MS	physical	26186194, 28514442, (Europe PMC)	NA	BioGRID
WAS	Affinity Capture-Western, Reconstituted Complex	physical	8805332, (Europe PMC)	NA	BioGRID
WDR26	Affinity Capture-Western	physical	26895380, (Europe PMC)	NA	BioGRID
WEE1	Negative Genetic	genetic	28319113, (Europe PMC)	NA	BioGRID
YWHAG	Affinity Capture-MS, anti bait coimmunoprecipitation, coimmunoprecipitation	physical, physical association	15324660, 17353931, (Europe PMC)	0.59	BioGRID, IntAct, MINT
ZAP70	Affinity Capture-Western	physical	15536084, (Europe PMC)	NA	BioGRID
ZDHHC17	Affinity Capture-Western, Two-hybrid	physical	24705354, (Europe PMC)	NA	BioGRID

Visualize Download

Interacting partner	Detection method	Interaction type	PubMed IDs	Interaction Score	Source
ABI1	array technology	direct interaction	20598684, (Europe PMC)	0.44	IntAct, MINT
ABL1	Affinity Capture-MS, Affinity Capture-Western, Reconstituted Complex, peptide array	physical, physical association	16135792, 16219545, 17474147, 19380743, 8294442, (Europe PMC)	0.40	BioGRID, IntAct
ABL2	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
AIRE	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
AKAP2	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
AKAP6	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
ALS2CR12	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
APOL5	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
APPL1	Affinity Capture-Western, Two-hybrid, two hybrid array, validated two hybrid	physical, physical association	12621049, 25814554, (Europe PMC)	0.49	BioGRID, IntAct
AR	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
ARAF	Reconstituted Complex, coimmunoprecipitation, phage display, pull down	direct interaction, physical, physical association	10967104, 11812000, (Europe PMC)	0.61	BioGRID, IntAct, MINT
ARHGEF11	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
ASAP1	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
ASAP2	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
AXL	Affinity Capture-Western, Biochemical Activity, coimmunoprecipitation, far western blotting	association, physical	18346204, 9178760, (Europe PMC)	0.46	BioGRID, IntAct, MINT
BICRA	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
BRCA1	Reconstituted Complex, peptide array	physical, physical association	16135792, 17474147, (Europe PMC)	0.40	BioGRID, IntAct
BRD4	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
BRPF3	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
CAST	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
CBL	Affinity Capture-MS, Affinity Capture-Western, Biochemical Activity, Far Western, Reconstituted Complex, Two-hybrid, anti bait coimmunoprecipitation, coimmunoprecipitation, experimental interaction detection, far western blotting, pull down, tandem affinity purification, two hybrid, two hybrid array, validated two hybrid	association, physical, physical association	10025673, 10358153, 10620516, 10918571, 11030146, 11042121, 11087752, 11157475, 11418612, 11944898, 11994282, 14530346, 15107835, 15556646, 15581361, 16135792, 16219545, 16289966, 16982329, 17237826, 18374639, 19190244, 19380743, 19861161, 21203488, 24113870, 25814554, 7642581, 7791764, 8612729, 8621719, 8662998, 8695807, 8702998, 8896416, 8941725, 8995243, 9092538, 9160881, 9174058, 9259313, 9414268, 9461587, 9541596, 9890943, 9890970, 9918857, 9988765, (Europe PMC)	0.49, 0.94	BioGRID, IntAct, MINT
CCL14	Two-hybrid, two hybrid array	physical, physical association	21988832, (Europe PMC)	0.37	BioGRID, IntAct
CD19	coimmunoprecipitation	association	7684160, (Europe PMC)	0.35	IntAct, MINT
CD22	coimmunoprecipitation	association	8647200, (Europe PMC)	0.35	IntAct
CD28	Affinity Capture-Western, Protein-peptide, coimmunoprecipitation, competition binding, pull down	association, physical	10820259, 11526404, 19190244, 7568038, 7584133, 7807015, 8146197, 8183372, 8621607, 9417079, (Europe PMC)	0.89	BioGRID, IntAct, MINT
CD5	pull down, surface plasmon resonance	association	9079809, (Europe PMC)	0.46	IntAct, MINT
CD7	Affinity Capture-Western, Reconstituted Complex, competition binding	association, physical	12594831, 8918688, (Europe PMC)	0.35	BioGRID, IntAct, MINT
CDC27	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
CDC42	anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, coimmunoprecipitation, experimental interaction detection, pull down	association, direct interaction, physical association	25284480, 7629060, 8034624, (Europe PMC)	0.79	IntAct, MINT
CHAF1A	Affinity Capture-MS, anti tag coimmunoprecipitation, peptide array	association, physical, physical association	17474147, 26496610, (Europe PMC)	0.56	BioGRID, IntAct
CKAP5	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
CLNK	Two-hybrid, two hybrid array, validated two hybrid	physical, physical association	25814554, (Europe PMC)	0.49	BioGRID, IntAct
CMIP	Affinity Capture-Western, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation	physical, physical association	20018188, (Europe PMC)	0.52	BioGRID, IntAct, MINT
CRK	Affinity Capture-MS, Affinity Capture-Western, Co-localization, Two-hybrid, proximity ligation assay, tandem affinity purification, two hybrid array, validated two hybrid	association, physical, physical association	10962563, 11418612, 19380743, 25241761, 25814554, (Europe PMC)	0.49, 0.56	BioGRID, IntAct
CRKL	Affinity Capture-Western, Reconstituted Complex, anti bait coimmunoprecipitation, proximity ligation assay	physical, physical association	11418612, 16135792, 16982329, 23397142, 9461587, (Europe PMC)	0.59	BioGRID, IntAct, MINT
CSDC2	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
CSDE1	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
CSF1R	Affinity Capture-Western, Co-localization, proximity ligation assay	physical, physical association	10025673, 25241761, (Europe PMC)	0.40	BioGRID, IntAct
CSF2RA	Affinity Capture-Western, peptide array	physical, physical association	12538575, 17474147, (Europe PMC)	0.40	BioGRID, IntAct
CSF2RB	anti bait coimmunoprecipitation, pull down	association	16437163, (Europe PMC)	0.46	IntAct, MINT
CTLA4	coimmunoprecipitation, pull down	association	7807015, 9398332, 9813138, (Europe PMC)	0.64	IntAct, MINT
CTNNB1	Co-localization, Reconstituted Complex, proximity ligation assay	physical, physical association	10477752, 25241761, (Europe PMC)	0.40	BioGRID, IntAct
DAB2	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
DAG1	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
DARS	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
DLG1	anti bait coimmunoprecipitation	association	25253337, (Europe PMC)	0.35	IntAct
DLGAP1	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
DLGAP2	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
DLGAP3	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
DLGAP4	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
DLX2	Two-hybrid, two hybrid array	physical, physical association	21988832, (Europe PMC)	0.37	BioGRID, IntAct
DLX4	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
DOCK3	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
DTNBP1	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
DUSP15	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
ECT2	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
EEF1D	display technology	physical association	20195357, (Europe PMC)	0.40	IntAct
EFS	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
EGFR	Affinity Capture-MS, Affinity Capture-Western, Co-localization, Protein-peptide, coimmunoprecipitation, competition binding, protein array, proximity ligation assay	association, direct interaction, physical, physical association	16273093, 19531499, 21701776, 25241761, 7797556, 8662998, (Europe PMC)	0.78	BioGRID, IntAct, MINT
ELK3	mammalian protein protein interaction trap, peptide array	physical association	17474147, 25416956, (Europe PMC)	0.57	IntAct
EP300	Affinity Capture-Western, anti tag coimmunoprecipitation	physical, physical association	21057544, (Europe PMC)	0.40	BioGRID, IntAct
EPX	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
ERBB2	Affinity Capture-Western, Protein-peptide, anti bait coimmunoprecipitation, protein array, pull down	association, direct interaction, physical	16273093, 16843263, 21075308, 9756944, (Europe PMC)	0.69	BioGRID, IntAct, MINT
ERBB3	Affinity Capture-MS, Affinity Capture-Western, Protein-peptide, anti bait coimmunoprecipitation, protein array, tandem affinity purification	association, direct interaction, physical, physical association	10383151, 10572067, 11546794, 11694521, 15812817, 16273093, 18803287, 20007781, 20227043, 21075308, 21278786, 22439932, 24189400, 9130710, 9756944, (Europe PMC)	0.92	BioGRID, IntAct, MINT
ESR1	Affinity Capture-Western, anti bait coimmunoprecipitation, proximity ligation assay	association, physical, physical association	11029009, 11689445, 17043237, 23065768, (Europe PMC)	0.56	BioGRID, IntAct
EXTL3	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
EZR	Affinity Capture-Western, Reconstituted Complex, pull down	association, physical	10377409, (Europe PMC)	0.35	BioGRID, IntAct, MINT
FANCA	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
FASLG	Co-localization, phage display, proximity ligation assay	direct interaction, physical, physical association	19807924, 25241761, (Europe PMC)	0.61	BioGRID, IntAct
FER	Two-hybrid, two hybrid array	physical, physical association	25814554, (Europe PMC)	0.37	BioGRID, IntAct
FGFR1	Co-localization, Reconstituted Complex, Two-hybrid, coimmunoprecipitation, proximity ligation assay, pull down	association, physical, physical association	15117958, 18412956, 25241761, 8321198, (Europe PMC)	0.62	BioGRID, IntAct, MINT
FLNA	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
FLNB	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
FLNC	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
FLT1	Affinity Capture-Western, coimmunoprecipitation, proximity ligation assay	association, physical, physical association	20805333, 23397142, 7657594, (Europe PMC)	0.56	BioGRID, IntAct, MINT
FLT3	Affinity Capture-Western, anti bait coimmunoprecipitation	physical, physical association	16982329, (Europe PMC)	0.40	BioGRID, IntAct, MINT
FOXH1	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
FYB1	pull down	association	22074159, (Europe PMC)	0.35	IntAct
FYN	Reconstituted Complex, mammalian protein protein interaction trap	physical, physical association	25416956, 8294442, (Europe PMC)	0.37	BioGRID, IntAct
GAB1	Affinity Capture-Western, Far Western, Reconstituted Complex, Two-hybrid, coimmunoprecipitation, fluorescence polarization spectroscopy, pull down, two hybrid	association, direct interaction, physical, physical association	10978177, 16638574, 23612964, 24728074, 8596638, 9658397, 9804835, 9891995, (Europe PMC)	0.80	BioGRID, IntAct, MINT
GAB2	Affinity Capture-Western, Reconstituted Complex, Two-hybrid, anti tag coimmunoprecipitation, pull down	association, physical, physical association	10871282, 11334882, 11782427, 14530346, 16135792, 16219545, 16253990, (Europe PMC)	0.56	BioGRID, IntAct, MINT
GABBR1	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
GABRA3	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
GHR	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
GRB10	Affinity Capture-Western, anti bait coimmunoprecipitation	physical, physical association	12783867, 23246379, (Europe PMC)	0.40	BioGRID, IntAct, MINT
GRB2	Affinity Capture-MS, Affinity Capture-Western, Reconstituted Complex, Two-hybrid, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, mammalian protein protein interaction trap, pull down, tandem affinity purification, two hybrid pooling approach	association, physical, physical association	11418612, 16219545, 18346204, 19380743, 20936779, 21706016, 25416956, 7642581, 7737969, 7759531, 9174058, 9541596, 9886492, (Europe PMC)	0.86	BioGRID, IntAct, MINT
GSPT1	Two-hybrid, two hybrid array	physical, physical association	21988832, (Europe PMC)	0.37	BioGRID, IntAct
HAVCR2	Affinity Capture-MS, anti bait coimmunoprecipitation, pull down	association, physical	26492563, 28514442, (Europe PMC)	0.46	BioGRID, IntAct
HCK	pull down	physical association	12029088, (Europe PMC)	0.40	IntAct, MINT
HOXA1	Two-hybrid, two hybrid array	physical, physical association	21988832, (Europe PMC)	0.37	BioGRID, IntAct
HRAS	Affinity Capture-Western, Co-localization, Reconstituted Complex, proximity ligation assay	physical, physical association	10212255, 25241761, 9150145, (Europe PMC)	0.40	BioGRID, IntAct
HSCB	anti bait coimmunoprecipitation	association	28380382, (Europe PMC)	0.35	IntAct
HSPA8	proximity-dependent biotin identification	association	29568061, (Europe PMC)	0.35	IntAct
HTT	Two-hybrid, two hybrid, two hybrid prey pooling approach	physical, physical association	17500595, 23275563, (Europe PMC)	0.55	BioGRID, IntAct
ICOS	anti bait coimmunoprecipitation	association, physical association	27135603, (Europe PMC)	0.50	IntAct
ID4	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
IGF1R	Co-localization, coimmunoprecipitation, proximity ligation assay, pull down, two hybrid	association, physical, physical association	25241761, 7589433, 7642582, 8603569, (Europe PMC)	0.75	BioGRID, IntAct, MINT
IKZF3	barcode fusion genetics two hybrid, validated two hybrid	physical association	27107012, (Europe PMC)	0.49	IntAct
INPPL1	Affinity Capture-MS, tandem affinity purification	association, physical	19380743, (Europe PMC)	0.35	BioGRID, IntAct
INSR	fluorescent resonance energy transfer, pull down	association, physical association	10500481, 11796522, 9593725, (Europe PMC)	0.69	IntAct, MINT
IRS1	Affinity Capture-Luminescence, Affinity Capture-Western, Far Western, Protein-peptide, Two-hybrid, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, coimmunoprecipitation, cross-linking study, enzymatic study, luminescence based mammalian interactome mapping, nuclear magnetic resonance, pull down, surface plasmon resonance, two hybrid, two hybrid array, validated two hybrid	association, physical, physical association	11403293, 11416002, 12107746, 12173038, 12730242, 1381348, 14511371, 14632132, 15514089, 16150444, 16230374, 16354680, 17640984, 19561084, 22974441, 23439647, 23643389, 25814554, 7680095, 7680644, 8175658, 8382612, 8628286, 9564850, (Europe PMC)	0.57, 0.92	BioGRID, IntAct, MINT
IRS2	Affinity Capture-MS, Affinity Capture-Western, Far Western, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation	association, physical, physical association	12107746, 15514089, 19561084, 21241768, 23439647, 23617393, 26496610, 8910607, 9334184, 9852124, (Europe PMC)	0.69	BioGRID, IntAct, MINT
IRS4	Affinity Capture-Luminescence, Affinity Capture-MS, anti tag coimmunoprecipitation	association, physical	25036637, (Europe PMC)	0.35	BioGRID, IntAct
JAK2	Negative Genetic, Reconstituted Complex, peptide array	genetic, physical, physical association	16135792, 17474147, 28319113, (Europe PMC)	0.40	BioGRID, IntAct
JMJD6	anti bait coimmunoprecipitation	association	24498420, (Europe PMC)	0.35	IntAct
KIF13A	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
KIR2DL1	lex-a dimerization assay, two hybrid	physical association	9751747, (Europe PMC)	0.49	IntAct, MINT
KIT	Affinity Capture-Western, Co-localization, Reconstituted Complex, Two-hybrid, coimmunoprecipitation, fluorescence polarization spectroscopy, proximity ligation assay	association, direct interaction, physical, physical association	10022833, 11071635, 1382595, 17452978, 24728074, 25241761, 7509796, 7537096, 9233773, (Europe PMC)	0.77	BioGRID, IntAct, MINT
LAMP1	proximity-dependent biotin identification	association	29568061, (Europe PMC)	0.35	IntAct
LAPTM4B	anti tag coimmunoprecipitation, pull down	physical association	20711237, (Europe PMC)	0.52	IntAct
LAT	Affinity Capture-Western, Reconstituted Complex, coimmunoprecipitation, pull down	association, physical	10811803, 11368773, (Europe PMC)	0.46	BioGRID, IntAct, MINT
LCK	Reconstituted Complex, pull down	physical, physical association	8246987, 8294442, (Europe PMC)	0.40	BioGRID, IntAct, MINT
LCP2	Affinity Capture-Western, Two-hybrid, pull down	physical, physical association	15388330, 15929943, (Europe PMC)	0.40	BioGRID, IntAct, MINT
LIG3	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
LNX2	barcode fusion genetics two hybrid, validated two hybrid	physical association	27107012, (Europe PMC)	0.49	IntAct
LRRK2	protein array	direct interaction	29513927, (Europe PMC)	0.44	IntAct
LTK	Affinity Capture-Western, coimmunoprecipitation	association, physical	8084603, 9223670, (Europe PMC)	0.35	BioGRID, IntAct, MINT
MAL	anti bait coimmunoprecipitation, confocal microscopy	colocalization, physical association	22366891, (Europe PMC)	0.46	IntAct
MAP2K7	anti bait coimmunoprecipitation, anti tag coimmunoprecipitation	association	25284480, (Europe PMC)	0.46	IntAct
MAP3K11	anti bait coimmunoprecipitation, anti tag coimmunoprecipitation	association	25284480, (Europe PMC)	0.46	IntAct
MAP4	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
MAP4K1	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
MAPK8	anti bait coimmunoprecipitation, anti tag coimmunoprecipitation	association, physical association	16982329, 25284480, (Europe PMC)	0.62	IntAct, MINT
MAPK9	anti bait coimmunoprecipitation, anti tag coimmunoprecipitation	association	25284480, (Europe PMC)	0.46	IntAct
MED28	Affinity Capture-Western, peptide array	physical, physical association	16964398, (Europe PMC)	0.40	BioGRID, IntAct, MINT
MEPE	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
MET	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
MYLK	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
MYO16	anti tag coimmunoprecipitation	physical association	21946561, (Europe PMC)	0.40	IntAct, MINT
MYRIP	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
NELFB	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
NFKBIA	Reconstituted Complex, coimmunoprecipitation, competition binding	association, physical	9892650, (Europe PMC)	0.46	BioGRID, IntAct, MINT
NISCH	Affinity Capture-MS, inference by socio-affinity scoring	physical, physical association	27173435, (Europe PMC)	0.27	BioGRID, IntAct
NR5A1	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
NTRK1	Affinity Capture-MS, coimmunoprecipitation, competition binding	association, physical	25921289, 8226808, (Europe PMC)	0.46	BioGRID, IntAct, MINT
NYAP2	Affinity Capture-MS, Reconstituted Complex, anti tag coimmunoprecipitation	association, physical	21946561, 26496610, (Europe PMC)	0.35	BioGRID, IntAct
PBXIP1	anti tag coimmunoprecipitation	association	17043237, (Europe PMC)	0.35	IntAct
PDGFRA	Affinity Capture-Western, Co-localization, proximity ligation assay	physical, physical association	17452978, 25241761, (Europe PMC)	0.40	BioGRID, IntAct
PDGFRB	Affinity Capture-MS, Affinity Capture-Western, Reconstituted Complex, biophysical, circular dichroism, classical fluorescence spectroscopy, coimmunoprecipitation, cross-linking study, isothermal titration calorimetry, nuclear magnetic resonance, proximity ligation assay, pull down, surface plasmon resonance, two hybrid	association, physical, physical association	10697503, 10752619, 11710529, 11896612, 1314164, 1330535, 15377662, 16135792, 19864249, 28514442, 7536927, 7680644, 7692233, 8382612, 8564419, 8670861, 9153411, (Europe PMC)	0.95	BioGRID, IntAct, MINT
PDIA2	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
PEBP1	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
PHACTR2	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
PIK3C2B	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
PIK3CA	Affinity Capture-MS, Affinity Capture-Western, Reconstituted Complex, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, phosphotransferase assay, pull down, x-ray crystallography	association, direct interaction, phosphorylation reaction, physical, physical association	11526404, 15377662, 16043515, 16135792, 19117013, 19574958, 19805105, 20018188, 20713702, 22402981, 23643389, 25253337, 26496610, 7929193, (Europe PMC)	0.96	BioGRID, IntAct, MINT
PIK3CB	Affinity Capture-MS, Affinity Capture-Western, Co-fractionation, Co-localization, anti tag coimmunoprecipitation, barcode fusion genetics two hybrid, proximity ligation assay, two hybrid, validated two hybrid	association, physical, physical association	20713702, 22939629, 25241761, 26344197, 26496610, 27107012, 8139559, (Europe PMC)	0.56, 0.69	BioGRID, IntAct
PIK3CD	Affinity Capture-MS, Affinity Capture-Western, Reconstituted Complex, anti bait coimmunoprecipitation, confocal microscopy, mass spectrometry study of hydrogen/deuterium exchange, molecular sieving, protein kinase assay, pull down, two hybrid array, two hybrid prey pooling approach	colocalization, direct interaction, physical, physical association	21827948, 22020336, 26496610, 9113989, (Europe PMC)	0.46, 0.49, 0.74	BioGRID, IntAct
PIK3R1	Reconstituted Complex, coimmunoprecipitation	association, physical	11337495, 8294442, (Europe PMC)	0.35	BioGRID, IntAct, MINT
PLCG1	pull down	physical association	9020117, (Europe PMC)	0.40	IntAct, MINT
PLCG2	Co-localization, peptide array, proximity ligation assay	physical, physical association	17474147, 25241761, (Europe PMC)	0.59	BioGRID, IntAct
POLR1B	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
PPFIA3	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
PTPN4	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
PTPN6	Two-hybrid, coimmunoprecipitation, pull down	association, physical	10488096, 11160222, (Europe PMC)	0.46	BioGRID, IntAct, MINT
PXN	Co-localization, proximity ligation assay	physical, physical association	23397142, 25241761, (Europe PMC)	0.59	BioGRID, IntAct
RAC1	anti bait coimmunoprecipitation, anti tag coimmunoprecipitation	association	25284480, (Europe PMC)	0.46	IntAct
RAPGEF1	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
RIPK4	anti tag coimmunoprecipitation	association	26972000, (Europe PMC)	0.35	IntAct
RPL13	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
RRAS	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
RXRA	Affinity Capture-Western, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, confocal microscopy	colocalization, physical, physical association	20541701, (Europe PMC)	0.56	BioGRID, IntAct
SCG2	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
SEPT2	anti bait coimmunoprecipitation	physical association	17024187, (Europe PMC)	0.40	IntAct, MINT
SH2D2A	Affinity Capture-Luminescence, Two-hybrid, luminescence based mammalian interactome mapping, two hybrid array, validated two hybrid	physical, physical association	25814554, (Europe PMC)	0.57	BioGRID, IntAct
SH3KBP1	Affinity Capture-Western, Reconstituted Complex, Two-hybrid, peptide array	physical, physical association	10921882, 15476827, 17474147, 20457601, (Europe PMC)	0.40	BioGRID, IntAct
SHANK2	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
SHANK3	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
SHC1	Affinity Capture-MS, Affinity Capture-Western, Reconstituted Complex, coimmunoprecipitation, proximity ligation assay, pull down, tandem affinity purification	association, physical, physical association	16135792, 16219545, 19380743, 19889638, 23397142, 7537361, 8621719, 8662998, 9541596, (Europe PMC)	0.83	BioGRID, IntAct, MINT
SIK2	protein kinase assay	phosphorylation reaction	27478041, (Europe PMC)	0.44	IntAct
SIRT1	Affinity Capture-Western, anti bait coimmunoprecipitation	physical, physical association	21241768, (Europe PMC)	0.40	BioGRID, IntAct
SLC23A1	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
SLC24A1	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
SNX17	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
SNX8	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
SOCS1	Two-hybrid, two hybrid array, validated two hybrid	physical, physical association	25814554, (Europe PMC)	0.49	BioGRID, IntAct
SOS1	Co-localization, peptide array, proximity ligation assay	physical, physical association	17474147, 25241761, (Europe PMC)	0.59	BioGRID, IntAct
SOS2	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
SPEN	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
SRC	Affinity Capture-Western, Co-localization, anti bait coimmunoprecipitation, proximity ligation assay	association, physical, physical association	10487518, 19861161, 19903481, 23065768, 23397142, 24498420, 25241761, (Europe PMC)	0.82	BioGRID, IntAct, MINT
SSTR2	anti bait coimmunoprecipitation, pull down, surface plasmon resonance	direct interaction, physical association	16917505, (Europe PMC)	0.64	IntAct, MINT
STAT3	two hybrid array, validated two hybrid	physical association	25814554, (Europe PMC)	0.49	IntAct
SUV39H2	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
SYK	Affinity Capture-Western, Reconstituted Complex, Two-hybrid, anti bait coimmunoprecipitation, pull down, two hybrid	physical, physical association	15536084, 16921024, (Europe PMC)	0.58	BioGRID, IntAct, MINT
SYNJ2	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
TGDS	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
TGOLN2	peptide array, proximity-dependent biotin identification	association, physical association	17474147, 29568061, (Europe PMC)	0.56	IntAct
THRA	anti bait coimmunoprecipitation	physical association	16966610, (Europe PMC)	0.40	IntAct
THRB	pull down	direct interaction	16446424, (Europe PMC)	0.44	IntAct
TIRAP	anti tag coimmunoprecipitation, fluorescence microscopy	colocalization, physical association	19574958, (Europe PMC)	0.46	IntAct, MINT
TLR2	fluorescent resonance energy transfer	physical association	23247210, (Europe PMC)	0.40	IntAct, MINT
TLR3	Affinity Capture-Western, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation	physical, physical association	15502848, 16858407, (Europe PMC)	0.52	BioGRID, IntAct, MINT
TMEM17	Proximity Label-MS, proximity-dependent biotin identification	association, physical	26638075, (Europe PMC)	0.35	BioGRID, IntAct
TNS4	Two-hybrid, two hybrid array, validated two hybrid	physical, physical association	25814554, (Europe PMC)	0.49	BioGRID, IntAct
TPSAB1	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
TPSB2	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
TPX2	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
TULP4	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
VAV1	Affinity Capture-Western, Reconstituted Complex, pull down	association, physical	17050525, 9162069, 9891995, (Europe PMC)	0.35	BioGRID, IntAct, MINT
VAV3	anti bait coimmunoprecipitation	physical association	16982329, (Europe PMC)	0.40	IntAct, MINT
VPS13A	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
WASF1	anti bait coimmunoprecipitation	physical association	21946561, (Europe PMC)	0.40	IntAct, MINT
YWHAG	Affinity Capture-MS, anti bait coimmunoprecipitation, coimmunoprecipitation	physical, physical association	15324660, 17353931, (Europe PMC)	0.59	BioGRID, IntAct, MINT
YWHAZ	pull down	association	10887121, (Europe PMC)	0.35	IntAct, MINT
ZC4H2	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
ZDHHC17	luminescence based mammalian interactome mapping, two hybrid array	physical association	24705354, (Europe PMC)	0.51	IntAct

Visualize Download

Interacting partner	Detection method	Interaction type	PubMed IDs	Interaction Score	Source
ARAF	Reconstituted Complex, coimmunoprecipitation, phage display, pull down	direct interaction, physical, physical association	10967104, 11812000, (Europe PMC)	0.61	BioGRID, IntAct, MINT
AXL	Affinity Capture-Western, Biochemical Activity, coimmunoprecipitation, far western blotting	association, physical	18346204, 9178760, (Europe PMC)	0.46	BioGRID, IntAct, MINT
CBL	Affinity Capture-MS, Affinity Capture-Western, Biochemical Activity, Far Western, Reconstituted Complex, Two-hybrid, anti bait coimmunoprecipitation, coimmunoprecipitation, experimental interaction detection, far western blotting, pull down, tandem affinity purification, two hybrid, two hybrid array, validated two hybrid	association, physical, physical association	10025673, 10358153, 10620516, 10918571, 11030146, 11042121, 11087752, 11157475, 11418612, 11944898, 11994282, 14530346, 15107835, 15556646, 15581361, 16135792, 16219545, 16289966, 16982329, 17237826, 18374639, 19190244, 19380743, 19861161, 21203488, 24113870, 25814554, 7642581, 7791764, 8612729, 8621719, 8662998, 8695807, 8702998, 8896416, 8941725, 8995243, 9092538, 9160881, 9174058, 9259313, 9414268, 9461587, 9541596, 9890943, 9890970, 9918857, 9988765, (Europe PMC)	0.49, 0.94	BioGRID, IntAct, MINT
CD19	coimmunoprecipitation	association	7684160, (Europe PMC)	0.35	IntAct, MINT
CD28	Affinity Capture-Western, Protein-peptide, coimmunoprecipitation, competition binding, pull down	association, physical	10820259, 11526404, 19190244, 7568038, 7584133, 7807015, 8146197, 8183372, 8621607, 9417079, (Europe PMC)	0.89	BioGRID, IntAct, MINT
CD5	pull down, surface plasmon resonance	association	9079809, (Europe PMC)	0.46	IntAct, MINT
CD7	Affinity Capture-Western, Reconstituted Complex, competition binding	association, physical	12594831, 8918688, (Europe PMC)	0.35	BioGRID, IntAct, MINT
CDC42	anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, coimmunoprecipitation, experimental interaction detection, pull down	association, direct interaction, physical association	25284480, 7629060, 8034624, (Europe PMC)	0.79	IntAct, MINT
CMIP	Affinity Capture-Western, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation	physical, physical association	20018188, (Europe PMC)	0.52	BioGRID, IntAct, MINT
CRKL	Affinity Capture-Western, Reconstituted Complex, anti bait coimmunoprecipitation, proximity ligation assay	physical, physical association	11418612, 16135792, 16982329, 23397142, 9461587, (Europe PMC)	0.59	BioGRID, IntAct, MINT
CSF2RB	anti bait coimmunoprecipitation, pull down	association	16437163, (Europe PMC)	0.46	IntAct, MINT
CTLA4	coimmunoprecipitation, pull down	association	7807015, 9398332, 9813138, (Europe PMC)	0.64	IntAct, MINT
EGFR	Affinity Capture-MS, Affinity Capture-Western, Co-localization, Protein-peptide, coimmunoprecipitation, competition binding, protein array, proximity ligation assay	association, direct interaction, physical, physical association	16273093, 19531499, 21701776, 25241761, 7797556, 8662998, (Europe PMC)	0.78	BioGRID, IntAct, MINT
ERBB2	Affinity Capture-Western, Protein-peptide, anti bait coimmunoprecipitation, protein array, pull down	association, direct interaction, physical	16273093, 16843263, 21075308, 9756944, (Europe PMC)	0.69	BioGRID, IntAct, MINT
ERBB3	Affinity Capture-MS, Affinity Capture-Western, Protein-peptide, anti bait coimmunoprecipitation, protein array, tandem affinity purification	association, direct interaction, physical, physical association	10383151, 10572067, 11546794, 11694521, 15812817, 16273093, 18803287, 20007781, 20227043, 21075308, 21278786, 22439932, 24189400, 9130710, 9756944, (Europe PMC)	0.92	BioGRID, IntAct, MINT
EZR	Affinity Capture-Western, Reconstituted Complex, pull down	association, physical	10377409, (Europe PMC)	0.35	BioGRID, IntAct, MINT
FGFR1	Co-localization, Reconstituted Complex, Two-hybrid, coimmunoprecipitation, proximity ligation assay, pull down	association, physical, physical association	15117958, 18412956, 25241761, 8321198, (Europe PMC)	0.62	BioGRID, IntAct, MINT
FLT1	Affinity Capture-Western, coimmunoprecipitation, proximity ligation assay	association, physical, physical association	20805333, 23397142, 7657594, (Europe PMC)	0.56	BioGRID, IntAct, MINT
FLT3	Affinity Capture-Western, anti bait coimmunoprecipitation	physical, physical association	16982329, (Europe PMC)	0.40	BioGRID, IntAct, MINT
GAB1	Affinity Capture-Western, Far Western, Reconstituted Complex, Two-hybrid, coimmunoprecipitation, fluorescence polarization spectroscopy, pull down, two hybrid	association, direct interaction, physical, physical association	10978177, 16638574, 23612964, 24728074, 8596638, 9658397, 9804835, 9891995, (Europe PMC)	0.80	BioGRID, IntAct, MINT
GAB2	Affinity Capture-Western, Reconstituted Complex, Two-hybrid, anti tag coimmunoprecipitation, pull down	association, physical, physical association	10871282, 11334882, 11782427, 14530346, 16135792, 16219545, 16253990, (Europe PMC)	0.56	BioGRID, IntAct, MINT
GRB10	Affinity Capture-Western, anti bait coimmunoprecipitation	physical, physical association	12783867, 23246379, (Europe PMC)	0.40	BioGRID, IntAct, MINT
GRB2	Affinity Capture-MS, Affinity Capture-Western, Reconstituted Complex, Two-hybrid, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, mammalian protein protein interaction trap, pull down, tandem affinity purification, two hybrid pooling approach	association, physical, physical association	11418612, 16219545, 18346204, 19380743, 20936779, 21706016, 25416956, 7642581, 7737969, 7759531, 9174058, 9541596, 9886492, (Europe PMC)	0.86	BioGRID, IntAct, MINT
HCK	pull down	physical association	12029088, (Europe PMC)	0.40	IntAct, MINT
IGF1R	Co-localization, coimmunoprecipitation, proximity ligation assay, pull down, two hybrid	association, physical, physical association	25241761, 7589433, 7642582, 8603569, (Europe PMC)	0.75	BioGRID, IntAct, MINT
INSR	fluorescent resonance energy transfer, pull down	association, physical association	10500481, 11796522, 9593725, (Europe PMC)	0.69	IntAct, MINT
IRS1	Affinity Capture-Luminescence, Affinity Capture-Western, Far Western, Protein-peptide, Two-hybrid, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, coimmunoprecipitation, cross-linking study, enzymatic study, luminescence based mammalian interactome mapping, nuclear magnetic resonance, pull down, surface plasmon resonance, two hybrid, two hybrid array, validated two hybrid	association, physical, physical association	11403293, 11416002, 12107746, 12173038, 12730242, 1381348, 14511371, 14632132, 15514089, 16150444, 16230374, 16354680, 17640984, 19561084, 22974441, 23439647, 23643389, 25814554, 7680095, 7680644, 8175658, 8382612, 8628286, 9564850, (Europe PMC)	0.57, 0.92	BioGRID, IntAct, MINT
IRS2	Affinity Capture-MS, Affinity Capture-Western, Far Western, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation	association, physical, physical association	12107746, 15514089, 19561084, 21241768, 23439647, 23617393, 26496610, 8910607, 9334184, 9852124, (Europe PMC)	0.69	BioGRID, IntAct, MINT
KIR2DL1	lex-a dimerization assay, two hybrid	physical association	9751747, (Europe PMC)	0.49	IntAct, MINT
KIT	Affinity Capture-Western, Co-localization, Reconstituted Complex, Two-hybrid, coimmunoprecipitation, fluorescence polarization spectroscopy, proximity ligation assay	association, direct interaction, physical, physical association	10022833, 11071635, 1382595, 17452978, 24728074, 25241761, 7509796, 7537096, 9233773, (Europe PMC)	0.77	BioGRID, IntAct, MINT
LAT	Affinity Capture-Western, Reconstituted Complex, coimmunoprecipitation, pull down	association, physical	10811803, 11368773, (Europe PMC)	0.46	BioGRID, IntAct, MINT
LCK	Reconstituted Complex, pull down	physical, physical association	8246987, 8294442, (Europe PMC)	0.40	BioGRID, IntAct, MINT
LCP2	Affinity Capture-Western, Two-hybrid, pull down	physical, physical association	15388330, 15929943, (Europe PMC)	0.40	BioGRID, IntAct, MINT
LTK	Affinity Capture-Western, coimmunoprecipitation	association, physical	8084603, 9223670, (Europe PMC)	0.35	BioGRID, IntAct, MINT
MAPK8	anti bait coimmunoprecipitation, anti tag coimmunoprecipitation	association, physical association	16982329, 25284480, (Europe PMC)	0.62	IntAct, MINT
MED28	Affinity Capture-Western, peptide array	physical, physical association	16964398, (Europe PMC)	0.40	BioGRID, IntAct, MINT
MYO16	anti tag coimmunoprecipitation	physical association	21946561, (Europe PMC)	0.40	IntAct, MINT
NFKBIA	Reconstituted Complex, coimmunoprecipitation, competition binding	association, physical	9892650, (Europe PMC)	0.46	BioGRID, IntAct, MINT
NTRK1	Affinity Capture-MS, coimmunoprecipitation, competition binding	association, physical	25921289, 8226808, (Europe PMC)	0.46	BioGRID, IntAct, MINT
PDGFRB	Affinity Capture-MS, Affinity Capture-Western, Reconstituted Complex, biophysical, circular dichroism, classical fluorescence spectroscopy, coimmunoprecipitation, cross-linking study, isothermal titration calorimetry, nuclear magnetic resonance, proximity ligation assay, pull down, surface plasmon resonance, two hybrid	association, physical, physical association	10697503, 10752619, 11710529, 11896612, 1314164, 1330535, 15377662, 16135792, 19864249, 28514442, 7536927, 7680644, 7692233, 8382612, 8564419, 8670861, 9153411, (Europe PMC)	0.95	BioGRID, IntAct, MINT
PIK3CA	Affinity Capture-MS, Affinity Capture-Western, Reconstituted Complex, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, phosphotransferase assay, pull down, x-ray crystallography	association, direct interaction, phosphorylation reaction, physical, physical association	11526404, 15377662, 16043515, 16135792, 19117013, 19574958, 19805105, 20018188, 20713702, 22402981, 23643389, 25253337, 26496610, 7929193, (Europe PMC)	0.96	BioGRID, IntAct, MINT
PIK3R1	Reconstituted Complex, coimmunoprecipitation	association, physical	11337495, 8294442, (Europe PMC)	0.35	BioGRID, IntAct, MINT
PLCG1	pull down	physical association	9020117, (Europe PMC)	0.40	IntAct, MINT
PTPN6	Two-hybrid, coimmunoprecipitation, pull down	association, physical	10488096, 11160222, (Europe PMC)	0.46	BioGRID, IntAct, MINT
SEPT2	anti bait coimmunoprecipitation	physical association	17024187, (Europe PMC)	0.40	IntAct, MINT
SHC1	Affinity Capture-MS, Affinity Capture-Western, Reconstituted Complex, coimmunoprecipitation, proximity ligation assay, pull down, tandem affinity purification	association, physical, physical association	16135792, 16219545, 19380743, 19889638, 23397142, 7537361, 8621719, 8662998, 9541596, (Europe PMC)	0.83	BioGRID, IntAct, MINT
SRC	Affinity Capture-Western, Co-localization, anti bait coimmunoprecipitation, proximity ligation assay	association, physical, physical association	10487518, 19861161, 19903481, 23065768, 23397142, 24498420, 25241761, (Europe PMC)	0.82	BioGRID, IntAct, MINT
SSTR2	anti bait coimmunoprecipitation, pull down, surface plasmon resonance	direct interaction, physical association	16917505, (Europe PMC)	0.64	IntAct, MINT
SYK	Affinity Capture-Western, Reconstituted Complex, Two-hybrid, anti bait coimmunoprecipitation, pull down, two hybrid	physical, physical association	15536084, 16921024, (Europe PMC)	0.58	BioGRID, IntAct, MINT
TIRAP	anti tag coimmunoprecipitation, fluorescence microscopy	colocalization, physical association	19574958, (Europe PMC)	0.46	IntAct, MINT
TLR2	fluorescent resonance energy transfer	physical association	23247210, (Europe PMC)	0.40	IntAct, MINT
TLR3	Affinity Capture-Western, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation	physical, physical association	15502848, 16858407, (Europe PMC)	0.52	BioGRID, IntAct, MINT
VAV1	Affinity Capture-Western, Reconstituted Complex, pull down	association, physical	17050525, 9162069, 9891995, (Europe PMC)	0.35	BioGRID, IntAct, MINT
VAV3	anti bait coimmunoprecipitation	physical association	16982329, (Europe PMC)	0.40	IntAct, MINT
WASF1	anti bait coimmunoprecipitation	physical association	21946561, (Europe PMC)	0.40	IntAct, MINT
YWHAG	Affinity Capture-MS, anti bait coimmunoprecipitation, coimmunoprecipitation	physical, physical association	15324660, 17353931, (Europe PMC)	0.59	BioGRID, IntAct, MINT
YWHAZ	pull down	association	10887121, (Europe PMC)	0.35	IntAct, MINT

Visualize Download

Interacting partner	Detection method	Interaction type	PubMed IDs	Interaction Score	Source
ABI1	Affinity Capture-Western, Protein-peptide	physical	20598684, (Europe PMC)	NA	BioGRID
ABI1	array technology	direct interaction	20598684, (Europe PMC)	0.44	IntAct, MINT
ABL1	Affinity Capture-MS, Affinity Capture-Western, Reconstituted Complex, peptide array	physical, physical association	16135792, 16219545, 17474147, 19380743, 8294442, (Europe PMC)	0.40	BioGRID, IntAct
ABL2	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
ACTA1	Affinity Capture-Western	physical	23353701, (Europe PMC)	NA	BioGRID
ADAM12	Affinity Capture-Western, Reconstituted Complex	physical	11313349, (Europe PMC)	NA	BioGRID
ADAMTS2	Two-hybrid	physical	18624398, (Europe PMC)	NA	BioGRID
AGAP2	Affinity Capture-Western, Reconstituted Complex	physical	11136977, (Europe PMC)	NA	BioGRID
AIRE	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
AKAP2	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
AKAP6	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
AKT1	Affinity Capture-Western	physical	19117013, (Europe PMC)	NA	BioGRID
ALK	Reconstituted Complex	physical	16135792, (Europe PMC)	NA	BioGRID
ALOX5	Affinity Capture-Western	physical	21200133, (Europe PMC)	NA	BioGRID
ALS2CR12	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
APOL5	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
APPL1	Affinity Capture-Western, Two-hybrid, two hybrid array, validated two hybrid	physical, physical association	12621049, 25814554, (Europe PMC)	0.49	BioGRID, IntAct
AR	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
ARAF	Reconstituted Complex, coimmunoprecipitation, phage display, pull down	direct interaction, physical, physical association	10967104, 11812000, (Europe PMC)	0.61	BioGRID, IntAct, MINT
ARHGAP1	Reconstituted Complex	physical	8253717, (Europe PMC)	NA	BioGRID
ARHGAP17	Reconstituted Complex	physical	11431473, (Europe PMC)	NA	BioGRID
ARHGAP32	Affinity Capture-Western	physical	12454018, (Europe PMC)	NA	BioGRID
ARHGEF11	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
ASAP1	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
ASAP2	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
AXL	Affinity Capture-Western, Biochemical Activity, coimmunoprecipitation, far western blotting	association, physical	18346204, 9178760, (Europe PMC)	0.46	BioGRID, IntAct, MINT
BCAR1	Affinity Capture-Western, Reconstituted Complex	physical	10799562, (Europe PMC)	NA	BioGRID
BCR	Far Western	physical	18346204, (Europe PMC)	NA	BioGRID
BICRA	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
BRCA1	Reconstituted Complex, peptide array	physical, physical association	16135792, 17474147, (Europe PMC)	0.40	BioGRID, IntAct
BRD4	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
BRPF3	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
CAST	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
CBL	Affinity Capture-MS, Affinity Capture-Western, Biochemical Activity, Far Western, Reconstituted Complex, Two-hybrid, anti bait coimmunoprecipitation, coimmunoprecipitation, experimental interaction detection, far western blotting, pull down, tandem affinity purification, two hybrid, two hybrid array, validated two hybrid	association, physical, physical association	10025673, 10358153, 10620516, 10918571, 11030146, 11042121, 11087752, 11157475, 11418612, 11944898, 11994282, 14530346, 15107835, 15556646, 15581361, 16135792, 16219545, 16289966, 16982329, 17237826, 18374639, 19190244, 19380743, 19861161, 21203488, 24113870, 25814554, 7642581, 7791764, 8612729, 8621719, 8662998, 8695807, 8702998, 8896416, 8941725, 8995243, 9092538, 9160881, 9174058, 9259313, 9414268, 9461587, 9541596, 9890943, 9890970, 9918857, 9988765, (Europe PMC)	0.49, 0.94	BioGRID, IntAct, MINT
CBLB	Affinity Capture-Western	physical	10022120, 11526404, 19190244, 9614102, (Europe PMC)	NA	BioGRID
CCL14	Two-hybrid, two hybrid array	physical, physical association	21988832, (Europe PMC)	0.37	BioGRID, IntAct
CD19	coimmunoprecipitation	association	7684160, (Europe PMC)	0.35	IntAct, MINT
CD22	coimmunoprecipitation	association	8647200, (Europe PMC)	0.35	IntAct
CD244	Affinity Capture-MS	physical	26186194, (Europe PMC)	NA	BioGRID
CD247	Affinity Capture-Western	physical	11526404, (Europe PMC)	NA	BioGRID
CD28	Affinity Capture-Western, Protein-peptide, coimmunoprecipitation, competition binding, pull down	association, physical	10820259, 11526404, 19190244, 7568038, 7584133, 7807015, 8146197, 8183372, 8621607, 9417079, (Europe PMC)	0.89	BioGRID, IntAct, MINT
CD3E	Affinity Capture-Western	physical	19190244, 9312149, (Europe PMC)	NA	BioGRID
CD40	Affinity Capture-Western	physical	21200133, (Europe PMC)	NA	BioGRID
CD5	pull down, surface plasmon resonance	association	9079809, (Europe PMC)	0.46	IntAct, MINT
CD7	Affinity Capture-Western, Reconstituted Complex, competition binding	association, physical	12594831, 8918688, (Europe PMC)	0.35	BioGRID, IntAct, MINT
CDC27	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
CDC42	anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, coimmunoprecipitation, experimental interaction detection, pull down	association, direct interaction, physical association	25284480, 7629060, 8034624, (Europe PMC)	0.79	IntAct, MINT
CHAF1A	Affinity Capture-MS, anti tag coimmunoprecipitation, peptide array	association, physical, physical association	17474147, 26496610, (Europe PMC)	0.56	BioGRID, IntAct
CKAP5	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
CLNK	Two-hybrid, two hybrid array, validated two hybrid	physical, physical association	25814554, (Europe PMC)	0.49	BioGRID, IntAct
CMIP	Affinity Capture-Western, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation	physical, physical association	20018188, (Europe PMC)	0.52	BioGRID, IntAct, MINT
CRK	Affinity Capture-MS, Affinity Capture-Western, Co-localization, Two-hybrid, proximity ligation assay, tandem affinity purification, two hybrid array, validated two hybrid	association, physical, physical association	10962563, 11418612, 19380743, 25241761, 25814554, (Europe PMC)	0.49, 0.56	BioGRID, IntAct
CRKL	Affinity Capture-Western, Reconstituted Complex, anti bait coimmunoprecipitation, proximity ligation assay	physical, physical association	11418612, 16135792, 16982329, 23397142, 9461587, (Europe PMC)	0.59	BioGRID, IntAct, MINT
CSDC2	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
CSDE1	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
CSF1R	Affinity Capture-Western, Co-localization, proximity ligation assay	physical, physical association	10025673, 25241761, (Europe PMC)	0.40	BioGRID, IntAct
CSF2RA	Affinity Capture-Western, peptide array	physical, physical association	12538575, 17474147, (Europe PMC)	0.40	BioGRID, IntAct
CSF2RB	anti bait coimmunoprecipitation, pull down	association	16437163, (Europe PMC)	0.46	IntAct, MINT
CTLA4	coimmunoprecipitation, pull down	association	7807015, 9398332, 9813138, (Europe PMC)	0.64	IntAct, MINT
CTNNB1	Co-localization, Reconstituted Complex, proximity ligation assay	physical, physical association	10477752, 25241761, (Europe PMC)	0.40	BioGRID, IntAct
CUL3	Affinity Capture-MS, Affinity Capture-Western	physical	21145461, 27708159, (Europe PMC)	NA	BioGRID
CXCL2	Two-hybrid	physical	18624398, (Europe PMC)	NA	BioGRID
CYP4A11	Two-hybrid	physical	18624398, (Europe PMC)	NA	BioGRID
DAB2	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
DAB2IP	Affinity Capture-Western, Reconstituted Complex	physical	19903888, (Europe PMC)	NA	BioGRID
DAG1	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
DARS	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
DEFA5	Affinity Capture-MS	physical	28514442, (Europe PMC)	NA	BioGRID
DLG1	anti bait coimmunoprecipitation	association	25253337, (Europe PMC)	0.35	IntAct
DLGAP1	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
DLGAP2	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
DLGAP3	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
DLGAP4	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
DLX2	Two-hybrid, two hybrid array	physical, physical association	21988832, (Europe PMC)	0.37	BioGRID, IntAct
DLX4	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
DNM2	Affinity Capture-Western	physical	21996738, (Europe PMC)	NA	BioGRID
DOCK3	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
DOK1	Protein-peptide, Reconstituted Complex	physical	11071635, 22974441, (Europe PMC)	NA	BioGRID
DTNBP1	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
DUSP15	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
ECT2	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
EEF1D	display technology	physical association	20195357, (Europe PMC)	0.40	IntAct
EFNB2	Affinity Capture-MS	physical	26186194, (Europe PMC)	NA	BioGRID
EFS	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
EGFR	Affinity Capture-MS, Affinity Capture-Western, Co-localization, Protein-peptide, coimmunoprecipitation, competition binding, protein array, proximity ligation assay	association, direct interaction, physical, physical association	16273093, 19531499, 21701776, 25241761, 7797556, 8662998, (Europe PMC)	0.78	BioGRID, IntAct, MINT
ELK3	mammalian protein protein interaction trap, peptide array	physical association	17474147, 25416956, (Europe PMC)	0.57	IntAct
EP300	Affinity Capture-Western, anti tag coimmunoprecipitation	physical, physical association	21057544, (Europe PMC)	0.40	BioGRID, IntAct
EPHA2	Affinity Capture-Western, Reconstituted Complex, Two-hybrid	physical	7982920, (Europe PMC)	NA	BioGRID
EPN1	Affinity Capture-Western	physical	24113870, (Europe PMC)	NA	BioGRID
EPOR	Affinity Capture-Western, PCA, Reconstituted Complex	physical	15644415, 24113870, 7559499, 9162069, (Europe PMC)	NA	BioGRID
EPX	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
ERBB2	Affinity Capture-Western, Protein-peptide, anti bait coimmunoprecipitation, protein array, pull down	association, direct interaction, physical	16273093, 16843263, 21075308, 9756944, (Europe PMC)	0.69	BioGRID, IntAct, MINT
ERBB3	Affinity Capture-MS, Affinity Capture-Western, Protein-peptide, anti bait coimmunoprecipitation, protein array, tandem affinity purification	association, direct interaction, physical, physical association	10383151, 10572067, 11546794, 11694521, 15812817, 16273093, 18803287, 20007781, 20227043, 21075308, 21278786, 22439932, 24189400, 9130710, 9756944, (Europe PMC)	0.92	BioGRID, IntAct, MINT
ESR1	Affinity Capture-Western, anti bait coimmunoprecipitation, proximity ligation assay	association, physical, physical association	11029009, 11689445, 17043237, 23065768, (Europe PMC)	0.56	BioGRID, IntAct
EXTL3	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
EZR	Affinity Capture-Western, Reconstituted Complex, pull down	association, physical	10377409, (Europe PMC)	0.35	BioGRID, IntAct, MINT
FANCA	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
FAS	Affinity Capture-Western	physical	18328427, (Europe PMC)	NA	BioGRID
FASLG	Co-localization, phage display, proximity ligation assay	direct interaction, physical, physical association	19807924, 25241761, (Europe PMC)	0.61	BioGRID, IntAct
FBXL2	Affinity Capture-Western	physical	23604317, (Europe PMC)	NA	BioGRID
FCGR2A	Affinity Capture-Western, Reconstituted Complex	physical	8631888, 9268059, (Europe PMC)	NA	BioGRID
FER	Two-hybrid, two hybrid array	physical, physical association	25814554, (Europe PMC)	0.37	BioGRID, IntAct
FES	Affinity Capture-Western	physical	8916957, (Europe PMC)	NA	BioGRID
FGFR1	Co-localization, Reconstituted Complex, Two-hybrid, coimmunoprecipitation, proximity ligation assay, pull down	association, physical, physical association	15117958, 18412956, 25241761, 8321198, (Europe PMC)	0.62	BioGRID, IntAct, MINT
FGFR2	Affinity Capture-Western	physical	18374639, (Europe PMC)	NA	BioGRID
FLNA	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
FLNB	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
FLNC	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
FLRT1	Affinity Capture-MS	physical	28514442, (Europe PMC)	NA	BioGRID
FLT1	Affinity Capture-Western, coimmunoprecipitation, proximity ligation assay	association, physical, physical association	20805333, 23397142, 7657594, (Europe PMC)	0.56	BioGRID, IntAct, MINT
FLT3	Affinity Capture-Western, anti bait coimmunoprecipitation	physical, physical association	16982329, (Europe PMC)	0.40	BioGRID, IntAct, MINT
FOXH1	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
FYB1	pull down	association	22074159, (Europe PMC)	0.35	IntAct
FYN	Reconstituted Complex, mammalian protein protein interaction trap	physical, physical association	25416956, 8294442, (Europe PMC)	0.37	BioGRID, IntAct
GAB1	Affinity Capture-Western, Far Western, Reconstituted Complex, Two-hybrid, coimmunoprecipitation, fluorescence polarization spectroscopy, pull down, two hybrid	association, direct interaction, physical, physical association	10978177, 16638574, 23612964, 24728074, 8596638, 9658397, 9804835, 9891995, (Europe PMC)	0.80	BioGRID, IntAct, MINT
GAB2	Affinity Capture-Western, Reconstituted Complex, Two-hybrid, anti tag coimmunoprecipitation, pull down	association, physical, physical association	10871282, 11334882, 11782427, 14530346, 16135792, 16219545, 16253990, (Europe PMC)	0.56	BioGRID, IntAct, MINT
GABBR1	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
GABRA3	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
GHR	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
GNAQ	Affinity Capture-Western	physical	12704201, (Europe PMC)	NA	BioGRID
GNB1	Affinity Capture-Western	physical	19117013, (Europe PMC)	NA	BioGRID
GRB10	Affinity Capture-Western, anti bait coimmunoprecipitation	physical, physical association	12783867, 23246379, (Europe PMC)	0.40	BioGRID, IntAct, MINT
GRB2	Affinity Capture-MS, Affinity Capture-Western, Reconstituted Complex, Two-hybrid, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, mammalian protein protein interaction trap, pull down, tandem affinity purification, two hybrid pooling approach	association, physical, physical association	11418612, 16219545, 18346204, 19380743, 20936779, 21706016, 25416956, 7642581, 7737969, 7759531, 9174058, 9541596, 9886492, (Europe PMC)	0.86	BioGRID, IntAct, MINT
GSPT1	Two-hybrid, two hybrid array	physical, physical association	21988832, (Europe PMC)	0.37	BioGRID, IntAct
HAVCR2	Affinity Capture-MS, anti bait coimmunoprecipitation, pull down	association, physical	26492563, 28514442, (Europe PMC)	0.46	BioGRID, IntAct
HCK	pull down	physical association	12029088, (Europe PMC)	0.40	IntAct, MINT
HCST	Protein-peptide	physical	10426994, (Europe PMC)	NA	BioGRID
HDAC3	Affinity Capture-Western	physical	22027828, (Europe PMC)	NA	BioGRID
HOXA1	Two-hybrid, two hybrid array	physical, physical association	21988832, (Europe PMC)	0.37	BioGRID, IntAct
HRAS	Affinity Capture-Western, Co-localization, Reconstituted Complex, proximity ligation assay	physical, physical association	10212255, 25241761, 9150145, (Europe PMC)	0.40	BioGRID, IntAct
HSCB	anti bait coimmunoprecipitation	association	28380382, (Europe PMC)	0.35	IntAct
HSPA8	proximity-dependent biotin identification	association	29568061, (Europe PMC)	0.35	IntAct
HTT	Two-hybrid, two hybrid, two hybrid prey pooling approach	physical, physical association	17500595, 23275563, (Europe PMC)	0.55	BioGRID, IntAct
ICOS	anti bait coimmunoprecipitation	association, physical association	27135603, (Europe PMC)	0.50	IntAct
ID4	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
IFNAR1	Affinity Capture-Western	physical	10542297, (Europe PMC)	NA	BioGRID
IGF1R	Co-localization, coimmunoprecipitation, proximity ligation assay, pull down, two hybrid	association, physical, physical association	25241761, 7589433, 7642582, 8603569, (Europe PMC)	0.75	BioGRID, IntAct, MINT
IKZF3	barcode fusion genetics two hybrid, validated two hybrid	physical association	27107012, (Europe PMC)	0.49	IntAct
IL1R1	Affinity Capture-Western	physical	9360994, (Europe PMC)	NA	BioGRID
IL20RA	Affinity Capture-MS	physical	28514442, (Europe PMC)	NA	BioGRID
IL6ST	Affinity Capture-Western	physical	10579793, (Europe PMC)	NA	BioGRID
INPP5D	Affinity Capture-Western	physical	9918857, (Europe PMC)	NA	BioGRID
INPPL1	Affinity Capture-MS, tandem affinity purification	association, physical	19380743, (Europe PMC)	0.35	BioGRID, IntAct
INSR	fluorescent resonance energy transfer, pull down	association, physical association	10500481, 11796522, 9593725, (Europe PMC)	0.69	IntAct, MINT
IRS1	Affinity Capture-Luminescence, Affinity Capture-Western, Far Western, Protein-peptide, Two-hybrid, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, coimmunoprecipitation, cross-linking study, enzymatic study, luminescence based mammalian interactome mapping, nuclear magnetic resonance, pull down, surface plasmon resonance, two hybrid, two hybrid array, validated two hybrid	association, physical, physical association	11403293, 11416002, 12107746, 12173038, 12730242, 1381348, 14511371, 14632132, 15514089, 16150444, 16230374, 16354680, 17640984, 19561084, 22974441, 23439647, 23643389, 25814554, 7680095, 7680644, 8175658, 8382612, 8628286, 9564850, (Europe PMC)	0.57, 0.92	BioGRID, IntAct, MINT
IRS2	Affinity Capture-MS, Affinity Capture-Western, Far Western, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation	association, physical, physical association	12107746, 15514089, 19561084, 21241768, 23439647, 23617393, 26496610, 8910607, 9334184, 9852124, (Europe PMC)	0.69	BioGRID, IntAct, MINT
IRS4	Affinity Capture-Luminescence, Affinity Capture-MS, anti tag coimmunoprecipitation	association, physical	25036637, (Europe PMC)	0.35	BioGRID, IntAct
ITSN1	Two-hybrid	physical	22558309, (Europe PMC)	NA	BioGRID
JAK2	Negative Genetic, Reconstituted Complex, peptide array	genetic, physical, physical association	16135792, 17474147, 28319113, (Europe PMC)	0.40	BioGRID, IntAct
JMJD6	anti bait coimmunoprecipitation	association	24498420, (Europe PMC)	0.35	IntAct
KBTBD2	Affinity Capture-Western, Reconstituted Complex	physical	27708159, (Europe PMC)	NA	BioGRID
KHDRBS1	Affinity Capture-Western, FRET, Protein-peptide, Reconstituted Complex	physical	10467411, 11604231, 22745667, 8175658, (Europe PMC)	NA	BioGRID
KIF13A	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
KIR2DL1	lex-a dimerization assay, two hybrid	physical association	9751747, (Europe PMC)	0.49	IntAct, MINT
KIT	Affinity Capture-Western, Co-localization, Reconstituted Complex, Two-hybrid, coimmunoprecipitation, fluorescence polarization spectroscopy, proximity ligation assay	association, direct interaction, physical, physical association	10022833, 11071635, 1382595, 17452978, 24728074, 25241761, 7509796, 7537096, 9233773, (Europe PMC)	0.77	BioGRID, IntAct, MINT
LAMP1	proximity-dependent biotin identification	association	29568061, (Europe PMC)	0.35	IntAct
LAPTM4B	anti tag coimmunoprecipitation, pull down	physical association	20711237, (Europe PMC)	0.52	IntAct
LAT	Affinity Capture-Western, Reconstituted Complex, coimmunoprecipitation, pull down	association, physical	10811803, 11368773, (Europe PMC)	0.46	BioGRID, IntAct, MINT
LCK	Reconstituted Complex, pull down	physical, physical association	8246987, 8294442, (Europe PMC)	0.40	BioGRID, IntAct, MINT
LCP2	Affinity Capture-Western, Two-hybrid, pull down	physical, physical association	15388330, 15929943, (Europe PMC)	0.40	BioGRID, IntAct, MINT
LIG3	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
LNX2	barcode fusion genetics two hybrid, validated two hybrid	physical association	27107012, (Europe PMC)	0.49	IntAct
LRRK2	protein array	direct interaction	29513927, (Europe PMC)	0.44	IntAct
LTK	Affinity Capture-Western, coimmunoprecipitation	association, physical	8084603, 9223670, (Europe PMC)	0.35	BioGRID, IntAct, MINT
MAL	anti bait coimmunoprecipitation, confocal microscopy	colocalization, physical association	22366891, (Europe PMC)	0.46	IntAct
MAP2K7	anti bait coimmunoprecipitation, anti tag coimmunoprecipitation	association	25284480, (Europe PMC)	0.46	IntAct
MAP3K11	anti bait coimmunoprecipitation, anti tag coimmunoprecipitation	association	25284480, (Europe PMC)	0.46	IntAct
MAP3K5	Affinity Capture-Western	physical	19903888, (Europe PMC)	NA	BioGRID
MAP4	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
MAP4K1	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
MAPK8	anti bait coimmunoprecipitation, anti tag coimmunoprecipitation	association, physical association	16982329, 25284480, (Europe PMC)	0.62	IntAct, MINT
MAPK9	anti bait coimmunoprecipitation, anti tag coimmunoprecipitation	association	25284480, (Europe PMC)	0.46	IntAct
MAPT	Affinity Capture-Western, Reconstituted Complex	physical	19681044, (Europe PMC)	NA	BioGRID
MED28	Affinity Capture-Western, peptide array	physical, physical association	16964398, (Europe PMC)	0.40	BioGRID, IntAct, MINT
MEPE	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
MET	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
MYLK	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
MYO16	Reconstituted Complex	physical	21946561, (Europe PMC)	NA	BioGRID
MYO16	anti tag coimmunoprecipitation	physical association	21946561, (Europe PMC)	0.40	IntAct, MINT
MYRIP	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
NCK1	Affinity Capture-Western	physical	11418612, (Europe PMC)	NA	BioGRID
NCL	Affinity Capture-Western	physical	16571724, (Europe PMC)	NA	BioGRID
NELFB	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
NFKBIA	Reconstituted Complex, coimmunoprecipitation, competition binding	association, physical	9892650, (Europe PMC)	0.46	BioGRID, IntAct, MINT
NISCH	Affinity Capture-MS, inference by socio-affinity scoring	physical, physical association	27173435, (Europe PMC)	0.27	BioGRID, IntAct
NLGN3	Affinity Capture-MS	physical	28514442, (Europe PMC)	NA	BioGRID
NPM1	Affinity Capture-MS	physical	14968112, (Europe PMC)	NA	BioGRID
NR5A1	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
NTRK1	Affinity Capture-MS, coimmunoprecipitation, competition binding	association, physical	25921289, 8226808, (Europe PMC)	0.46	BioGRID, IntAct, MINT
NTRK2	Two-hybrid	physical	12074588, (Europe PMC)	NA	BioGRID
NYAP1	Reconstituted Complex	physical	21946561, (Europe PMC)	NA	BioGRID
NYAP2	Affinity Capture-MS, Reconstituted Complex, anti tag coimmunoprecipitation	association, physical	21946561, 26496610, (Europe PMC)	0.35	BioGRID, IntAct
PBXIP1	anti tag coimmunoprecipitation	association	17043237, (Europe PMC)	0.35	IntAct
PCBP1	Affinity Capture-MS	physical	26186194, 28514442, (Europe PMC)	NA	BioGRID
PDE4D	Far Western	physical	10571082, (Europe PMC)	NA	BioGRID
PDGFRA	Affinity Capture-Western, Co-localization, proximity ligation assay	physical, physical association	17452978, 25241761, (Europe PMC)	0.40	BioGRID, IntAct
PDGFRB	Affinity Capture-MS, Affinity Capture-Western, Reconstituted Complex, biophysical, circular dichroism, classical fluorescence spectroscopy, coimmunoprecipitation, cross-linking study, isothermal titration calorimetry, nuclear magnetic resonance, proximity ligation assay, pull down, surface plasmon resonance, two hybrid	association, physical, physical association	10697503, 10752619, 11710529, 11896612, 1314164, 1330535, 15377662, 16135792, 19864249, 28514442, 7536927, 7680644, 7692233, 8382612, 8564419, 8670861, 9153411, (Europe PMC)	0.95	BioGRID, IntAct, MINT
PDIA2	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
PEBP1	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
PECAM1	Affinity Capture-Western	physical	9774384, (Europe PMC)	NA	BioGRID
PHACTR2	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
PIK3C2B	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
PIK3CA	Affinity Capture-MS, Affinity Capture-Western, Reconstituted Complex, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, phosphotransferase assay, pull down, x-ray crystallography	association, direct interaction, phosphorylation reaction, physical, physical association	11526404, 15377662, 16043515, 16135792, 19117013, 19574958, 19805105, 20018188, 20713702, 22402981, 23643389, 25253337, 26496610, 7929193, (Europe PMC)	0.96	BioGRID, IntAct, MINT
PIK3CB	Affinity Capture-MS, Affinity Capture-Western, Co-fractionation, Co-localization, anti tag coimmunoprecipitation, barcode fusion genetics two hybrid, proximity ligation assay, two hybrid, validated two hybrid	association, physical, physical association	20713702, 22939629, 25241761, 26344197, 26496610, 27107012, 8139559, (Europe PMC)	0.56, 0.69	BioGRID, IntAct
PIK3CD	Affinity Capture-MS, Affinity Capture-Western, Reconstituted Complex, anti bait coimmunoprecipitation, confocal microscopy, mass spectrometry study of hydrogen/deuterium exchange, molecular sieving, protein kinase assay, pull down, two hybrid array, two hybrid prey pooling approach	colocalization, direct interaction, physical, physical association	21827948, 22020336, 26496610, 9113989, (Europe PMC)	0.46, 0.49, 0.74	BioGRID, IntAct
PIK3R1	Reconstituted Complex, coimmunoprecipitation	association, physical	11337495, 8294442, (Europe PMC)	0.35	BioGRID, IntAct, MINT
PIK3R2	Affinity Capture-MS	physical	19380743, 26186194, 28514442, (Europe PMC)	NA	BioGRID
PIK3R3	Affinity Capture-MS	physical	28514442, (Europe PMC)	NA	BioGRID
PLCG1	pull down	physical association	9020117, (Europe PMC)	0.40	IntAct, MINT
PLCG2	Co-localization, peptide array, proximity ligation assay	physical, physical association	17474147, 25241761, (Europe PMC)	0.59	BioGRID, IntAct
POLR1B	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
PPFIA3	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
PRMT2	Affinity Capture-MS	physical	26186194, (Europe PMC)	NA	BioGRID
PROM1	Affinity Capture-Western, Reconstituted Complex	physical	23569237, (Europe PMC)	NA	BioGRID
PTGER3	Affinity Capture-MS	physical	26186194, (Europe PMC)	NA	BioGRID
PTK2	Affinity Capture-Western, Far Western	physical	10973983, 11119718, 19889638, 7537275, (Europe PMC)	NA	BioGRID
PTPN11	Affinity Capture-Western	physical	10962556, 11593409, 16371368, 9361008, 9886492, 9918857, (Europe PMC)	NA	BioGRID
PTPN4	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
PTPN6	Two-hybrid, coimmunoprecipitation, pull down	association, physical	10488096, 11160222, (Europe PMC)	0.46	BioGRID, IntAct, MINT
PTPRK	Proximity Label-MS	physical	27880917, (Europe PMC)	NA	BioGRID
PTTG1	Affinity Capture-Western	physical	15845362, (Europe PMC)	NA	BioGRID
PXK	Affinity Capture-Western	physical	20086096, (Europe PMC)	NA	BioGRID
PXN	Co-localization, proximity ligation assay	physical, physical association	23397142, 25241761, (Europe PMC)	0.59	BioGRID, IntAct
RAB5A	Affinity Capture-Western	physical	15377662, (Europe PMC)	NA	BioGRID
RAC1	anti bait coimmunoprecipitation, anti tag coimmunoprecipitation	association	25284480, (Europe PMC)	0.46	IntAct
RAPGEF1	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
RASD2	Affinity Capture-Western, Reconstituted Complex	physical	22683505, (Europe PMC)	NA	BioGRID
RET	Reconstituted Complex	physical	10995764, (Europe PMC)	NA	BioGRID
RIPK4	anti tag coimmunoprecipitation	association	26972000, (Europe PMC)	0.35	IntAct
RNF19B	Affinity Capture-MS	physical	28514442, (Europe PMC)	NA	BioGRID
RPL13	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
RRAS	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
RRAS2	Affinity Capture-Western	physical	11850823, (Europe PMC)	NA	BioGRID
RXRA	Affinity Capture-Western, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, confocal microscopy	colocalization, physical, physical association	20541701, (Europe PMC)	0.56	BioGRID, IntAct
SCG2	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
SELPLG	Affinity Capture-Western	physical	17632516, (Europe PMC)	NA	BioGRID
SEPT2	anti bait coimmunoprecipitation	physical association	17024187, (Europe PMC)	0.40	IntAct, MINT
SH2D2A	Affinity Capture-Luminescence, Two-hybrid, luminescence based mammalian interactome mapping, two hybrid array, validated two hybrid	physical, physical association	25814554, (Europe PMC)	0.57	BioGRID, IntAct
SH3KBP1	Affinity Capture-Western, Reconstituted Complex, Two-hybrid, peptide array	physical, physical association	10921882, 15476827, 17474147, 20457601, (Europe PMC)	0.40	BioGRID, IntAct
SHANK2	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
SHANK3	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
SHB	Affinity Capture-Western, Reconstituted Complex	physical	7537362, (Europe PMC)	NA	BioGRID
SHC1	Affinity Capture-MS, Affinity Capture-Western, Reconstituted Complex, coimmunoprecipitation, proximity ligation assay, pull down, tandem affinity purification	association, physical, physical association	16135792, 16219545, 19380743, 19889638, 23397142, 7537361, 8621719, 8662998, 9541596, (Europe PMC)	0.83	BioGRID, IntAct, MINT
SIK2	protein kinase assay	phosphorylation reaction	27478041, (Europe PMC)	0.44	IntAct
SIRT1	Affinity Capture-Western, anti bait coimmunoprecipitation	physical, physical association	21241768, (Europe PMC)	0.40	BioGRID, IntAct
SLC23A1	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
SLC24A1	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
SNX17	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
SNX32	Affinity Capture-MS	physical	28514442, (Europe PMC)	NA	BioGRID
SNX8	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
SOCS1	Two-hybrid, two hybrid array, validated two hybrid	physical, physical association	25814554, (Europe PMC)	0.49	BioGRID, IntAct
SOCS6	Affinity Capture-MS	physical	12052866, (Europe PMC)	NA	BioGRID
SOS1	Co-localization, peptide array, proximity ligation assay	physical, physical association	17474147, 25241761, (Europe PMC)	0.59	BioGRID, IntAct
SOS2	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
SPEN	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
SQSTM1	Affinity Capture-Western, Far Western	physical	9564850, (Europe PMC)	NA	BioGRID
SRC	Affinity Capture-Western, Co-localization, anti bait coimmunoprecipitation, proximity ligation assay	association, physical, physical association	10487518, 19861161, 19903481, 23065768, 23397142, 24498420, 25241761, (Europe PMC)	0.82	BioGRID, IntAct, MINT
SSTR2	anti bait coimmunoprecipitation, pull down, surface plasmon resonance	direct interaction, physical association	16917505, (Europe PMC)	0.64	IntAct, MINT
STAT3	Two-hybrid	physical	25814554, (Europe PMC)	NA	BioGRID
STAT3	two hybrid array, validated two hybrid	physical association	25814554, (Europe PMC)	0.49	IntAct
SUV39H2	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
SYK	Affinity Capture-Western, Reconstituted Complex, Two-hybrid, anti bait coimmunoprecipitation, pull down, two hybrid	physical, physical association	15536084, 16921024, (Europe PMC)	0.58	BioGRID, IntAct, MINT
SYN1	Affinity Capture-Western	physical	10899172, (Europe PMC)	NA	BioGRID
SYNJ2	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
SYNM	Affinity Capture-Western	physical	17437541, (Europe PMC)	NA	BioGRID
TGDS	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
TGFBR1	Affinity Capture-Western	physical	9435577, (Europe PMC)	NA	BioGRID
TGFBR2	Affinity Capture-MS, Affinity Capture-Western	physical	26186194, 28514442, 9435577, (Europe PMC)	NA	BioGRID
TGOLN2	peptide array, proximity-dependent biotin identification	association, physical association	17474147, 29568061, (Europe PMC)	0.56	IntAct
THRA	anti bait coimmunoprecipitation	physical association	16966610, (Europe PMC)	0.40	IntAct
THRB	pull down	direct interaction	16446424, (Europe PMC)	0.44	IntAct
TIRAP	anti tag coimmunoprecipitation, fluorescence microscopy	colocalization, physical association	19574958, (Europe PMC)	0.46	IntAct, MINT
TLR2	fluorescent resonance energy transfer	physical association	23247210, (Europe PMC)	0.40	IntAct, MINT
TLR3	Affinity Capture-Western, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation	physical, physical association	15502848, 16858407, (Europe PMC)	0.52	BioGRID, IntAct, MINT
TMEM17	Proximity Label-MS, proximity-dependent biotin identification	association, physical	26638075, (Europe PMC)	0.35	BioGRID, IntAct
TNFRSF1A	Affinity Capture-Western	physical	18606683, (Europe PMC)	NA	BioGRID
TNIP1	Affinity Capture-Western	physical	17632516, (Europe PMC)	NA	BioGRID
TNS4	Two-hybrid, two hybrid array, validated two hybrid	physical, physical association	25814554, (Europe PMC)	0.49	BioGRID, IntAct
TPSAB1	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
TPSB2	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
TPX2	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
TTR	Two-hybrid	physical	18624398, (Europe PMC)	NA	BioGRID
TUBA1B	Affinity Capture-Western, Reconstituted Complex	physical	7592789, (Europe PMC)	NA	BioGRID
TULP4	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
TYRO3	Affinity Capture-Western, Two-hybrid	physical	10627473, (Europe PMC)	NA	BioGRID
VAV1	Affinity Capture-Western, Reconstituted Complex, pull down	association, physical	17050525, 9162069, 9891995, (Europe PMC)	0.35	BioGRID, IntAct, MINT
VAV3	anti bait coimmunoprecipitation	physical association	16982329, (Europe PMC)	0.40	IntAct, MINT
VHL	Negative Genetic	genetic	28319113, (Europe PMC)	NA	BioGRID
VPS13A	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
VSIG4	Affinity Capture-MS	physical	26186194, 28514442, (Europe PMC)	NA	BioGRID
WAS	Affinity Capture-Western, Reconstituted Complex	physical	8805332, (Europe PMC)	NA	BioGRID
WASF1	anti bait coimmunoprecipitation	physical association	21946561, (Europe PMC)	0.40	IntAct, MINT
WDR26	Affinity Capture-Western	physical	26895380, (Europe PMC)	NA	BioGRID
WEE1	Negative Genetic	genetic	28319113, (Europe PMC)	NA	BioGRID
YWHAG	Affinity Capture-MS, anti bait coimmunoprecipitation, coimmunoprecipitation	physical, physical association	15324660, 17353931, (Europe PMC)	0.59	BioGRID, IntAct, MINT
YWHAZ	pull down	association	10887121, (Europe PMC)	0.35	IntAct, MINT
ZAP70	Affinity Capture-Western	physical	15536084, (Europe PMC)	NA	BioGRID
ZC4H2	peptide array	physical association	17474147, (Europe PMC)	0.40	IntAct
ZDHHC17	Affinity Capture-Western, Two-hybrid	physical	24705354, (Europe PMC)	NA	BioGRID
ZDHHC17	luminescence based mammalian interactome mapping, two hybrid array	physical association	24705354, (Europe PMC)	0.51	IntAct

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PIK3R1