DEPOD - human DEPhOsphorylation Database

Basic Information
Phosphatases
Pathway
Interacting Proteins
Phosphorylating Kinases

Gene Name	RAF1 (QuickGO)	Interactive visualization of RAF1 structures (A quick tutorial to explore the interctive visulaization) Representative structure: 1C1Y
Synonyms	RAF1, RAF
Protein Name	RAF1
Alternative Name(s)	RAF proto-oncogene serine/threonine-protein kinase;2.7.11.1;Proto-oncogene c-RAF;cRaf;Raf-1;
Protein Family	Belongs to the protein kinase superfamily TKL Ser/Thrprotein kinase family RAF subfamily
EntrezGene ID	5894 (Comparitive Toxicogenomics)
UniProt AC (Human)	P04049 (protein sequence)
Enzyme Class	2.7.11.1 (BRENDA )
Molecular Weight	73052 Dalton
Protein Length	648 amino acids (AA)
Genome Browsers	NCBI \| ENSG00000132155 (Ensembl) \| UCSC
Crosslinking annotations	Query our ID-mapping table
Orthologues	Quest For Orthologues (QFO) \| GeneTree \| eggNOG - KOG0193 \| eggNOG - ENOG410Y4UP
Phosphorylation Network	Visualize

Domain organization, Expression, Diseases

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Localization, Function, Catalytic activity and Sequence

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Localization (UniProt annotation)
Cytoplasm Cell membrane MitochondrionNucleus Note=Colocalizes with RGS14 and BRAF in both thecytoplasm and membranes Phosphorylation at Ser-259 impairs itsmembrane accumulation Recruited to the cell membrane by theactive Ras protein Phosphorylation at Ser-338 and Ser-339 by PAK1is required for its mitochondrial localization Retinoic acid-induced Ser-621 phosphorylated form of RAF1 is predominantlylocalized at the nucleus
Function (UniProt annotation)
Serine/threonine-protein kinase that acts as aregulatory link between the membrane-associated Ras GTPases andthe MAPK/ERK cascade, and this critical regulatory link functionsas a switch determining cell fate decisions includingproliferation, differentiation, apoptosis, survival and oncogenictransformation RAF1 activation initiates a mitogen-activatedprotein kinase (MAPK) cascade that comprises a sequentialphosphorylation of the dual-specific MAPK kinases (MAP2K1/MEK1 andMAP2K2/MEK2) and the extracellular signal-regulated kinases(MAPK3/ERK1 and MAPK1/ERK2) The phosphorylated form of RAF1 (onresidues Ser-338 and Ser-339, by PAK1) phosphorylates BAD/Bcl2-antagonist of cell death at 'Ser-75' Phosphorylates adenylylcyclases: ADCY2, ADCY5 and ADCY6, resulting in their activationPhosphorylates PPP1R12A resulting in inhibition of the phosphataseactivity Phosphorylates TNNT2/cardiac muscle troponin T Canpromote NF-kB activation and inhibit signal transducers involvedin motility (ROCK2), apoptosis (MAP3K5/ASK1 and STK3/MST2),proliferation and angiogenesis (RB1) Can protect cells fromapoptosis also by translocating to the mitochondria where it bindsBCL2 and displaces BAD/Bcl2-antagonist of cell death RegulatesRho signaling and migration, and is required for normal woundhealing Plays a role in the oncogenic transformation ofepithelial cells via repression of the TJ protein, occludin (OCLN)by inducing the up-regulation of a transcriptional repressorSNAI2/SLUG, which induces down-regulation of OCLN Restrictscaspase activation in response to selected stimuli, notably Fasstimulation, pathogen-mediated macrophage apoptosis, and erythroiddifferentiation
Catalytic Activity (UniProt annotation)
ATP + a protein = ADP + a phosphoprotein
Protein Sequence
MEHIQGAWKTISNGFGFKDAVFDGSSCISPTIVQQFGYQRRASDDGKLTDPSKTSNTIRVFLPNKQRTVVNVRNGMSLHD CLMKALKVRGLQPECCAVFRLLHEHKGKKARLDWNTDAASLIGEELQVDFLDHVPLTTHNFARKTFLKLAFCDICQKFLL NGFRCQTCGYKFHEHCSTKVPTMCVDWSNIRQLLLFPNSTIGDSGVPALPSLTMRRMRESVSRMPVSSQHRYSTPHAFTF NTSSPSSEGSLSQRQRSTSTPNVHMVSTTLPVDSRMIEDAIRSHSESASPSALSSSPNNLSPTGWSQPKTPVPAQRERAP VSGTQEKNKIRPRGQRDSSYYWEIEASEVMLSTRIGSGSFGTVYKGKWHGDVAVKILKVVDPTPEQFQAFRNEVAVLRKT RHVNILLFMGYMTKDNLAIVTQWCEGSSLYKHLHVQETKFQMFQLIDIARQTAQGMDYLHAKNIIHRDMKSNNIFLHEGL TVKIGDFGLATVKSRWSGSQQVEQPTGSVLWMAPEVIRMQDNNPFSFQSDVYSYGIVLYELMTGELPYSHINNRDQIIFM VGRGYASPDLSKLYKNCPKAMKRLVADCVKKVKEERPLFPQILSSIELLQHSLPKINRSASEPSLHRAAHTEDINACTLT TSPRLPVF

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:0000165	P:MAPK cascade
GO:0000186	P:activation of MAPKK activity
GO:0001666	P:response to hypoxia
GO:0002223	P:stimulatory C-type lectin receptor signaling pathway
GO:0004672	F:protein kinase activity
GO:0004674	F:protein serine/threonine kinase activity
GO:0004709	F:MAP kinase kinase kinase activity
GO:0005524	F:ATP binding
GO:0005737	C:cytoplasm
GO:0005741	C:mitochondrial outer membrane
GO:0005794	C:Golgi apparatus
GO:0005829	C:cytosol
GO:0005886	C:plasma membrane
GO:0006468	P:protein phosphorylation
GO:0006915	P:apoptotic process
GO:0007165	P:signal transduction
GO:0007190	P:activation of adenylate cyclase activity
GO:0007275	P:multicellular organism development
GO:0007507	P:heart development
GO:0008179	F:adenylate cyclase binding
GO:0008283	P:cell proliferation
GO:0008285	P:negative regulation of cell proliferation
GO:0009968	P:negative regulation of signal transduction
GO:0010856	F:adenylate cyclase activator activity
GO:0016301	F:kinase activity
GO:0016607	C:nuclear speck
GO:0019899	F:enzyme binding
GO:0030154	P:cell differentiation
GO:0030168	P:platelet activation
GO:0030878	P:thyroid gland development
GO:0031143	C:pseudopodium
GO:0031333	P:negative regulation of protein complex assembly
GO:0031434	F:mitogen-activated protein kinase kinase binding
GO:0033138	P:positive regulation of peptidyl-serine phosphorylation
GO:0034220	P:ion transmembrane transport
GO:0035019	P:somatic stem cell population maintenance
GO:0035023	P:regulation of Rho protein signal transduction
GO:0035773	P:insulin secretion involved in cellular response to glucose stimulus
GO:0035994	P:response to muscle stretch
GO:0042060	P:wound healing
GO:0042802	F:identical protein binding
GO:0042981	P:regulation of apoptotic process
GO:0043066	P:negative regulation of apoptotic process
GO:0043154	P:negative regulation of cysteine-type endopeptidase activity involved in apoptotic process
GO:0045104	P:intermediate filament cytoskeleton organization
GO:0045595	P:regulation of cell differentiation
GO:0045944	P:positive regulation of transcription by RNA polymerase II
GO:0046872	F:metal ion binding
GO:0046982	F:protein heterodimerization activity
GO:0048011	P:neurotrophin TRK receptor signaling pathway
GO:0048538	P:thymus development
GO:0060324	P:face development
GO:0070374	P:positive regulation of ERK1 and ERK2 cascade
GO:0071550	P:death-inducing signaling complex assembly
GO:1902042	P:negative regulation of extrinsic apoptotic signaling pathway via death domain receptors
GO:2000145	P:regulation of cell motility

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.
hsa04010	MAPK signaling pathway	The mitogen-activated protein kinase (MAPK) cascade is a highly conserved module that is involved in various cellular functions, including cell proliferation, differentiation and migration. Mammals express at least four distinctly regulated groups of MAPKs, extracellular signal-related kinases (ERK)-1/2, Jun amino-terminal kinases (JNK1/2/3), p38 proteins (p38alpha/beta/gamma/delta) and ERK5, that are activated by specific MAPKKs: MEK1/2 for ERK1/2, MKK3/6 for the p38, MKK4/7 (JNKK1/2) for the JNKs, and MEK5 for ERK5. Each MAPKK, however, can be activated by more than one MAPKKK, increasing the complexity and diversity of MAPK signalling. Presumably each MAPKKK confers responsiveness to distinct stimuli. For example, activation of ERK1/2 by growth factors depends on the MAPKKK c-Raf, but other MAPKKKs may activate ERK1/2 in response to pro-inflammatory stimuli.
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.
hsa04022	cGMP-PKG signaling pathway	Cyclic GMP (cGMP) is the intracellular second messenger that mediates the action of nitric oxide (NO) and natriuretic peptides (NPs), regulating a broad array of physiologic processes. The elevated intracellular cGMP level exerts its physiological action through two forms of cGMP-dependent protein kinase (PKG), cGMP-regulated phosphodiesterases (PDE2, PDE3) and cGMP-gated cation channels, among which PKGs might be the primary mediator. PKG1 isoform-specific activation of established substrates leads to reduction of cytosolic calcium concentration and/or decrease in the sensitivity of myofilaments to Ca2+ (Ca2+-desensitization), resulting in smooth muscle relaxation. In cardiac myocyte, PKG directly phosphorylates a member of the transient potential receptor canonical channel family, TRPC6, suppressing this nonselective ion channel's Ca2+ conductance, G-alpha-q agonist-induced NFAT activation, and myocyte hypertrophic responses. PKG also opens mitochondrial ATP-sensitive K+ (mitoKATP) channels and subsequent release of ROS triggers cardioprotection.
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.
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.
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.
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.
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.
hsa04270	Vascular smooth muscle contraction	The vascular smooth muscle cell (VSMC) is a highly specialized cell whose principal function is contraction. On contraction, VSMCs shorten, thereby decreasing the diameter of a blood vessel to regulate the blood flow and pressure. The principal mechanisms that regulate the contractile state of VSMCs are changes in cytosolic Ca2+ concentration ([Ca2+]c). In response to vasoconstrictor stimuli, Ca2+ is mobilized from intracellular stores and/or the extracellular space to increase [Ca2+]c in VSMCs. The increase in [Ca2+]c, in turn, activates the Ca2+-CaM-MLCK pathway and stimulates MLC20 phosphorylation, leading to myosin-actin interactions and, hence, the development of contractile force. The sensitivity of contractile myofilaments or MLC20 phosphorylation to Ca2+ can be secondarily modulated by other signaling pathways. During receptor stimulation, the contractile force is greatly enhanced by the inhibition of myosin phosphatase. Rho/Rho kinase, PKC, and arachidonic acid have been proposed to play a pivotal role in this enhancement. The signaling events that mediate relaxation include the removal of a contractile agonist (passive relaxation) and activation of cyclic nucleotide-dependent signaling pathways in the continued presence of a contractile agonist (active relaxation). Active relaxation occurs through the inhibition of both Ca2+ mobilization and myofilament Ca2+ sensitivity in VSMCs.
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.
hsa04371	Apelin signaling pathway	Apelin is an endogenous peptide capable of binding the apelin receptor (APJ), which was originally described as an orphan G-protein-coupled receptor. Apelin and APJ are widely expressed in various tissues and organ systems. They are implicated in different key physiological processes such as angiogenesis, cardiovascular functions, cell proliferation and energy metabolism regulation. On the other hand, this ligand receptor couple is also involved in several pathologies including diabetes, obesity, cardiovascular disease and cancer.
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.
hsa04540	Gap junction	Gap junctions contain intercellular channels that allow direct communication between the cytosolic compartments of adjacent cells. Each gap junction channel is formed by docking of two 'hemichannels', each containing six connexins, contributed by each neighboring cell. These channels permit the direct transfer of small molecules including ions, amino acids, nucleotides, second messengers and other metabolites between adjacent cells. Gap junctional communication is essential for many physiological events, including embryonic development, electrical coupling, metabolic transport, apoptosis, and tissue homeostasis. Communication through Gap Junction is sensitive to a variety of stimuli, including changes in the level of intracellular Ca2+, pH, transjunctional applied voltage and phosphorylation/dephosphorylation processes. This figure represents the possible activation routes of different protein kinases involved in Cx43 and Cx36 phosphorylation.
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.
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.
hsa04720	Long-term potentiation	Hippocampal long-term potentiation (LTP), a long-lasting increase in synaptic efficacy, is the molecular basis for learning and memory. Tetanic stimulation of afferents in the CA1 region of the hippocampus induces glutamate release and activation of glutamate receptors in dendritic spines. A large increase in [Ca2+]i resulting from influx through NMDA receptors leads to constitutive activation of CaM kinase II (CaM KII) . Constitutively active CaM kinase II phosphorylates AMPA receptors, resulting in potentiation of the ionic conductance of AMPA receptors. Early-phase LTP (E-LTP) expression is due, in part, to this phosphorylation of the AMPA receptor. It is hypothesized that postsynaptic Ca2+ increases generated through NMDA receptors activate several signal transduction pathways including the Erk/MAP kinase and cAMP regulatory pathways. The convergence of these pathways at the level of the CREB/CRE transcriptional pathway may increase expression of a family of genes required for late-phase LTP (L-LTP).
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.
hsa04726	Serotonergic synapse	Serotonin (5-Hydroxytryptamine, 5-HT) is a monoamine neurotransmitter that plays important roles in physiological functions such as learning and memory, emotion, sleep, pain, motor function and endocrine secretion, as well as in pathological states including abnormal mood and cognition. Once released from presynaptic axonal terminals, 5-HT binds to receptors, which have been divided into 7 subfamilies on the basis of conserved structures and signaling mechanisms. These families include the ionotropic 5-HT3 receptors and G-protein-coupled 5-HT receptors, the 5-HT1 (Gi /Go -coupled), 5-HT2(Gq-coupled), 5-HT4/6/7 (Gs-coupled) and 5-HT5 receptors. Presynaptically localized 5-HT1B receptors are thought to be the autoreceptors that suppress excess 5-HT release. 5-HT's actions are terminated by transporter- mediated reuptake into neurons, leading to catabolism by monoamine oxidase.
hsa04730	Long-term depression	Cerebellar long-term depression (LTD), thought to be a molecular and cellular basis for cerebellar learning, is a process involving a decrease in the synaptic strength between parallel fiber (PF) and Purkinje cells (PCs) induced by the conjunctive activation of PFs and climbing fiber (CF). Multiple signal transduction pathways have been shown to be involved in this process. Activation of PFs terminating on spines in dendritic branchlets leads to glutamate release and activation of both AMPA and mGluRs. Activation of CFs, which make multiple synaptic contacts on proximal dendrites, also via AMPA receptors, opens voltage-gated calcium channels (VGCCs) and causes a generalized influx of calcium. These cellular signals, generated from two different synaptic origins, trigger a cascade of events culminating in a phosphorylation-dependent, long-term reduction in AMPA receptor sensitivity at the PF-PC synapse. This may take place either through receptor internalization and/or through receptor desensitization.
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.
hsa04912	GnRH signaling pathway	Gonadotropin-releasing hormone (GnRH) secretion from the hypothalamus acts upon its receptor in the anterior pituitary to regulate the production and release of the gonadotropins, LH and FSH. The GnRHR is coupled to Gq/11 proteins to activate phospholipase C which transmits its signal to diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). DAG activates the intracellular protein kinase C (PKC) pathway and IP3 stimulates release of intracellular calcium. In addition to the classical Gq/11, coupling of Gs is occasionally observed in a cell-specific fashion. Signaling downstream of protein kinase C (PKC) leads to transactivation of the epidermal growth factor (EGF) receptor and activation of mitogen-activated protein kinases (MAPKs), including extracellular-signal-regulated kinase (ERK), Jun N-terminal kinase (JNK) and p38 MAPK. Active MAPKs translocate to the nucleus, resulting in activation of transcription factors and rapid induction of early genes.
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.
hsa04916	Melanogenesis	Cutaneous melanin pigment plays a critical role in camouflage, mimicry, social communication, and protection against harmful effects of solar radiation. Melanogenesis is under complex regulatory control by multiple agents. The most important positive regulator of melanogenesis is the MC1 receptor with its ligands melanocortic peptides. MC1R activates the cyclic AMP (cAMP) response-element binding protein (CREB). Increased expression of MITF and its activation by phosphorylation (P) stimulate the transcription of tyrosinase (TYR), tyrosinase-related protein 1 (TYRP1), and dopachrome tautomerase (DCT), which produce melanin. Melanin synthesis takes place within specialized intracellular organelles named melanosomes. Melanin-containing melanosomes then move from the perinuclear region to the dendrite tips and are transferred to keratinocytes by a still not well-characterized mechanism.
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.
hsa04921	Oxytocin signaling pathway	Oxytocin (OT) is a nonapeptide synthesized by the magno-cellular neurons located in the supraoptic (SON) and paraventricular (PVN) nuclei of the hypothalamus. It exerts a wide variety of central and peripheral effects. However, its best-known and most well-established roles are stimulation of uterine contractions during parturition and milk release during lactation. Oxytocin also influences cardiovascular regulation and various social behaviors. The actions of OT are all mediated by one type of OT receptor (OTR). This is a transmembrane receptor belonging to the G-protein-coupled receptor superfamily. The main signaling pathway is the Gq/PLC/Ins3 pathway, but the MAPK and the RhoA/Rho kinase pathways are also activated, contributing to increased prostaglandin production and direct contractile effect on myometrial cells. In the cardiovascular system, OTR is associated with the ANP-cGMP and NO-cGMP pathways, which reduce the force and rate of contraction and increase vasodilatation.
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.
hsa04928	Parathyroid hormone synthesis, secretion and action	Parathyroid hormone (PTH) is a key regulator of calcium and phosphorus homeostasis. The principal regulators of PTH secretion are extracellular ionized calcium (Ca2+) and 1,25-dihydroxyvitamin D (1,25(OH)2D3). Under conditions of dietary Ca restriction, a decrement in serum Ca concentration induces release of PTH from the parathyroid gland. PTH acts on bone and kidney to stimulate bone turnover, increase the circulating levels of 1,25(OH)2D3 and calcium and inhibit the reabsorption of phosphate from the glomerular filtrate. This hormone exerts its actions via binding to the PTH/PTH-related peptide receptor (PTH1R). PTH1R primarily activates two sub-types of heterotrimeric Gproteins: Gs and Gq , which in turn regulate the activity of adenylyl cyclases and phospholipase C (PLC) that control the flow of cAMP/PKA and IP/PKC signaling cascades, respectively.
hsa05034	Alcoholism	Alcoholism, also called dependence on alcohol (ethanol), is a chronic relapsing disorder that is progressive and has serious detrimental health outcomes. As one of the primary mediators of the rewarding effects of alcohol, dopaminergic ventral tegmental area (VTA) projections to the nucleus accumbens (NAc) have been identified. Acute exposure to alcohol stimulates dopamine release into the NAc, which activates D1 receptors, stimulating PKA signaling and subsequent CREB-mediated gene expression, whereas chronic alcohol exposure leads to an adaptive downregulation of this pathway, in particular of CREB function. The decreased CREB function in the NAc may promote the intake of drugs of abuse to achieve an increase in reward and thus may be involved in the regulation of positive affective states of addiction. PKA signaling also affects NMDA receptor activity and may play an important role in neuroadaptation in response to chronic alcohol exposure.
hsa05152	Tuberculosis	Tuberculosis, or TB, is an infectious disease caused by Mycobacterium tuberculosis. One third of the world's population is thought to be infected with TB. About 90% of those infected result in latent infections, and about 10% of latent infections develop active diseases when their immune system is impaired due to the age, other diseases such as AIDS or exposure to immunosuppressive drugs. TB is transmitted through the air and primarily attacks the lungs, then it can spread by the circulatory system to other parts of body. Once TB bacilli have entered the host by the respiratory route and infected macrophages in the lungs, they interfere with phagosomal maturation, antigen presentation, apoptosis and host immune system to establish persistent or latent infection.
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.
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.
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.
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
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.
hsa05206	MicroRNAs in cancer	MicroRNA (miRNA) is a cluster of small non-encoding RNA molecules of 21 - 23 nucleotides in length, which controls gene expression post-transcriptionally either via the degradation of target mRNAs or the inhibition of protein translation. Using high-throughput profiling, dysregulation of miRNAs has been widely observed in different stages of cancer. The upregulation (overexpression) of specific miRNAs could lead to the repression of tumor suppressor gene expression, and conversely the downregulation of specific miRNAs could result in an increase of oncogene expression; both these situations induce subsequent malignant effects on cell proliferation, differentiation, and apoptosis that lead to tumor growth and progress. The miRNA signatures of cancer observed in various studies differ significantly. These inconsistencies occur due to the differences in the study populations and methodologies used. This pathway map shows the summarized results from various studies in 9 cancers, each of which is presented in a review article.
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.
hsa05219	Bladder cancer	The urothelium covers the luminal surface of almost the entire urinary tract, extending from the renal pelvis, through the ureter and bladder, to the proximal urethra. The majority of urothelial carcinoma are bladder carcinomas, and urothelial carcinomas of the renal pelvis and ureter account for only approximately 7% of the total. Urothelial tumours arise and evolve through divergent phenotypic pathways. Some tumours progress from urothelial hyperplasia to low-grade non-invasive superficial papillary tumours. More aggressive variants arise either from flat, high-grade carcinoma in situ (CIS) and progress to invasive tumours, or they arise de novo as invasive tumours. Low-grade papillary tumors frequently show a constitutive activation of the receptor tyrosine kinase-Ras pathway, exhibiting activating mutations in the HRAS and fibroblast growth factor receptor 3 (FGFR3) genes. In contrast, CIS and invasive tumors frequently show alterations in the TP53 and RB genes and pathways. Invasion and metastases are promoted by several factors that alter the tumour microenvironment, including the aberrant expression of E-cadherins (E-cad), matrix metalloproteinases (MMPs), angiogenic factors such as vascular endothelial growth factor (VEGF).
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.
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.

Pathway ID	Pathway Name	Pathway Description (KEGG)
R-HSA-2672351	Stimuli-sensing channels.	Ion channels that mediate sensations such as pain, warmth, cold, taste pressure and vision. Channels that mediate these sensations include acid-sensing ion channels (ASICs) (Wang & Xu 2011, Qadri et al. 2012, Deval et al. 2010) and the transient receptor potential channels (TRPCs) (Takahashi et al. 2012, Numata et al. 2011 in \TRP Channels\Zhu, MX editor, CRC Press, 2011, Ramsey et al. 2006, Montell 2005). Many channels are sensitive to changes in calcium (Ca2+) levels, both inside and outside the cell. Examples are protein tweety homologs 2 and 3 (TTYH2, 3) (Suzuki 2006), bestrophins 1-4 (BEST1-4) (Sun et al. 2002, Tsunenari et al. 2003, Kunzelmann et al. 2009, Hartzell et al. 2008) and ryanodine receptor tetramers (RYRs) (Beard et al. 2009)
R-HSA-392517	Rap1 signalling.	Rap1 (Ras-proximate-1) is a small G protein in the Ras superfamily. Like all G proteins, Rap1 is activated when bound GDP is exchanged for GTP. Rap1 is targeted to lipid membranes by the covalent attachment of lipid moieties to its carboxyl terminus. Movement of Rap1 from endosomal membranes to the plasma membrane upon activation has been reported in several cell types including Jurkat T cells and megakaryocytes. On activation, Rap1 undergoes conformational changes that facilitate recruitment of a variety of effectors, triggering it's participation in integrin signaling, ERK activation, and others
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-442742	CREB phosphorylation through the activation of Ras.	Ca2+ influx through the NMDA receptor initiates subsequent molecular pathways that have a defined role in establishing long-lasting synaptic changes. The molecular signaling initiated by a rise in Ca2+ within the spine leads to phosphorylation of Cyclic AMP Response Element binding protein (CREB) at serine 133 which is involved in the transcription of genes that results in long lasting changes in the synapse. The phosphorylation of CREB by increased Ca2+ can be brought about by distinct molecular pathways that may involve MAP kinase, activation of adenylate cyclase, activation of CaMKII and/or the activation of CaMKIV
R-HSA-5621575	CD209 (DC-SIGN) signaling.	CD209 (also called as DC-SIGN (DC-specific intracellular adhesion molecule-3-grabbing non-integrin)) is a type II transmembrane C-type lectin receptor preferentially expressed on dendritic cells (DCs). CD209 functions as a pattern recognition receptor (PRR) that recognises several microorganisms and pathogens, contributing to generation of pathogen-tailored immune responses (Gringhuis & Geijtenbeek 2010, den Dunnen et al. 2009, Svajger et al. 2010). CD209 interacts with different mannose-expressing pathogens such as Mycobacterium tuberculosis and HIV-1 (Gringhuis et al. 2007, Geijtenbeek et al. 2000a). It also acts as an adhesion receptor that interacts with ICAM2 (intracellular adhesion molecule-2) on endothelial cells and ICAM3 on T cells (Geijtenbeek et al. 2000b,c). \nCD209 functions not only as an independent PRR, but is also implicated in the modulation of Toll-like receptor (TLR) signaling at the level of the transcription factor NF-kB (Gringhuis et al. 2009). CLEC7A (Dectin-1) and CD209 (DC-SIGN) signalling modulates Toll-like receptor (TLR) signalling through the kinase RAF1 that is independent of the SYK pathway but integrated with it at the level of NF-kB activation. The activation of RAF1 by CLEC7A or CD209 does not lead to activation of extracellular signal-regulated kinase 1 (ERK1)/2 or Mitogen-activated protein kinase kinase 1 (MEK1)/2 but leads to the phosphorylation and subsequent acetylation of RELA (p65). RELA phosphorylated on S276 not only positively regulates the activity of p65 through acetylation of p65, but also represses RELB activity by sequestering active RELB into inactive p65-RELB dimers that do not bind DNA (Gringhuis et al. 2007, Svajger et al. 2010, Jacque et al. 2005). RAF1-dependent signaling pathway is crucial in dectin-1 mediated immunity as it modulates both the canonical (promoting p65 phosphorylation and acetylation) and non-canonical (forming inactive p65-RELB dimers) NK-kB activation
R-HSA-5673000	RAF activation.	Mammals have three RAF isoforms, A, B and C, that are activated downstream of RAS and stimulate the MAPK pathway. Although CRAF (also known as RAF-1) was the first identified and remains perhaps the best studied, BRAF is most similar to the RAF expressed in other organisms. Notably, MAPK (ERK) activation is more compromised in BRAF-deficient cells than in CRAF or ARAF deficient cells (Bonner et al, 1985; Mikula et al, 2001, Huser et al, 2001, Mercer et al, 2002; reviewed in Leicht et al, 2007; Matallanas et al, 2011; Cseh et al, 2014). Consistent with its important role in MAPK pathway activation, mutations in the BRAF gene, but not in those for A- or CRAF, are associated with cancer development (Davies et al, 2002; reviewed in Leicht et al, 2007). ARAF and CRAF may have arisen through gene duplication events, and may play additional roles in MAPK-independent signaling (Hindley and Kolch, 2002; Murakami and Morrison, 2001).Despite divergences in function, all mammalian RAF proteins share three conserved regions (CRs) and each interacts with RAS and MEK proteins, although with different affinities. The N-terminal CR1 contains a RAS-binding domain (RBD) and a cysteine-rich domain (CRD) that mediate interactions with RAS and the phospholipid membrane. CR2 contains inhibitory phosphorylation sites that impact RAS binding and RAF activation, while the C-terminal CR3 contains the bi-lobed kinase domain with its activation loop, and an adjacent upstream \N-terminal acidic motif\-S(S/G)YY in C- and A-RAF,respectively, and SSDD in B-RAF - that is required for RAF activation (Tran et al, 2005; Dhillon et al, 2002; Chong et al, 2001; Cutler et al, 1998; Chong et al, 2003; reviewed in Matallanas et al, 2011).Regulation of RAF activity involves multiple phosphorylation and dephosphorylation events, intramolecular conformational changes, homo- and heterodimerization between RAF monomers and changes to protein binding partners, including scaffolding proteins which bring pathway members together (reviewed in Matallanas et al, 2011; Cseh et al, 2014). The details of this regulation are not completely known and differ slightly from one RAF isoform to another. Briefly, in the inactive state, RAF phosphorylation on conserved serine residues in CR2 promote an interaction with 14-3-3 dimers, maintaining the kinase in a closed conformation. Upon RAS activation, these sites are dephosphorylated, allowing the RAF CRD and RBD to bind RAS and phospholipids, facilitating membrane recruitment. RAF activation requires homo- or heterodimerization, which promotes autophosphorylation in the activation loop of the receiving monomer. Of the three isoforms, only BRAF is able to initiate this allosteric activation of other RAF monomers (Hu et al, 2013; Heidorn et al, 2010; Garnett et al, 2005). This activity depends on negative charge in the N-terminal acidic region (NtA; S(S/G)YY or SSDD) adjacent to the kinase domain. In BRAF, this region carries permanent negative charge due to the presence of the two aspartate residues in place of the tyrosine residues of A- and CRAF. In addition, unique to BRAF, one of the serine residues of the NtA is constitutively phosphorylated. In A- and CRAF, residues in this region are subject to phosphorylation by activated MEK downstream of RAF activation, establishing a positive feedback loop and allowing activated A- and CRAF monomers to act as transactivators in turn (Hu et al, 2013; reviewed in Cseh et al, 2014). RAF signaling is terminated through dephosphorylation of the NtA region and phosphorylation of the residues that mediate the inhibitory interaction with 14-3-3, promoting a return to the inactive state (reviewed in Matallanas et al, 2011; Cseh et al, 2014)
R-HSA-5674135	MAP2K and MAPK activation.	Activated RAF proteins are restricted substrate kinases whose primary downstream targets are the two MAP2K proteins, MAPK2K1 and MAP2K2 (also known as MEK1 and MEK2) (reviewed in Roskoski, 2010, Roskoski, 2012a). Phosphorylation of the MAPK2K activation loop primes them to phosphorylate the primary effector of the activated MAPK pathway, the two MAPK proteins MAPK3 and MAPK1 (also known as ERK1 and 2). Unlike their upstream counterparts, MAPK3 and MAPK1 catalyze the phosphorylation of hundreds of cytoplasmic and nuclear targets including transcription factors and regulatory molecules (reviewed in Roskoski, 2012b). Activation of MAP2K and MAPK proteins downstream of activated RAF generally occurs in the context of a higher order scaffolding complex that regulates the specificity and localization of the pathway (reviewed in Brown and Sacks, 2009; Matallanas et al, 2011)
R-HSA-5674499	Negative feedback regulation of MAPK pathway.	MAPK pathway activation is limited by a number of negative feedback loops established by MAPK-dependent phosphorylations
R-HSA-5675221	Negative regulation of MAPK pathway.	The duration and extent of activated MAPK signaling is regulated at many levels through mechanisms that include phosphorylation and dephosphorylation, changes to protein interacting partners and subcellular localization (reviewed in Matallanas et al, 2011). Activated RAF proteins are subject to MAPK-dependent phosphorylation that promotes the subsequent dephosphorylation of the activation loop and NtA region, terminating RAF kinase activity. This dephosphorylation, catalyzed by PP2A and PP5, primes the RAF proteins for PKA or AKT-mediated phosphorylation of residues S259 and S621, restoring the 14-3-3 binding sites and returning the RAF proteins to the inactive state (von Kriegsheim et al, 2006; Dougherty et al, 2005; reviewed in Matallanas et al, 2011). The phosphorylated RAF1 NtA is also subject to additional regulation through binding to the PEBP1 protein, which promotes its dissociation from MAP2K substrates (Shin et al, 2009). Activated MAPK proteins also phosphorylate T292 of MAP2K1; this phosphorylation limits the activity of MAP2K1, and indirectly affects MAP2K2 activity through by modulating the activity of the MAP2K heterodimer (Catalanotti et al, 2009; reviewed in Matallanas et al, 2011).Dephosphorylation of MAPKs by the dual specificity MAPK phosphatases (DUSPs) plays a key role in limiting the extent of pathway activation (Owens et al, 2007; reviewed in Roskoski, 2012b). Class I DUSPs are localized in the nucleus and are induced by activation of the MAPK pathway, establishing a negative feedback loop, while class II DUSPs dephosphorylate cytoplasmic MAPKs (reviewed in Rososki, 2012b).MAPK signaling is also regulated by the RAS GAP-mediated stimulation of intrinsic RAS GTPase activity which returns RAS to the inactive, GDP bound state (reviewed in King et al, 2013)
R-HSA-6802946	Signaling by moderate kinase activity BRAF mutants.	In addition to the highly prevalent and activating V600E BRAF mutations, numerous moderately activating and less common mutations have also been identified in human cancers (Forbes et al, 2015)
R-HSA-6802948	Signaling by high-kinase activity BRAF mutants.	BRAF is mutated in about 8% of human cancers, with high prevalence in hairy cell leukemia, melanoma, papillary thyroid and ovarian carcinomas, colorectal cancer and a variety of other tumors (Davies et al, 2002; reviewed in Samatar and Poulikakos, 2014). Most BRAF mutations fall in the activation loop region of the kinase or the adjacent glycine rich region. These mutations promote increased kinase activity either by mimicking the effects of activation loop phosphorylations or by promoting the active conformation of the enzyme (Davies et al, 2002; Wan et al, 2004). Roughly 90% of BRAF mutants are represented by the single missense mutation BRAF V600E (Davies et al, 2002; Wan et al, 2004). Other highly active kinase mutants of BRAF include BRAF G469A and BRAF T599dup. G469 is in the glycine rich region of the kinase domain which plays a role in orienting ATP for catalysis, while T599 is one of the two conserved regulatory phosphorylation sites of the activation loop. Each of these mutants has highly enhanced basal kinase activities, phosphorylates MEK and ERK in vitro and in vivo and is transforming when expressed in vivo (Davies et al, 2002; Wan et al, 2004; Eisenhardt et al, 2011). Further functional characterization shows that these highly active mutants are largely resistant to disruption of the BRAF dimer interface, suggesting that they are able to act as monomers (Roring et al, 2012; Brummer et al, 2006; Freeman et al, 2013; Garnett et al, 2005). Activating BRAF mutations occur for the most part independently of RAS activating mutations, and RAS activity levels are generally low in BRAF mutant cells. Moreover, the kinase activity of these mutants is only slightly elevated by coexpression of G12V KRAS, and biological activity of the highly active BRAF mutants is independent of RAS binding (Brummer et al, 2006; Wan et al, 2004; Davies et al, 2002; Garnett et al, 2005). Although BRAF V600E is inhibited by RAF inhibitors such as vemurafenib, resistance frequently develops, in some cases mediated by the expression of a splice variant that lacks the RAS binding domain and shows elevated dimerization compared to the full length V600E mutant (Poulikakos et al, 2011; reviewed in Lito et al, 2013)
R-HSA-6802949	Signaling by RAS mutants.	Members of the RAS gene family were the first oncogenes to be identified, and mutations in RAS are present in ~20-30% of human cancers (reviewed in Prior et al, 2012). Mutations in the KRAS gene are the most prevalent, and are found with high frequency in colorectal cancer, non-small cell lung cancer and pancreatic cancer, among others. The reasons for the lower prevalence of HRAS and NRAS mutations in human cancers are not fully understood, but may reflect gene-specific functions as well as differential codon usage and spatio-temporal regulation (reviewed in Prior et al, 2012; Stephen et al, 2014; Pylayeva-Gupta et al, 2011). Activating RAS mutations contribute to cellular proliferation, transformation and survival by activating the MAPK signaling pathway, the AKT pathway and the RAL GDS pathway, among others (reviewed in Stephen et al, 2014; Pylayeva-Gupta et al, 2011).Although the frequency and distribution varies between RAS genes and cancer types, the vast majority of activating RAS mutations occur at one of three residues - G12, G13 and Q61. Mutations at these sites favour the RAS:GTP bound form and yield constitutively active versions of the protein (reviewed in Prior et al, 2012)
R-HSA-6802952	Signaling by BRAF and RAF fusions.	In addition to the more prevalent point mutations, BRAF and RAF1 are also subject to activation as a result of translocation events that yield truncated or fusion products (Jones et al, 2008; Cin et al, 2011; Palanisamy et al, 2010; Ciampi et al, 2005; Stransky et al, 2014; Hutchinson et al, 2013; Zhang et al, 2013; Lee et al, 2012; Ricarte-Filho et al, 2013; reviewed in Lavoie and Therrien et al, 2015). In general these events put the C-terminal kinase domain of BRAF or RAF1 downstream of an N-terminal sequence provided by a partner protein. This removes the N-terminal region of the RAF protein, relieving the autoinhibition imposed by this region of the protein. In addition, some but not all of the fusion partner proteins have been shown to contain coiled-coil or other dimerization domains. Taken together, the fusion proteins are thought to dimerize constitutively and activate downstream signaling (Jones et al, 2008; Lee et al, 2012; Hutchinson et al, 2013; Ciampi et al, 2005; Cin et al, 2011; Stransky et al, 2014)
R-HSA-6802955	Paradoxical activation of RAF signaling by kinase inactive BRAF.	While BRAF-specific inhibitors inhibit MAPK/ERK activation in the presence of the BRAF V600E mutant, paradoxical activation of ERK signaling has been observed after treatment of cells with inhibitor in the presence of WT BRAF (Wan et al, 2004; Garnett et al, 2005; Heidorn et al, 2010; Hazivassiliou et al, 2010; Poulikakos et al, 2010). This paradoxical ERK activation is also seen in cells expressing kinase-dead or impaired versions of BRAF such as D594V, which occur with low frequency in some cancers (Wan et al, 2004; Heidorn et al, 2010). Unlike BRAF V600E, which occurs exclusively of activating RAS mutations, kinase-impaired versions of BRAF are coincident with RAS mutations in human cancers, and indeed, paradoxical activation of ERK signaling in the presence of inactive BRAF is enhanced in the presence of oncogenic RAS (Heidorn et al, 2010; reviewed in Holderfield et al, 2014). Although the details remain to be worked out, paradoxical ERK activation in the presence of inactive BRAF appears to rely on enhanced dimerization with and transactivation of CRAF (Heidorn et al, 2010; Hazivassiliou et al, 2010; Poulikakos et al, 2010; Roring et al, 2012; Rajakulendran et al, 2009; Holderfield et al, 2013; Freeman et al, 2013; reviewed in Roskoski, 2010; Samatar and Poulikakos, 2014; Lavoie and Therrien, 2015)

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Interacting partner	Detection method	Interaction type	PubMed IDs	Interaction Score	Source
AGTR1	Affinity Capture-Western	physical	11226259, (Europe PMC)	NA	BioGRID
AKT1	Affinity Capture-Western, Biochemical Activity, proximity ligation assay, pull down	physical, physical association	10576742, 19058874, 19197339, 25241761, (Europe PMC)	0.59	BioGRID, IntAct, MINT
AMER1	Affinity Capture-MS, inference by socio-affinity scoring	physical, physical association	27173435, (Europe PMC)	0.27	BioGRID, IntAct
AR	Co-purification	physical	8349631, (Europe PMC)	NA	BioGRID
ARRB2	Affinity Capture-Western	physical	11226259, (Europe PMC)	NA	BioGRID
BAD	Biochemical Activity, Co-localization, proximity ligation assay	physical, physical association	15849194, 19667065, 23397142, 25241761, (Europe PMC)	0.59	BioGRID, IntAct
BAG1	Affinity Capture-Western, Reconstituted Complex, Two-hybrid, coimmunoprecipitation, two hybrid	physical, physical association	11231577, 8692945, (Europe PMC)	0.51	BioGRID, IntAct, MINT
BCL2	Affinity Capture-Western, Reconstituted Complex, Two-hybrid	physical	12488548, 15849194, 8929532, (Europe PMC)	NA	BioGRID
BCL2L1	Co-localization, Reconstituted Complex, proximity ligation assay	physical, physical association	25241761, 8929532, (Europe PMC)	0.40	BioGRID, IntAct
BCL6	Biochemical Activity	physical	15849194, (Europe PMC)	NA	BioGRID
BIRC2	Reconstituted Complex	physical	19011619, (Europe PMC)	NA	BioGRID
BIRC3	Reconstituted Complex	physical	19011619, (Europe PMC)	NA	BioGRID
BIRC7	Affinity Capture-Western	physical	22711539, (Europe PMC)	NA	BioGRID
BRAF	Affinity Capture-MS, Affinity Capture-Western, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, solid phase assay	association, direct interaction, physical, physical association	11325826, 18332145, 20130576, 20141835, 20212043, 22169110, 22510884, 23153539, 23680146, 23934108, 25155755, 26466569, 28514442, (Europe PMC)	0.96	BioGRID, IntAct, MINT
BRAP	Affinity Capture-Western	physical	18332145, (Europe PMC)	NA	BioGRID
CALM1	Affinity Capture-Western	physical	11585916, (Europe PMC)	NA	BioGRID
CALU	Affinity Capture-MS, anti tag coimmunoprecipitation	association, physical	25852190, 26496610, (Europe PMC)	0.53	BioGRID, IntAct
CASZ1	Two-hybrid, two hybrid array	physical, physical association	25640309, (Europe PMC)	0.37	BioGRID, IntAct, MINT
CCT3	Two-hybrid, two hybrid	physical, physical association	12620389, (Europe PMC)	0.37	BioGRID, IntAct
CCT8	Affinity Capture-MS, anti tag coimmunoprecipitation	association, physical	25852190, (Europe PMC)	0.35	BioGRID, IntAct
CDC25A	Affinity Capture-Western, Reconstituted Complex, anti bait coimmunoprecipitation	physical, physical association	7644510, 7744247, 9230211, (Europe PMC)	0.40	BioGRID, IntAct
CDC37	Affinity Capture-Luminescence, Affinity Capture-MS, anti tag coimmunoprecipitation, luminescence based mammalian interactome mapping, tandem affinity purification	association, physical, physical association	17979178, 24189400, 25036637, (Europe PMC)	0.71	BioGRID, IntAct
CDK20	Affinity Capture-MS	physical	23602568, (Europe PMC)	NA	BioGRID
CFLAR	Affinity Capture-Western, Two-hybrid, two hybrid array	physical, physical association	10837247, 16537561, 21988832, (Europe PMC)	0.37	BioGRID, IntAct
CIAO2B	Affinity Capture-MS	physical	23891004, (Europe PMC)	NA	BioGRID
CNKSR1	Reconstituted Complex	physical	15075335, (Europe PMC)	NA	BioGRID
CNKSR2	Affinity Capture-Western	physical	14597674, (Europe PMC)	NA	BioGRID
COPS5	Affinity Capture-MS, anti tag coimmunoprecipitation	association, physical	26496610, (Europe PMC)	0.35	BioGRID, IntAct
COPS7A	Two-hybrid	physical	16364241, (Europe PMC)	NA	BioGRID
DCAF8	Two-hybrid	physical	16364241, (Europe PMC)	NA	BioGRID
DNAJA1	Affinity Capture-MS, anti tag coimmunoprecipitation	association, physical	25852190, (Europe PMC)	0.35	BioGRID, IntAct
DYNLL1	Affinity Capture-MS, inference by socio-affinity scoring	physical, physical association	27173435, (Europe PMC)	0.27	BioGRID, IntAct
DYNLL2	Affinity Capture-MS, inference by socio-affinity scoring	physical, physical association	27173435, (Europe PMC)	0.27	BioGRID, IntAct
EEF1A1	Affinity Capture-Western, Co-localization	physical	17332776, (Europe PMC)	NA	BioGRID
EEF1E1	Affinity Capture-MS, anti tag coimmunoprecipitation	association, physical	26496610, (Europe PMC)	0.35	BioGRID, IntAct
EGFR	PCA, Two-hybrid, ubiquitin reconstruction	physical, physical association	24658140, 25402006, (Europe PMC)	0.37	BioGRID, IntAct
EIF3D	Affinity Capture-MS	physical	27173435, (Europe PMC)	NA	BioGRID
EMD	Affinity Capture-MS, anti tag coimmunoprecipitation	association, physical	25852190, (Europe PMC)	0.35	BioGRID, IntAct
ERAS	Affinity Capture-Western	physical	12774123, (Europe PMC)	NA	BioGRID
FYCO1	Two-hybrid	physical	16364241, (Europe PMC)	NA	BioGRID
FYN	Affinity Capture-Western, Reconstituted Complex	physical	7517401, (Europe PMC)	NA	BioGRID
GNB2	Affinity Capture-Western	physical	7782277, (Europe PMC)	NA	BioGRID
GNG4	Reconstituted Complex	physical	7782277, (Europe PMC)	NA	BioGRID
GPRASP2	Affinity Capture-MS	physical	24778252, (Europe PMC)	NA	BioGRID
GRB10	Affinity Capture-Western, Co-fractionation, Reconstituted Complex, Two-hybrid	physical	10585452, 9553107, (Europe PMC)	NA	BioGRID
HERC2	Affinity Capture-MS	physical	25476789, (Europe PMC)	NA	BioGRID
HIPK4	Affinity Capture-MS	physical	23602568, (Europe PMC)	NA	BioGRID
HRAS	Affinity Capture-Western, Reconstituted Complex, Two-hybrid, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, confocal microscopy, fluorescent resonance energy transfer, molecular sieving, pull down, two hybrid, x-ray crystallography	colocalization, direct interaction, physical, physical association	10369681, 10783161, 10882715, 10887184, 10922060, 12379659, 12620389, 14654780, 14724584, 15031288, 15664191, 15688026, 16803888, 18073111, 18273062, 19063885, 19222999, 19696784, 20080631, 20133694, 20178605, 22169110, 24929361, 25684575, 26721396, 7862125, 7969158, 8332187, 8332195, 8530446, 8628317, 8670882, 9144171, 9150145, 9154803, 9523700, (Europe PMC)	0.97	BioGRID, IntAct, MINT
HSP90AA1	Affinity Capture-Luminescence, Affinity Capture-MS, Affinity Capture-Western, luminescence based mammalian interactome mapping	physical, physical association	15618521, 16093354, 16330544, 16504566, 17409432, 17699868, 19011619, 20039095, 20159553, 22939624, 23118896, 24462205, 25036637, 27703006, 8408024, 8962087, (Europe PMC)	0.40	BioGRID, IntAct
HSPA4	Affinity Capture-MS, Affinity Capture-Western	physical	16093354, 16322212, (Europe PMC)	NA	BioGRID
HSPA5	Affinity Capture-Western, Reconstituted Complex	physical	18064632, (Europe PMC)	NA	BioGRID
HSPA8	Affinity Capture-MS, Affinity Capture-Western	physical	16093354, 20039095, (Europe PMC)	NA	BioGRID
HSPD1	Affinity Capture-MS	physical	15618521, (Europe PMC)	NA	BioGRID
HUWE1	Affinity Capture-Western	physical	25022756, (Europe PMC)	NA	BioGRID
ILK	Affinity Capture-MS, anti tag coimmunoprecipitation, tandem affinity purification	association, physical	23455922, 25852190, 26496610, (Europe PMC)	0.64	BioGRID, IntAct
IQCB1	Affinity Capture-MS, inference by socio-affinity scoring	physical, physical association	27173435, (Europe PMC)	0.27	BioGRID, IntAct
IRS4	Affinity Capture-Luminescence, Affinity Capture-MS, anti tag coimmunoprecipitation	association, physical	25036637, (Europe PMC)	0.35	BioGRID, IntAct
JAK1	Affinity Capture-Western	physical	9446616, (Europe PMC)	NA	BioGRID
JAK2	Reconstituted Complex	physical	8876196, (Europe PMC)	NA	BioGRID
KRAS	Affinity Capture-MS, Affinity Capture-Western, Reconstituted Complex, Synthetic Lethality, Two-hybrid, anti tag coimmunoprecipitation, fluorescent resonance energy transfer, pull down	association, direct interaction, genetic, physical, physical association	10783161, 10882715, 10958680, 15192046, 16041367, 16093354, 19029954, 20080631, 20802526, 23153539, 25852190, 26627737, 26721396, 28162770, (Europe PMC)	0.35, 0.68	BioGRID, IntAct
KSR1	Biochemical Activity, anti bait coimmunoprecipitation	physical, physical association	11741534, 24929361, (Europe PMC)	0.40	BioGRID, IntAct
LAS1L	Affinity Capture-MS, inference by socio-affinity scoring	physical, physical association	27173435, (Europe PMC)	0.27	BioGRID, IntAct
LATS1	Affinity Capture-Western	physical	17889669, (Europe PMC)	NA	BioGRID
LCK	Affinity Capture-Western	physical	8939988, (Europe PMC)	NA	BioGRID
LOX	Reconstituted Complex	physical	22438909, (Europe PMC)	NA	BioGRID
LRPAP1	Two-hybrid	physical	10783161, (Europe PMC)	NA	BioGRID
LTK	Affinity Capture-Western	physical	8084603, (Europe PMC)	NA	BioGRID
MAD2L1	Affinity Capture-MS, anti tag coimmunoprecipitation	association, physical	26496610, (Europe PMC)	0.35	BioGRID, IntAct
MAP2K1	Affinity Capture-MS, Affinity Capture-Western, Biochemical Activity, Reconstituted Complex, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, pull down, surface plasmon resonance, tandem affinity purification	association, direct interaction, physical, physical association	10757792, 10958680, 15485920, 15866172, 16093354, 17724343, 17979178, 18556463, 19058874, 19197339, 20212043, 21336309, 23934108, 24746704, 25155755, 26496610, 27703006, 9311917, (Europe PMC)	0.44, 0.95	BioGRID, IntAct, MINT
MAP2K2	Affinity Capture-Western, Two-hybrid, anti tag coimmunoprecipitation, two hybrid	association, physical, physical association	11909642, 16364241, 19058874, 21988832, 24746704, 9808624, (Europe PMC)	0.67	BioGRID, IntAct
MAP3K1	Affinity Capture-Western, Reconstituted Complex	physical	10969079, (Europe PMC)	NA	BioGRID
MAP3K5	Affinity Capture-Western, Reconstituted Complex	physical	11427728, (Europe PMC)	NA	BioGRID
MAPK1	Affinity Capture-Western, Biochemical Activity	physical	10958680, 11409918, 15664191, 16093354, 19058874, (Europe PMC)	NA	BioGRID
MAPK3	Affinity Capture-Western, Biochemical Activity	physical	11409918, 19058874, (Europe PMC)	NA	BioGRID
MAPK7	Affinity Capture-Western, Reconstituted Complex	physical	10531364, (Europe PMC)	NA	BioGRID
MAPK8	Two-hybrid, two hybrid array	physical, physical association	21988832, (Europe PMC)	0.37	BioGRID, IntAct
MAPK8IP3	Affinity Capture-Western, Reconstituted Complex	physical	10523642, 11044439, (Europe PMC)	NA	BioGRID
MMS19	Affinity Capture-MS	physical	22678362, (Europe PMC)	NA	BioGRID
MOV10	Affinity Capture-RNA	physical	22658674, (Europe PMC)	NA	BioGRID
MRAS	Affinity Capture-Western, Reconstituted Complex, fluorescent resonance energy transfer	direct interaction, physical	10498616, 20080631, 25022756, (Europe PMC)	0.44	BioGRID, IntAct
MRC2	Two-hybrid, two hybrid array	physical, physical association	25640309, (Europe PMC)	0.37	BioGRID, IntAct, MINT
MSH2	Affinity Capture-MS, inference by socio-affinity scoring	physical, physical association	27173435, (Europe PMC)	0.27	BioGRID, IntAct
MYBPC1	Two-hybrid	physical	16364241, (Europe PMC)	NA	BioGRID
MYC	Affinity Capture-MS, Reconstituted Complex, tandem affinity purification	association, physical	17314511, 9315742, (Europe PMC)	0.35	BioGRID, IntAct
NCAPG2	Affinity Capture-MS, inference by socio-affinity scoring	physical, physical association	27173435, (Europe PMC)	0.27	BioGRID, IntAct
NEDD4	Reconstituted Complex	physical	19953087, (Europe PMC)	NA	BioGRID
NEDD4L	Affinity Capture-Western	physical	19380724, (Europe PMC)	NA	BioGRID
NPHP4	Affinity Capture-MS, inference by socio-affinity scoring	physical, physical association	27173435, (Europe PMC)	0.27	BioGRID, IntAct
NPLOC4	Two-hybrid	physical	16364241, (Europe PMC)	NA	BioGRID
NR3C1	Affinity Capture-Western	physical	11005817, (Europe PMC)	NA	BioGRID
NRAS	Affinity Capture-Western, Synthetic Lethality, anti tag coimmunoprecipitation, fluorescent resonance energy transfer, pull down, two hybrid array, two hybrid prey pooling approach	direct interaction, genetic, physical, physical association	10882715, 18641128, 20080631, 21478863, 28162770, (Europe PMC)	0.80	BioGRID, IntAct
NUP107	Affinity Capture-MS, inference by socio-affinity scoring	physical, physical association	27173435, (Europe PMC)	0.27	BioGRID, IntAct
NUP133	Affinity Capture-MS, inference by socio-affinity scoring	physical, physical association	27173435, (Europe PMC)	0.27	BioGRID, IntAct
NUP160	Affinity Capture-MS, inference by socio-affinity scoring	physical, physical association	27173435, (Europe PMC)	0.27	BioGRID, IntAct
NXF1	Affinity Capture-RNA	physical	22658674, (Europe PMC)	NA	BioGRID
OIP5	Two-hybrid	physical	12620389, (Europe PMC)	NA	BioGRID
PACSIN3	Two-hybrid	physical	16364241, (Europe PMC)	NA	BioGRID
PAK1	Affinity Capture-Western, Biochemical Activity, Reconstituted Complex	physical	11733498, (Europe PMC)	NA	BioGRID
PCDH7	Affinity Capture-MS, anti tag coimmunoprecipitation	association, physical	26496610, (Europe PMC)	0.35	BioGRID, IntAct
PDGFRB	Reconstituted Complex, proximity ligation assay	physical, physical association	23397142, 2475255, (Europe PMC)	0.40	BioGRID, IntAct
PDLIM2	Two-hybrid, two hybrid array	physical, physical association	25640309, (Europe PMC)	0.37	BioGRID, IntAct, MINT
PEBP1	Affinity Capture-Western, Reconstituted Complex, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, peptide array, pull down, surface plasmon resonance	association, direct interaction, physical, physical association	10757792, 14654844, 17097642, 21831839, (Europe PMC)	0.76	BioGRID, IntAct, MINT
PEBP4	Affinity Capture-Western, Reconstituted Complex, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, pull down	association, physical, physical association	15302887, 19197339, (Europe PMC)	0.60	BioGRID, IntAct, MINT
PHB	Affinity Capture-Western, Reconstituted Complex, anti bait coimmunoprecipitation	physical, physical association	10523633, 16041367, 24568222, (Europe PMC)	0.40	BioGRID, IntAct
PHKA2	Two-hybrid	physical	12620389, (Europe PMC)	NA	BioGRID
PIN1	Affinity Capture-Western, anti tag coimmunoprecipitation	association, physical, physical association	15664191, 20179103, 20179161, (Europe PMC)	0.56	BioGRID, IntAct
PKM	Two-hybrid, two hybrid	physical, physical association	12620389, (Europe PMC)	0.37	BioGRID, IntAct
PPP1CC	Affinity Capture-Western	physical	12374792, (Europe PMC)	NA	BioGRID
PPP2CA	Affinity Capture-Western, anti tag coimmunoprecipitation, phosphatase assay	dephosphorylation reaction, physical, physical association	16041367, 16239230, (Europe PMC)	0.54	BioGRID, IntAct, MINT
PPP2CB	Two-hybrid, two hybrid array	physical, physical association	21988832, (Europe PMC)	0.37	BioGRID, IntAct
PPP2R1A	Affinity Capture-Western	physical	16041367, (Europe PMC)	NA	BioGRID
PPP2R2B	Affinity Capture-Western	physical	16041367, (Europe PMC)	NA	BioGRID
PRKAR1A	Two-hybrid	physical	16364241, (Europe PMC)	NA	BioGRID
PRKCE	Affinity Capture-Western	physical	11350735, (Europe PMC)	NA	BioGRID
PRKCZ	Affinity Capture-Western, Reconstituted Complex	physical	10620507, (Europe PMC)	NA	BioGRID
PRKG1	Affinity Capture-Western	physical	12237340, (Europe PMC)	NA	BioGRID
PRPF6	Two-hybrid	physical	10848612, (Europe PMC)	NA	BioGRID
PURA	Two-hybrid	physical	16364241, (Europe PMC)	NA	BioGRID
RAF1	Affinity Capture-Western, anti tag coimmunoprecipitation, tandem affinity purification, x-ray crystallography	association, direct interaction, physical, physical association	16093354, 17979178, 20130576, 22169110, 22510884, 27703006, (Europe PMC)	0.81	BioGRID, IntAct, MINT
RANBP9	Affinity Capture-Western, Two-hybrid	physical	16364241, 23118896, (Europe PMC)	NA	BioGRID
RAP1A	Co-crystal Structure, Reconstituted Complex, Two-hybrid, x-ray crystallography	direct interaction, physical	10454553, 7791872, 7862125, 8756332, 9867809, (Europe PMC)	0.62	BioGRID, IntAct
RASD2	Reconstituted Complex	physical	14724584, (Europe PMC)	NA	BioGRID
RB1	Affinity Capture-Western, Biochemical Activity, Reconstituted Complex, Two-hybrid, anti bait coimmunoprecipitation	physical, physical association	10523633, 15485920, 19058874, 21139044, 9819434, (Europe PMC)	0.40	BioGRID, IntAct
RBBP8	Two-hybrid, two hybrid array	physical, physical association	21988832, (Europe PMC)	0.37	BioGRID, IntAct
RBL2	Affinity Capture-Western, Reconstituted Complex, Two-hybrid	physical	9819434, (Europe PMC)	NA	BioGRID
RFXANK	Biochemical Activity	physical	10329666, (Europe PMC)	NA	BioGRID
RHEB	Affinity Capture-Western, Reconstituted Complex, Two-hybrid, pull down	direct interaction, physical	15150271, 15854902, 19222999, 9001246, (Europe PMC)	0.44	BioGRID, IntAct, MINT
RMDN3	Co-localization	physical	25862004, (Europe PMC)	NA	BioGRID
RPGRIP1L	Affinity Capture-MS, inference by socio-affinity scoring	physical, physical association	27173435, (Europe PMC)	0.27	BioGRID, IntAct
RRAS	Affinity Capture-Western, Two-hybrid	physical	10848612, 19805522, (Europe PMC)	NA	BioGRID
RRAS2	Reconstituted Complex, Two-hybrid, two hybrid	physical, physical association	10557073, 10783161, 12620389, (Europe PMC)	0.37	BioGRID, IntAct
SCNN1B	Affinity Capture-Western	physical	19380724, (Europe PMC)	NA	BioGRID
SFN	Affinity Capture-MS, Affinity Capture-Western, FRET, anti tag coimmunoprecipitation, biochemical, tandem affinity purification	association, physical, physical association	11697890, 15778465, 16041367, 16093354, 25852190, 26578655, (Europe PMC)	0.67	BioGRID, IntAct, MINT
SGK1	Affinity Capture-Western	physical	19380724, 20947508, (Europe PMC)	NA	BioGRID
SH3KBP1	Affinity Capture-Western	physical	24167568, (Europe PMC)	NA	BioGRID
SHOC2	Affinity Capture-Western	physical	10783161, 25022756, 26519477, (Europe PMC)	NA	BioGRID
SPATA7	Affinity Capture-MS, inference by socio-affinity scoring, tandem affinity purification	association, physical, physical association	27173435, (Europe PMC)	0.27, 0.35	BioGRID, IntAct
SPRY2	Affinity Capture-Western	physical	12717443, (Europe PMC)	NA	BioGRID
SPRY4	Affinity Capture-Western	physical	12717443, (Europe PMC)	NA	BioGRID
SRC	Affinity Capture-Western, Reconstituted Complex	physical	7517401, (Europe PMC)	NA	BioGRID
SS18L2	Affinity Capture-MS, anti tag coimmunoprecipitation	association, physical	26496610, (Europe PMC)	0.35	BioGRID, IntAct
STK26	Two-hybrid	physical	11306563, (Europe PMC)	NA	BioGRID
STK3	Affinity Capture-MS, Affinity Capture-Western, Reconstituted Complex, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, peptide array, pull down	direct interaction, physical, physical association	15618521, 17889669, 20086174, 20212043, 24929361, (Europe PMC)	0.65	BioGRID, IntAct
STUB1	Affinity Capture-Western, Biochemical Activity, Reconstituted Complex	physical	15215316, 15936278, 19011619, 22350907, (Europe PMC)	NA	BioGRID
SYNPO	Affinity Capture-MS, anti tag coimmunoprecipitation	association, physical	26496610, (Europe PMC)	0.35	BioGRID, IntAct
TBXA2R	Affinity Capture-Western	physical	16413928, (Europe PMC)	NA	BioGRID
TIMM50	Affinity Capture-MS, anti tag coimmunoprecipitation, two hybrid	association, physical, physical association	12620389, 25852190, (Europe PMC)	0.55	BioGRID, IntAct
TMEM63B	Affinity Capture-MS, anti tag coimmunoprecipitation	association, physical	26496610, (Europe PMC)	0.35	BioGRID, IntAct
TMEM70	Two-hybrid	physical	16364241, (Europe PMC)	NA	BioGRID
TRIM25	Affinity Capture-RNA	physical	29117863, (Europe PMC)	NA	BioGRID
TSC22D3	Affinity Capture-Western, Reconstituted Complex	physical	12391160, 19380724, (Europe PMC)	NA	BioGRID
UBE2D2	Biochemical Activity	physical	11676916, (Europe PMC)	NA	BioGRID
VAV1	Affinity Capture-Western	physical	8900182, (Europe PMC)	NA	BioGRID
VCP	Affinity Capture-MS	physical	23383273, (Europe PMC)	NA	BioGRID
VDAC1	Affinity Capture-Western	physical	12079506, (Europe PMC)	NA	BioGRID
WDR83	Affinity Capture-Western	physical	15118098, (Europe PMC)	NA	BioGRID
XIAP	Affinity Capture-Western, Biochemical Activity, Co-localization, Reconstituted Complex, Two-hybrid, proximity ligation assay	physical, physical association	16964381, 19011619, 25241761, (Europe PMC)	0.40	BioGRID, IntAct
XPO1	Affinity Capture-MS	physical	26673895, (Europe PMC)	NA	BioGRID
YWHAB	Affinity Capture-MS, Affinity Capture-Western, Reconstituted Complex, Two-hybrid, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, biochemical, two hybrid	association, physical, physical association	10620507, 10848612, 11697890, 12360521, 12620389, 16041367, 16093354, 19595761, 24255178, 25852190, 7644510, 7882972, 7935795, 8085158, 8702721, (Europe PMC)	0.93	BioGRID, IntAct, MINT
YWHAE	Affinity Capture-MS, Affinity Capture-Western, Two-hybrid, anti tag coimmunoprecipitation, biochemical, two hybrid	association, physical, physical association	11697890, 16041367, 16093354, 17979178, 19608861, 25852190, 7644510, 8702721, (Europe PMC)	0.66	BioGRID, IntAct, MINT
YWHAG	Affinity Capture-MS, Affinity Capture-Western, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, biochemical	association, physical, physical association	10433554, 10620507, 11697890, 16041367, 16093354, 17353931, 25852190, (Europe PMC)	0.67	BioGRID, IntAct, MINT
YWHAH	Affinity Capture-MS, Affinity Capture-Western, anti tag coimmunoprecipitation, biochemical, tandem affinity purification	association, physical, physical association	10620507, 11697890, 11969417, 16041367, 16093354, 17979178, 25852190, 26496610, 8702721, (Europe PMC)	0.77	BioGRID, IntAct, MINT
YWHAQ	Affinity Capture-MS, Affinity Capture-Western, Reconstituted Complex, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, biochemical, pull down	association, physical, physical association	10620507, 10757792, 11697890, 15618521, 16041367, 16093354, 17353931, 25852190, 7479742, 7760835, 8663231, (Europe PMC)	0.74	BioGRID, IntAct, MINT
YWHAZ	Affinity Capture-MS, Affinity Capture-Western, Reconstituted Complex, Two-hybrid, anti tag coimmunoprecipitation, biochemical, coimmunoprecipitation, lex-a dimerization assay, peptide array, pull down, surface plasmon resonance, tandem affinity purification, two hybrid, x-ray crystallography	association, direct interaction, physical, physical association	10611249, 10620507, 10887173, 11697890, 12861023, 14688280, 15664191, 16041367, 16093354, 16306228, 17979178, 19049963, 20052757, 20679480, 22222486, 25852190, 7628630, 7935795, 7939632, 8085158, 8601312, 9153224, 9261098, 9632690, (Europe PMC)	0.95	BioGRID, IntAct, MINT
YY1	Two-hybrid, two hybrid array	physical, physical association	21988832, (Europe PMC)	0.37	BioGRID, IntAct

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Interacting partner	Detection method	Interaction type	PubMed IDs	Interaction Score	Source
ACOX1	anti tag coimmunoprecipitation	association	26496610, (Europe PMC)	0.35	IntAct
AKT1	Affinity Capture-Western, Biochemical Activity, proximity ligation assay, pull down	physical, physical association	10576742, 19058874, 19197339, 25241761, (Europe PMC)	0.59	BioGRID, IntAct, MINT
AMER1	Affinity Capture-MS, inference by socio-affinity scoring	physical, physical association	27173435, (Europe PMC)	0.27	BioGRID, IntAct
ARAF	anti bait coimmunoprecipitation	association	20130576, (Europe PMC)	0.35	IntAct
BAD	Biochemical Activity, Co-localization, proximity ligation assay	physical, physical association	15849194, 19667065, 23397142, 25241761, (Europe PMC)	0.59	BioGRID, IntAct
BAG1	Affinity Capture-Western, Reconstituted Complex, Two-hybrid, coimmunoprecipitation, two hybrid	physical, physical association	11231577, 8692945, (Europe PMC)	0.51	BioGRID, IntAct, MINT
BAG2	luminescence based mammalian interactome mapping	physical association	25036637, (Europe PMC)	0.40	IntAct
BCL2L1	Co-localization, Reconstituted Complex, proximity ligation assay	physical, physical association	25241761, 8929532, (Europe PMC)	0.40	BioGRID, IntAct
BRAF	Affinity Capture-MS, Affinity Capture-Western, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, solid phase assay	association, direct interaction, physical, physical association	11325826, 18332145, 20130576, 20141835, 20212043, 22169110, 22510884, 23153539, 23680146, 23934108, 25155755, 26466569, 28514442, (Europe PMC)	0.96	BioGRID, IntAct, MINT
CACYBP	luminescence based mammalian interactome mapping	physical association	25036637, (Europe PMC)	0.40	IntAct
CALU	Affinity Capture-MS, anti tag coimmunoprecipitation	association, physical	25852190, 26496610, (Europe PMC)	0.53	BioGRID, IntAct
CASZ1	Two-hybrid, two hybrid array	physical, physical association	25640309, (Europe PMC)	0.37	BioGRID, IntAct, MINT
CCT3	Two-hybrid, two hybrid	physical, physical association	12620389, (Europe PMC)	0.37	BioGRID, IntAct
CCT8	Affinity Capture-MS, anti tag coimmunoprecipitation	association, physical	25852190, (Europe PMC)	0.35	BioGRID, IntAct
CDC25A	Affinity Capture-Western, Reconstituted Complex, anti bait coimmunoprecipitation	physical, physical association	7644510, 7744247, 9230211, (Europe PMC)	0.40	BioGRID, IntAct
CDC37	Affinity Capture-Luminescence, Affinity Capture-MS, anti tag coimmunoprecipitation, luminescence based mammalian interactome mapping, tandem affinity purification	association, physical, physical association	17979178, 24189400, 25036637, (Europe PMC)	0.71	BioGRID, IntAct
CFLAR	Affinity Capture-Western, Two-hybrid, two hybrid array	physical, physical association	10837247, 16537561, 21988832, (Europe PMC)	0.37	BioGRID, IntAct
COPS3	two hybrid	physical association	12620389, (Europe PMC)	0.37	IntAct
COPS5	Affinity Capture-MS, anti tag coimmunoprecipitation	association, physical	26496610, (Europe PMC)	0.35	BioGRID, IntAct
CPS1	two hybrid	physical association	12620389, (Europe PMC)	0.37	IntAct
CRKL	proximity ligation assay	physical association	23397142, (Europe PMC)	0.40	IntAct
DNAJA1	Affinity Capture-MS, anti tag coimmunoprecipitation	association, physical	25852190, (Europe PMC)	0.35	BioGRID, IntAct
DYNLL1	Affinity Capture-MS, inference by socio-affinity scoring	physical, physical association	27173435, (Europe PMC)	0.27	BioGRID, IntAct
DYNLL2	Affinity Capture-MS, inference by socio-affinity scoring	physical, physical association	27173435, (Europe PMC)	0.27	BioGRID, IntAct
EEF1E1	Affinity Capture-MS, anti tag coimmunoprecipitation	association, physical	26496610, (Europe PMC)	0.35	BioGRID, IntAct
EFEMP1	two hybrid	physical association	12620389, (Europe PMC)	0.37	IntAct
EGFR	PCA, Two-hybrid, ubiquitin reconstruction	physical, physical association	24658140, 25402006, (Europe PMC)	0.37	BioGRID, IntAct
EMD	Affinity Capture-MS, anti tag coimmunoprecipitation	association, physical	25852190, (Europe PMC)	0.35	BioGRID, IntAct
FKBPL	luminescence based mammalian interactome mapping	physical association	25036637, (Europe PMC)	0.40	IntAct
HRAS	Affinity Capture-Western, Reconstituted Complex, Two-hybrid, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, confocal microscopy, fluorescent resonance energy transfer, molecular sieving, pull down, two hybrid, x-ray crystallography	colocalization, direct interaction, physical, physical association	10369681, 10783161, 10882715, 10887184, 10922060, 12379659, 12620389, 14654780, 14724584, 15031288, 15664191, 15688026, 16803888, 18073111, 18273062, 19063885, 19222999, 19696784, 20080631, 20133694, 20178605, 22169110, 24929361, 25684575, 26721396, 7862125, 7969158, 8332187, 8332195, 8530446, 8628317, 8670882, 9144171, 9150145, 9154803, 9523700, (Europe PMC)	0.97	BioGRID, IntAct, MINT
HSP90AA1	Affinity Capture-Luminescence, Affinity Capture-MS, Affinity Capture-Western, luminescence based mammalian interactome mapping	physical, physical association	15618521, 16093354, 16330544, 16504566, 17409432, 17699868, 19011619, 20039095, 20159553, 22939624, 23118896, 24462205, 25036637, 27703006, 8408024, 8962087, (Europe PMC)	0.40	BioGRID, IntAct
HSP90AB1	anti bait coimmunoprecipitation, luminescence based mammalian interactome mapping, tandem affinity purification	association, physical association	16330544, 17979178, 22939624, (Europe PMC)	0.69	IntAct
HSPA5	anti bait coimmunoprecipitation, cosedimentation, pull down	colocalization, physical association	18064632, (Europe PMC)	0.58	IntAct
ILK	Affinity Capture-MS, anti tag coimmunoprecipitation, tandem affinity purification	association, physical	23455922, 25852190, 26496610, (Europe PMC)	0.64	BioGRID, IntAct
INTS10	two hybrid	physical association	12620389, (Europe PMC)	0.37	IntAct
IQCB1	Affinity Capture-MS, inference by socio-affinity scoring	physical, physical association	27173435, (Europe PMC)	0.27	BioGRID, IntAct
IRS4	Affinity Capture-Luminescence, Affinity Capture-MS, anti tag coimmunoprecipitation	association, physical	25036637, (Europe PMC)	0.35	BioGRID, IntAct
KRAS	Affinity Capture-MS, Affinity Capture-Western, Reconstituted Complex, Synthetic Lethality, Two-hybrid, anti tag coimmunoprecipitation, fluorescent resonance energy transfer, pull down	association, direct interaction, genetic, physical, physical association	10783161, 10882715, 10958680, 15192046, 16041367, 16093354, 19029954, 20080631, 20802526, 23153539, 25852190, 26627737, 26721396, 28162770, (Europe PMC)	0.35, 0.68	BioGRID, IntAct
KRT18	coimmunoprecipitation, experimental interaction detection	phosphorylation reaction, physical association	15314064, (Europe PMC)	0.49	IntAct, MINT
KRT19	coimmunoprecipitation	physical association	15314064, (Europe PMC)	0.40	IntAct, MINT
KRT8	experimental interaction detection	association	15314064, (Europe PMC)	0.22	IntAct, MINT
KSR1	Biochemical Activity, anti bait coimmunoprecipitation	physical, physical association	11741534, 24929361, (Europe PMC)	0.40	BioGRID, IntAct
LAS1L	Affinity Capture-MS, inference by socio-affinity scoring	physical, physical association	27173435, (Europe PMC)	0.27	BioGRID, IntAct
MAD2L1	Affinity Capture-MS, anti tag coimmunoprecipitation	association, physical	26496610, (Europe PMC)	0.35	BioGRID, IntAct
MAP2K1	Affinity Capture-MS, Affinity Capture-Western, Biochemical Activity, Reconstituted Complex, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, pull down, surface plasmon resonance, tandem affinity purification	association, direct interaction, physical, physical association	10757792, 10958680, 15485920, 15866172, 16093354, 17724343, 17979178, 18556463, 19058874, 19197339, 20212043, 21336309, 23934108, 24746704, 25155755, 26496610, 27703006, 9311917, (Europe PMC)	0.44, 0.95	BioGRID, IntAct, MINT
MAP2K2	Affinity Capture-Western, Two-hybrid, anti tag coimmunoprecipitation, two hybrid	association, physical, physical association	11909642, 16364241, 19058874, 21988832, 24746704, 9808624, (Europe PMC)	0.67	BioGRID, IntAct
MAPK6	anti tag coimmunoprecipitation	association	26972000, (Europe PMC)	0.35	IntAct
MAPK8	Two-hybrid, two hybrid array	physical, physical association	21988832, (Europe PMC)	0.37	BioGRID, IntAct
MLF1	luminescence based mammalian interactome mapping	physical association	25036637, (Europe PMC)	0.40	IntAct
MRAS	Affinity Capture-Western, Reconstituted Complex, fluorescent resonance energy transfer	direct interaction, physical	10498616, 20080631, 25022756, (Europe PMC)	0.44	BioGRID, IntAct
MRC2	Two-hybrid, two hybrid array	physical, physical association	25640309, (Europe PMC)	0.37	BioGRID, IntAct, MINT
MSH2	Affinity Capture-MS, inference by socio-affinity scoring	physical, physical association	27173435, (Europe PMC)	0.27	BioGRID, IntAct
MYC	Affinity Capture-MS, Reconstituted Complex, tandem affinity purification	association, physical	17314511, 9315742, (Europe PMC)	0.35	BioGRID, IntAct
NCAPG2	Affinity Capture-MS, inference by socio-affinity scoring	physical, physical association	27173435, (Europe PMC)	0.27	BioGRID, IntAct
NFATC3	anti bait coimmunoprecipitation	physical association	24330068, (Europe PMC)	0.40	IntAct, MINT
NPHP4	Affinity Capture-MS, inference by socio-affinity scoring	physical, physical association	27173435, (Europe PMC)	0.27	BioGRID, IntAct
NRAS	Affinity Capture-Western, Synthetic Lethality, anti tag coimmunoprecipitation, fluorescent resonance energy transfer, pull down, two hybrid array, two hybrid prey pooling approach	direct interaction, genetic, physical, physical association	10882715, 18641128, 20080631, 21478863, 28162770, (Europe PMC)	0.80	BioGRID, IntAct
NUDCD3	luminescence based mammalian interactome mapping	physical association	25036637, (Europe PMC)	0.40	IntAct
NUDT14	two hybrid	physical association	12620389, (Europe PMC)	0.37	IntAct
NUP107	Affinity Capture-MS, inference by socio-affinity scoring	physical, physical association	27173435, (Europe PMC)	0.27	BioGRID, IntAct
NUP133	Affinity Capture-MS, inference by socio-affinity scoring	physical, physical association	27173435, (Europe PMC)	0.27	BioGRID, IntAct
NUP160	Affinity Capture-MS, inference by socio-affinity scoring	physical, physical association	27173435, (Europe PMC)	0.27	BioGRID, IntAct
OIP5	two hybrid	physical association	12620389, (Europe PMC)	0.37	IntAct
PAK1	protein kinase assay	phosphorylation reaction	17097642, (Europe PMC)	0.44	IntAct, MINT
PAK2	nuclear magnetic resonance, protein kinase assay	direct interaction, phosphorylation reaction	16837009, (Europe PMC)	0.56	IntAct
PAQR3	anti bait coimmunoprecipitation, anti tag coimmunoprecipitation	association, physical association	17724343, (Europe PMC)	0.58	IntAct
PBK	two hybrid	physical association	12620389, (Europe PMC)	0.37	IntAct
PCDH7	Affinity Capture-MS, anti tag coimmunoprecipitation	association, physical	26496610, (Europe PMC)	0.35	BioGRID, IntAct
PDGFRB	Reconstituted Complex, proximity ligation assay	physical, physical association	23397142, 2475255, (Europe PMC)	0.40	BioGRID, IntAct
PDLIM2	Two-hybrid, two hybrid array	physical, physical association	25640309, (Europe PMC)	0.37	BioGRID, IntAct, MINT
PEBP1	Affinity Capture-Western, Reconstituted Complex, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, peptide array, pull down, surface plasmon resonance	association, direct interaction, physical, physical association	10757792, 14654844, 17097642, 21831839, (Europe PMC)	0.76	BioGRID, IntAct, MINT
PEBP4	Affinity Capture-Western, Reconstituted Complex, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, pull down	association, physical, physical association	15302887, 19197339, (Europe PMC)	0.60	BioGRID, IntAct, MINT
PHB	Affinity Capture-Western, Reconstituted Complex, anti bait coimmunoprecipitation	physical, physical association	10523633, 16041367, 24568222, (Europe PMC)	0.40	BioGRID, IntAct
PIN1	Affinity Capture-Western, anti tag coimmunoprecipitation	association, physical, physical association	15664191, 20179103, 20179161, (Europe PMC)	0.56	BioGRID, IntAct
PKM	Two-hybrid, two hybrid	physical, physical association	12620389, (Europe PMC)	0.37	BioGRID, IntAct
PPP2CA	Affinity Capture-Western, anti tag coimmunoprecipitation, phosphatase assay	dephosphorylation reaction, physical, physical association	16041367, 16239230, (Europe PMC)	0.54	BioGRID, IntAct, MINT
PPP2CB	Two-hybrid, two hybrid array	physical, physical association	21988832, (Europe PMC)	0.37	BioGRID, IntAct
PPP2R5C	anti tag coimmunoprecipitation, phosphatase assay	dephosphorylation reaction, physical association	16239230, (Europe PMC)	0.54	IntAct, MINT
PSMD2	luminescence based mammalian interactome mapping	physical association	25036637, (Europe PMC)	0.40	IntAct
RAF1	Affinity Capture-Western, anti tag coimmunoprecipitation, tandem affinity purification, x-ray crystallography	association, direct interaction, physical, physical association	16093354, 17979178, 20130576, 22169110, 22510884, 27703006, (Europe PMC)	0.81	BioGRID, IntAct, MINT
RALGDS	pull down	association	19075231, (Europe PMC)	0.35	IntAct
RAP1A	Co-crystal Structure, Reconstituted Complex, Two-hybrid, x-ray crystallography	direct interaction, physical	10454553, 7791872, 7862125, 8756332, 9867809, (Europe PMC)	0.62	BioGRID, IntAct
RB1	Affinity Capture-Western, Biochemical Activity, Reconstituted Complex, Two-hybrid, anti bait coimmunoprecipitation	physical, physical association	10523633, 15485920, 19058874, 21139044, 9819434, (Europe PMC)	0.40	BioGRID, IntAct
RBBP8	Two-hybrid, two hybrid array	physical, physical association	21988832, (Europe PMC)	0.37	BioGRID, IntAct
RCAN1	pull down	physical association	15935327, (Europe PMC)	0.40	IntAct
RHEB	Affinity Capture-Western, Reconstituted Complex, Two-hybrid, pull down	direct interaction, physical	15150271, 15854902, 19222999, 9001246, (Europe PMC)	0.44	BioGRID, IntAct, MINT
RIPK4	anti tag coimmunoprecipitation	association	26972000, (Europe PMC)	0.35	IntAct
RPGRIP1L	Affinity Capture-MS, inference by socio-affinity scoring	physical, physical association	27173435, (Europe PMC)	0.27	BioGRID, IntAct
RRAS2	Reconstituted Complex, Two-hybrid, two hybrid	physical, physical association	10557073, 10783161, 12620389, (Europe PMC)	0.37	BioGRID, IntAct
SFN	Affinity Capture-MS, Affinity Capture-Western, FRET, anti tag coimmunoprecipitation, biochemical, tandem affinity purification	association, physical, physical association	11697890, 15778465, 16041367, 16093354, 25852190, 26578655, (Europe PMC)	0.67	BioGRID, IntAct, MINT
SPATA7	Affinity Capture-MS, inference by socio-affinity scoring, tandem affinity purification	association, physical, physical association	27173435, (Europe PMC)	0.27, 0.35	BioGRID, IntAct
SS18L2	Affinity Capture-MS, anti tag coimmunoprecipitation	association, physical	26496610, (Europe PMC)	0.35	BioGRID, IntAct
STIP1	luminescence based mammalian interactome mapping	physical association	25036637, (Europe PMC)	0.40	IntAct
STK3	Affinity Capture-MS, Affinity Capture-Western, Reconstituted Complex, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, peptide array, pull down	direct interaction, physical, physical association	15618521, 17889669, 20086174, 20212043, 24929361, (Europe PMC)	0.65	BioGRID, IntAct
STUB1	luminescence based mammalian interactome mapping	physical association	25036637, (Europe PMC)	0.40	IntAct
SYNPO	Affinity Capture-MS, anti tag coimmunoprecipitation	association, physical	26496610, (Europe PMC)	0.35	BioGRID, IntAct
TIMM50	Affinity Capture-MS, anti tag coimmunoprecipitation, two hybrid	association, physical, physical association	12620389, 25852190, (Europe PMC)	0.55	BioGRID, IntAct
TMEM63B	Affinity Capture-MS, anti tag coimmunoprecipitation	association, physical	26496610, (Europe PMC)	0.35	BioGRID, IntAct
XIAP	Affinity Capture-Western, Biochemical Activity, Co-localization, Reconstituted Complex, Two-hybrid, proximity ligation assay	physical, physical association	16964381, 19011619, 25241761, (Europe PMC)	0.40	BioGRID, IntAct
YWHAB	Affinity Capture-MS, Affinity Capture-Western, Reconstituted Complex, Two-hybrid, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, biochemical, two hybrid	association, physical, physical association	10620507, 10848612, 11697890, 12360521, 12620389, 16041367, 16093354, 19595761, 24255178, 25852190, 7644510, 7882972, 7935795, 8085158, 8702721, (Europe PMC)	0.93	BioGRID, IntAct, MINT
YWHAE	Affinity Capture-MS, Affinity Capture-Western, Two-hybrid, anti tag coimmunoprecipitation, biochemical, two hybrid	association, physical, physical association	11697890, 16041367, 16093354, 17979178, 19608861, 25852190, 7644510, 8702721, (Europe PMC)	0.66	BioGRID, IntAct, MINT
YWHAG	Affinity Capture-MS, Affinity Capture-Western, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, biochemical	association, physical, physical association	10433554, 10620507, 11697890, 16041367, 16093354, 17353931, 25852190, (Europe PMC)	0.67	BioGRID, IntAct, MINT
YWHAH	Affinity Capture-MS, Affinity Capture-Western, anti tag coimmunoprecipitation, biochemical, tandem affinity purification	association, physical, physical association	10620507, 11697890, 11969417, 16041367, 16093354, 17979178, 25852190, 26496610, 8702721, (Europe PMC)	0.77	BioGRID, IntAct, MINT
YWHAQ	Affinity Capture-MS, Affinity Capture-Western, Reconstituted Complex, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, biochemical, pull down	association, physical, physical association	10620507, 10757792, 11697890, 15618521, 16041367, 16093354, 17353931, 25852190, 7479742, 7760835, 8663231, (Europe PMC)	0.74	BioGRID, IntAct, MINT
YWHAZ	Affinity Capture-MS, Affinity Capture-Western, Reconstituted Complex, Two-hybrid, anti tag coimmunoprecipitation, biochemical, coimmunoprecipitation, lex-a dimerization assay, peptide array, pull down, surface plasmon resonance, tandem affinity purification, two hybrid, x-ray crystallography	association, direct interaction, physical, physical association	10611249, 10620507, 10887173, 11697890, 12861023, 14688280, 15664191, 16041367, 16093354, 16306228, 17979178, 19049963, 20052757, 20679480, 22222486, 25852190, 7628630, 7935795, 7939632, 8085158, 8601312, 9153224, 9261098, 9632690, (Europe PMC)	0.95	BioGRID, IntAct, MINT
YY1	Two-hybrid, two hybrid array	physical, physical association	21988832, (Europe PMC)	0.37	BioGRID, IntAct

Visualize Download

Interacting partner	Detection method	Interaction type	PubMed IDs	Interaction Score	Source
BAG1	Affinity Capture-Western, Reconstituted Complex, Two-hybrid, coimmunoprecipitation, two hybrid	physical, physical association	11231577, 8692945, (Europe PMC)	0.51	BioGRID, IntAct, MINT
BRAF	Affinity Capture-MS, Affinity Capture-Western, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, solid phase assay	association, direct interaction, physical, physical association	11325826, 18332145, 20130576, 20141835, 20212043, 22169110, 22510884, 23153539, 23680146, 23934108, 25155755, 26466569, 28514442, (Europe PMC)	0.96	BioGRID, IntAct, MINT
CASZ1	Two-hybrid, two hybrid array	physical, physical association	25640309, (Europe PMC)	0.37	BioGRID, IntAct, MINT
HRAS	Affinity Capture-Western, Reconstituted Complex, Two-hybrid, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, confocal microscopy, fluorescent resonance energy transfer, molecular sieving, pull down, two hybrid, x-ray crystallography	colocalization, direct interaction, physical, physical association	10369681, 10783161, 10882715, 10887184, 10922060, 12379659, 12620389, 14654780, 14724584, 15031288, 15664191, 15688026, 16803888, 18073111, 18273062, 19063885, 19222999, 19696784, 20080631, 20133694, 20178605, 22169110, 24929361, 25684575, 26721396, 7862125, 7969158, 8332187, 8332195, 8530446, 8628317, 8670882, 9144171, 9150145, 9154803, 9523700, (Europe PMC)	0.97	BioGRID, IntAct, MINT
KRT18	coimmunoprecipitation, experimental interaction detection	phosphorylation reaction, physical association	15314064, (Europe PMC)	0.49	IntAct, MINT
KRT19	coimmunoprecipitation	physical association	15314064, (Europe PMC)	0.40	IntAct, MINT
KRT8	experimental interaction detection	association	15314064, (Europe PMC)	0.22	IntAct, MINT
MAP2K1	Affinity Capture-MS, Affinity Capture-Western, Biochemical Activity, Reconstituted Complex, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, pull down, surface plasmon resonance, tandem affinity purification	association, direct interaction, physical, physical association	10757792, 10958680, 15485920, 15866172, 16093354, 17724343, 17979178, 18556463, 19058874, 19197339, 20212043, 21336309, 23934108, 24746704, 25155755, 26496610, 27703006, 9311917, (Europe PMC)	0.44, 0.95	BioGRID, IntAct, MINT
MRC2	Two-hybrid, two hybrid array	physical, physical association	25640309, (Europe PMC)	0.37	BioGRID, IntAct, MINT
NFATC3	anti bait coimmunoprecipitation	physical association	24330068, (Europe PMC)	0.40	IntAct, MINT
PAK1	protein kinase assay	phosphorylation reaction	17097642, (Europe PMC)	0.44	IntAct, MINT
PDLIM2	Two-hybrid, two hybrid array	physical, physical association	25640309, (Europe PMC)	0.37	BioGRID, IntAct, MINT
PEBP1	Affinity Capture-Western, Reconstituted Complex, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, peptide array, pull down, surface plasmon resonance	association, direct interaction, physical, physical association	10757792, 14654844, 17097642, 21831839, (Europe PMC)	0.76	BioGRID, IntAct, MINT
PEBP4	Affinity Capture-Western, Reconstituted Complex, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, pull down	association, physical, physical association	15302887, 19197339, (Europe PMC)	0.60	BioGRID, IntAct, MINT
PPP2CA	Affinity Capture-Western, anti tag coimmunoprecipitation, phosphatase assay	dephosphorylation reaction, physical, physical association	16041367, 16239230, (Europe PMC)	0.54	BioGRID, IntAct, MINT
PPP2R5C	anti tag coimmunoprecipitation, phosphatase assay	dephosphorylation reaction, physical association	16239230, (Europe PMC)	0.54	IntAct, MINT
RAF1	Affinity Capture-Western, anti tag coimmunoprecipitation, tandem affinity purification, x-ray crystallography	association, direct interaction, physical, physical association	16093354, 17979178, 20130576, 22169110, 22510884, 27703006, (Europe PMC)	0.81	BioGRID, IntAct, MINT
RHEB	Affinity Capture-Western, Reconstituted Complex, Two-hybrid, pull down	direct interaction, physical	15150271, 15854902, 19222999, 9001246, (Europe PMC)	0.44	BioGRID, IntAct, MINT
SFN	Affinity Capture-MS, Affinity Capture-Western, FRET, anti tag coimmunoprecipitation, biochemical, tandem affinity purification	association, physical, physical association	11697890, 15778465, 16041367, 16093354, 25852190, 26578655, (Europe PMC)	0.67	BioGRID, IntAct, MINT
YWHAB	Affinity Capture-MS, Affinity Capture-Western, Reconstituted Complex, Two-hybrid, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, biochemical, two hybrid	association, physical, physical association	10620507, 10848612, 11697890, 12360521, 12620389, 16041367, 16093354, 19595761, 24255178, 25852190, 7644510, 7882972, 7935795, 8085158, 8702721, (Europe PMC)	0.93	BioGRID, IntAct, MINT
YWHAE	Affinity Capture-MS, Affinity Capture-Western, Two-hybrid, anti tag coimmunoprecipitation, biochemical, two hybrid	association, physical, physical association	11697890, 16041367, 16093354, 17979178, 19608861, 25852190, 7644510, 8702721, (Europe PMC)	0.66	BioGRID, IntAct, MINT
YWHAG	Affinity Capture-MS, Affinity Capture-Western, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, biochemical	association, physical, physical association	10433554, 10620507, 11697890, 16041367, 16093354, 17353931, 25852190, (Europe PMC)	0.67	BioGRID, IntAct, MINT
YWHAH	Affinity Capture-MS, Affinity Capture-Western, anti tag coimmunoprecipitation, biochemical, tandem affinity purification	association, physical, physical association	10620507, 11697890, 11969417, 16041367, 16093354, 17979178, 25852190, 26496610, 8702721, (Europe PMC)	0.77	BioGRID, IntAct, MINT
YWHAQ	Affinity Capture-MS, Affinity Capture-Western, Reconstituted Complex, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, biochemical, pull down	association, physical, physical association	10620507, 10757792, 11697890, 15618521, 16041367, 16093354, 17353931, 25852190, 7479742, 7760835, 8663231, (Europe PMC)	0.74	BioGRID, IntAct, MINT
YWHAZ	Affinity Capture-MS, Affinity Capture-Western, Reconstituted Complex, Two-hybrid, anti tag coimmunoprecipitation, biochemical, coimmunoprecipitation, lex-a dimerization assay, peptide array, pull down, surface plasmon resonance, tandem affinity purification, two hybrid, x-ray crystallography	association, direct interaction, physical, physical association	10611249, 10620507, 10887173, 11697890, 12861023, 14688280, 15664191, 16041367, 16093354, 16306228, 17979178, 19049963, 20052757, 20679480, 22222486, 25852190, 7628630, 7935795, 7939632, 8085158, 8601312, 9153224, 9261098, 9632690, (Europe PMC)	0.95	BioGRID, IntAct, MINT

Visualize Download

Interacting partner	Detection method	Interaction type	PubMed IDs	Interaction Score	Source
ACOX1	Affinity Capture-MS	physical	26496610, (Europe PMC)	NA	BioGRID
ACOX1	anti tag coimmunoprecipitation	association	26496610, (Europe PMC)	0.35	IntAct
AGTR1	Affinity Capture-Western	physical	11226259, (Europe PMC)	NA	BioGRID
AKT1	Affinity Capture-Western, Biochemical Activity, proximity ligation assay, pull down	physical, physical association	10576742, 19058874, 19197339, 25241761, (Europe PMC)	0.59	BioGRID, IntAct, MINT
AMER1	Affinity Capture-MS, inference by socio-affinity scoring	physical, physical association	27173435, (Europe PMC)	0.27	BioGRID, IntAct
AR	Co-purification	physical	8349631, (Europe PMC)	NA	BioGRID
ARAF	anti bait coimmunoprecipitation	association	20130576, (Europe PMC)	0.35	IntAct
ARRB2	Affinity Capture-Western	physical	11226259, (Europe PMC)	NA	BioGRID
BAD	Biochemical Activity, Co-localization, proximity ligation assay	physical, physical association	15849194, 19667065, 23397142, 25241761, (Europe PMC)	0.59	BioGRID, IntAct
BAG1	Affinity Capture-Western, Reconstituted Complex, Two-hybrid, coimmunoprecipitation, two hybrid	physical, physical association	11231577, 8692945, (Europe PMC)	0.51	BioGRID, IntAct, MINT
BAG2	luminescence based mammalian interactome mapping	physical association	25036637, (Europe PMC)	0.40	IntAct
BCL2	Affinity Capture-Western, Reconstituted Complex, Two-hybrid	physical	12488548, 15849194, 8929532, (Europe PMC)	NA	BioGRID
BCL2L1	Co-localization, Reconstituted Complex, proximity ligation assay	physical, physical association	25241761, 8929532, (Europe PMC)	0.40	BioGRID, IntAct
BCL6	Biochemical Activity	physical	15849194, (Europe PMC)	NA	BioGRID
BIRC2	Reconstituted Complex	physical	19011619, (Europe PMC)	NA	BioGRID
BIRC3	Reconstituted Complex	physical	19011619, (Europe PMC)	NA	BioGRID
BIRC7	Affinity Capture-Western	physical	22711539, (Europe PMC)	NA	BioGRID
BRAF	Affinity Capture-MS, Affinity Capture-Western, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, solid phase assay	association, direct interaction, physical, physical association	11325826, 18332145, 20130576, 20141835, 20212043, 22169110, 22510884, 23153539, 23680146, 23934108, 25155755, 26466569, 28514442, (Europe PMC)	0.96	BioGRID, IntAct, MINT
BRAP	Affinity Capture-Western	physical	18332145, (Europe PMC)	NA	BioGRID
CACYBP	luminescence based mammalian interactome mapping	physical association	25036637, (Europe PMC)	0.40	IntAct
CALM1	Affinity Capture-Western	physical	11585916, (Europe PMC)	NA	BioGRID
CALU	Affinity Capture-MS, anti tag coimmunoprecipitation	association, physical	25852190, 26496610, (Europe PMC)	0.53	BioGRID, IntAct
CASZ1	Two-hybrid, two hybrid array	physical, physical association	25640309, (Europe PMC)	0.37	BioGRID, IntAct, MINT
CCT3	Two-hybrid, two hybrid	physical, physical association	12620389, (Europe PMC)	0.37	BioGRID, IntAct
CCT8	Affinity Capture-MS, anti tag coimmunoprecipitation	association, physical	25852190, (Europe PMC)	0.35	BioGRID, IntAct
CDC25A	Affinity Capture-Western, Reconstituted Complex, anti bait coimmunoprecipitation	physical, physical association	7644510, 7744247, 9230211, (Europe PMC)	0.40	BioGRID, IntAct
CDC37	Affinity Capture-Luminescence, Affinity Capture-MS, anti tag coimmunoprecipitation, luminescence based mammalian interactome mapping, tandem affinity purification	association, physical, physical association	17979178, 24189400, 25036637, (Europe PMC)	0.71	BioGRID, IntAct
CDK20	Affinity Capture-MS	physical	23602568, (Europe PMC)	NA	BioGRID
CFLAR	Affinity Capture-Western, Two-hybrid, two hybrid array	physical, physical association	10837247, 16537561, 21988832, (Europe PMC)	0.37	BioGRID, IntAct
CIAO2B	Affinity Capture-MS	physical	23891004, (Europe PMC)	NA	BioGRID
CNKSR1	Reconstituted Complex	physical	15075335, (Europe PMC)	NA	BioGRID
CNKSR2	Affinity Capture-Western	physical	14597674, (Europe PMC)	NA	BioGRID
COPS3	two hybrid	physical association	12620389, (Europe PMC)	0.37	IntAct
COPS5	Affinity Capture-MS, anti tag coimmunoprecipitation	association, physical	26496610, (Europe PMC)	0.35	BioGRID, IntAct
COPS7A	Two-hybrid	physical	16364241, (Europe PMC)	NA	BioGRID
CPS1	two hybrid	physical association	12620389, (Europe PMC)	0.37	IntAct
CRKL	proximity ligation assay	physical association	23397142, (Europe PMC)	0.40	IntAct
DCAF8	Two-hybrid	physical	16364241, (Europe PMC)	NA	BioGRID
DNAJA1	Affinity Capture-MS, anti tag coimmunoprecipitation	association, physical	25852190, (Europe PMC)	0.35	BioGRID, IntAct
DYNLL1	Affinity Capture-MS, inference by socio-affinity scoring	physical, physical association	27173435, (Europe PMC)	0.27	BioGRID, IntAct
DYNLL2	Affinity Capture-MS, inference by socio-affinity scoring	physical, physical association	27173435, (Europe PMC)	0.27	BioGRID, IntAct
EEF1A1	Affinity Capture-Western, Co-localization	physical	17332776, (Europe PMC)	NA	BioGRID
EEF1E1	Affinity Capture-MS, anti tag coimmunoprecipitation	association, physical	26496610, (Europe PMC)	0.35	BioGRID, IntAct
EFEMP1	two hybrid	physical association	12620389, (Europe PMC)	0.37	IntAct
EGFR	PCA, Two-hybrid, ubiquitin reconstruction	physical, physical association	24658140, 25402006, (Europe PMC)	0.37	BioGRID, IntAct
EIF3D	Affinity Capture-MS	physical	27173435, (Europe PMC)	NA	BioGRID
EMD	Affinity Capture-MS, anti tag coimmunoprecipitation	association, physical	25852190, (Europe PMC)	0.35	BioGRID, IntAct
ERAS	Affinity Capture-Western	physical	12774123, (Europe PMC)	NA	BioGRID
FKBPL	luminescence based mammalian interactome mapping	physical association	25036637, (Europe PMC)	0.40	IntAct
FYCO1	Two-hybrid	physical	16364241, (Europe PMC)	NA	BioGRID
FYN	Affinity Capture-Western, Reconstituted Complex	physical	7517401, (Europe PMC)	NA	BioGRID
GNB2	Affinity Capture-Western	physical	7782277, (Europe PMC)	NA	BioGRID
GNG4	Reconstituted Complex	physical	7782277, (Europe PMC)	NA	BioGRID
GPRASP2	Affinity Capture-MS	physical	24778252, (Europe PMC)	NA	BioGRID
GRB10	Affinity Capture-Western, Co-fractionation, Reconstituted Complex, Two-hybrid	physical	10585452, 9553107, (Europe PMC)	NA	BioGRID
HERC2	Affinity Capture-MS	physical	25476789, (Europe PMC)	NA	BioGRID
HIPK4	Affinity Capture-MS	physical	23602568, (Europe PMC)	NA	BioGRID
HRAS	Affinity Capture-Western, Reconstituted Complex, Two-hybrid, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, confocal microscopy, fluorescent resonance energy transfer, molecular sieving, pull down, two hybrid, x-ray crystallography	colocalization, direct interaction, physical, physical association	10369681, 10783161, 10882715, 10887184, 10922060, 12379659, 12620389, 14654780, 14724584, 15031288, 15664191, 15688026, 16803888, 18073111, 18273062, 19063885, 19222999, 19696784, 20080631, 20133694, 20178605, 22169110, 24929361, 25684575, 26721396, 7862125, 7969158, 8332187, 8332195, 8530446, 8628317, 8670882, 9144171, 9150145, 9154803, 9523700, (Europe PMC)	0.97	BioGRID, IntAct, MINT
HSP90AA1	Affinity Capture-Luminescence, Affinity Capture-MS, Affinity Capture-Western, luminescence based mammalian interactome mapping	physical, physical association	15618521, 16093354, 16330544, 16504566, 17409432, 17699868, 19011619, 20039095, 20159553, 22939624, 23118896, 24462205, 25036637, 27703006, 8408024, 8962087, (Europe PMC)	0.40	BioGRID, IntAct
HSP90AB1	anti bait coimmunoprecipitation, luminescence based mammalian interactome mapping, tandem affinity purification	association, physical association	16330544, 17979178, 22939624, (Europe PMC)	0.69	IntAct
HSPA4	Affinity Capture-MS, Affinity Capture-Western	physical	16093354, 16322212, (Europe PMC)	NA	BioGRID
HSPA5	Affinity Capture-Western, Reconstituted Complex	physical	18064632, (Europe PMC)	NA	BioGRID
HSPA5	anti bait coimmunoprecipitation, cosedimentation, pull down	colocalization, physical association	18064632, (Europe PMC)	0.58	IntAct
HSPA8	Affinity Capture-MS, Affinity Capture-Western	physical	16093354, 20039095, (Europe PMC)	NA	BioGRID
HSPD1	Affinity Capture-MS	physical	15618521, (Europe PMC)	NA	BioGRID
HUWE1	Affinity Capture-Western	physical	25022756, (Europe PMC)	NA	BioGRID
ILK	Affinity Capture-MS, anti tag coimmunoprecipitation, tandem affinity purification	association, physical	23455922, 25852190, 26496610, (Europe PMC)	0.64	BioGRID, IntAct
INTS10	two hybrid	physical association	12620389, (Europe PMC)	0.37	IntAct
IQCB1	Affinity Capture-MS, inference by socio-affinity scoring	physical, physical association	27173435, (Europe PMC)	0.27	BioGRID, IntAct
IRS4	Affinity Capture-Luminescence, Affinity Capture-MS, anti tag coimmunoprecipitation	association, physical	25036637, (Europe PMC)	0.35	BioGRID, IntAct
JAK1	Affinity Capture-Western	physical	9446616, (Europe PMC)	NA	BioGRID
JAK2	Reconstituted Complex	physical	8876196, (Europe PMC)	NA	BioGRID
KRAS	Affinity Capture-MS, Affinity Capture-Western, Reconstituted Complex, Synthetic Lethality, Two-hybrid, anti tag coimmunoprecipitation, fluorescent resonance energy transfer, pull down	association, direct interaction, genetic, physical, physical association	10783161, 10882715, 10958680, 15192046, 16041367, 16093354, 19029954, 20080631, 20802526, 23153539, 25852190, 26627737, 26721396, 28162770, (Europe PMC)	0.35, 0.68	BioGRID, IntAct
KRT18	coimmunoprecipitation, experimental interaction detection	phosphorylation reaction, physical association	15314064, (Europe PMC)	0.49	IntAct, MINT
KRT19	coimmunoprecipitation	physical association	15314064, (Europe PMC)	0.40	IntAct, MINT
KRT8	experimental interaction detection	association	15314064, (Europe PMC)	0.22	IntAct, MINT
KSR1	Biochemical Activity, anti bait coimmunoprecipitation	physical, physical association	11741534, 24929361, (Europe PMC)	0.40	BioGRID, IntAct
LAS1L	Affinity Capture-MS, inference by socio-affinity scoring	physical, physical association	27173435, (Europe PMC)	0.27	BioGRID, IntAct
LATS1	Affinity Capture-Western	physical	17889669, (Europe PMC)	NA	BioGRID
LCK	Affinity Capture-Western	physical	8939988, (Europe PMC)	NA	BioGRID
LOX	Reconstituted Complex	physical	22438909, (Europe PMC)	NA	BioGRID
LRPAP1	Two-hybrid	physical	10783161, (Europe PMC)	NA	BioGRID
LTK	Affinity Capture-Western	physical	8084603, (Europe PMC)	NA	BioGRID
MAD2L1	Affinity Capture-MS, anti tag coimmunoprecipitation	association, physical	26496610, (Europe PMC)	0.35	BioGRID, IntAct
MAP2K1	Affinity Capture-MS, Affinity Capture-Western, Biochemical Activity, Reconstituted Complex, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, pull down, surface plasmon resonance, tandem affinity purification	association, direct interaction, physical, physical association	10757792, 10958680, 15485920, 15866172, 16093354, 17724343, 17979178, 18556463, 19058874, 19197339, 20212043, 21336309, 23934108, 24746704, 25155755, 26496610, 27703006, 9311917, (Europe PMC)	0.44, 0.95	BioGRID, IntAct, MINT
MAP2K2	Affinity Capture-Western, Two-hybrid, anti tag coimmunoprecipitation, two hybrid	association, physical, physical association	11909642, 16364241, 19058874, 21988832, 24746704, 9808624, (Europe PMC)	0.67	BioGRID, IntAct
MAP3K1	Affinity Capture-Western, Reconstituted Complex	physical	10969079, (Europe PMC)	NA	BioGRID
MAP3K5	Affinity Capture-Western, Reconstituted Complex	physical	11427728, (Europe PMC)	NA	BioGRID
MAPK1	Affinity Capture-Western, Biochemical Activity	physical	10958680, 11409918, 15664191, 16093354, 19058874, (Europe PMC)	NA	BioGRID
MAPK3	Affinity Capture-Western, Biochemical Activity	physical	11409918, 19058874, (Europe PMC)	NA	BioGRID
MAPK6	anti tag coimmunoprecipitation	association	26972000, (Europe PMC)	0.35	IntAct
MAPK7	Affinity Capture-Western, Reconstituted Complex	physical	10531364, (Europe PMC)	NA	BioGRID
MAPK8	Two-hybrid, two hybrid array	physical, physical association	21988832, (Europe PMC)	0.37	BioGRID, IntAct
MAPK8IP3	Affinity Capture-Western, Reconstituted Complex	physical	10523642, 11044439, (Europe PMC)	NA	BioGRID
MLF1	luminescence based mammalian interactome mapping	physical association	25036637, (Europe PMC)	0.40	IntAct
MMS19	Affinity Capture-MS	physical	22678362, (Europe PMC)	NA	BioGRID
MOV10	Affinity Capture-RNA	physical	22658674, (Europe PMC)	NA	BioGRID
MRAS	Affinity Capture-Western, Reconstituted Complex, fluorescent resonance energy transfer	direct interaction, physical	10498616, 20080631, 25022756, (Europe PMC)	0.44	BioGRID, IntAct
MRC2	Two-hybrid, two hybrid array	physical, physical association	25640309, (Europe PMC)	0.37	BioGRID, IntAct, MINT
MSH2	Affinity Capture-MS, inference by socio-affinity scoring	physical, physical association	27173435, (Europe PMC)	0.27	BioGRID, IntAct
MYBPC1	Two-hybrid	physical	16364241, (Europe PMC)	NA	BioGRID
MYC	Affinity Capture-MS, Reconstituted Complex, tandem affinity purification	association, physical	17314511, 9315742, (Europe PMC)	0.35	BioGRID, IntAct
NCAPG2	Affinity Capture-MS, inference by socio-affinity scoring	physical, physical association	27173435, (Europe PMC)	0.27	BioGRID, IntAct
NEDD4	Reconstituted Complex	physical	19953087, (Europe PMC)	NA	BioGRID
NEDD4L	Affinity Capture-Western	physical	19380724, (Europe PMC)	NA	BioGRID
NFATC3	anti bait coimmunoprecipitation	physical association	24330068, (Europe PMC)	0.40	IntAct, MINT
NPHP4	Affinity Capture-MS, inference by socio-affinity scoring	physical, physical association	27173435, (Europe PMC)	0.27	BioGRID, IntAct
NPLOC4	Two-hybrid	physical	16364241, (Europe PMC)	NA	BioGRID
NR3C1	Affinity Capture-Western	physical	11005817, (Europe PMC)	NA	BioGRID
NRAS	Affinity Capture-Western, Synthetic Lethality, anti tag coimmunoprecipitation, fluorescent resonance energy transfer, pull down, two hybrid array, two hybrid prey pooling approach	direct interaction, genetic, physical, physical association	10882715, 18641128, 20080631, 21478863, 28162770, (Europe PMC)	0.80	BioGRID, IntAct
NUDCD3	luminescence based mammalian interactome mapping	physical association	25036637, (Europe PMC)	0.40	IntAct
NUDT14	two hybrid	physical association	12620389, (Europe PMC)	0.37	IntAct
NUP107	Affinity Capture-MS, inference by socio-affinity scoring	physical, physical association	27173435, (Europe PMC)	0.27	BioGRID, IntAct
NUP133	Affinity Capture-MS, inference by socio-affinity scoring	physical, physical association	27173435, (Europe PMC)	0.27	BioGRID, IntAct
NUP160	Affinity Capture-MS, inference by socio-affinity scoring	physical, physical association	27173435, (Europe PMC)	0.27	BioGRID, IntAct
NXF1	Affinity Capture-RNA	physical	22658674, (Europe PMC)	NA	BioGRID
OIP5	Two-hybrid	physical	12620389, (Europe PMC)	NA	BioGRID
OIP5	two hybrid	physical association	12620389, (Europe PMC)	0.37	IntAct
PACSIN3	Two-hybrid	physical	16364241, (Europe PMC)	NA	BioGRID
PAK1	Affinity Capture-Western, Biochemical Activity, Reconstituted Complex	physical	11733498, (Europe PMC)	NA	BioGRID
PAK1	protein kinase assay	phosphorylation reaction	17097642, (Europe PMC)	0.44	IntAct, MINT
PAK2	nuclear magnetic resonance, protein kinase assay	direct interaction, phosphorylation reaction	16837009, (Europe PMC)	0.56	IntAct
PAQR3	anti bait coimmunoprecipitation, anti tag coimmunoprecipitation	association, physical association	17724343, (Europe PMC)	0.58	IntAct
PBK	two hybrid	physical association	12620389, (Europe PMC)	0.37	IntAct
PCDH7	Affinity Capture-MS, anti tag coimmunoprecipitation	association, physical	26496610, (Europe PMC)	0.35	BioGRID, IntAct
PDGFRB	Reconstituted Complex, proximity ligation assay	physical, physical association	23397142, 2475255, (Europe PMC)	0.40	BioGRID, IntAct
PDLIM2	Two-hybrid, two hybrid array	physical, physical association	25640309, (Europe PMC)	0.37	BioGRID, IntAct, MINT
PEBP1	Affinity Capture-Western, Reconstituted Complex, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, peptide array, pull down, surface plasmon resonance	association, direct interaction, physical, physical association	10757792, 14654844, 17097642, 21831839, (Europe PMC)	0.76	BioGRID, IntAct, MINT
PEBP4	Affinity Capture-Western, Reconstituted Complex, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, pull down	association, physical, physical association	15302887, 19197339, (Europe PMC)	0.60	BioGRID, IntAct, MINT
PHB	Affinity Capture-Western, Reconstituted Complex, anti bait coimmunoprecipitation	physical, physical association	10523633, 16041367, 24568222, (Europe PMC)	0.40	BioGRID, IntAct
PHKA2	Two-hybrid	physical	12620389, (Europe PMC)	NA	BioGRID
PIN1	Affinity Capture-Western, anti tag coimmunoprecipitation	association, physical, physical association	15664191, 20179103, 20179161, (Europe PMC)	0.56	BioGRID, IntAct
PKM	Two-hybrid, two hybrid	physical, physical association	12620389, (Europe PMC)	0.37	BioGRID, IntAct
PPP1CC	Affinity Capture-Western	physical	12374792, (Europe PMC)	NA	BioGRID
PPP2CA	Affinity Capture-Western, anti tag coimmunoprecipitation, phosphatase assay	dephosphorylation reaction, physical, physical association	16041367, 16239230, (Europe PMC)	0.54	BioGRID, IntAct, MINT
PPP2CB	Two-hybrid, two hybrid array	physical, physical association	21988832, (Europe PMC)	0.37	BioGRID, IntAct
PPP2R1A	Affinity Capture-Western	physical	16041367, (Europe PMC)	NA	BioGRID
PPP2R2B	Affinity Capture-Western	physical	16041367, (Europe PMC)	NA	BioGRID
PPP2R5C	anti tag coimmunoprecipitation, phosphatase assay	dephosphorylation reaction, physical association	16239230, (Europe PMC)	0.54	IntAct, MINT
PRKAR1A	Two-hybrid	physical	16364241, (Europe PMC)	NA	BioGRID
PRKCE	Affinity Capture-Western	physical	11350735, (Europe PMC)	NA	BioGRID
PRKCZ	Affinity Capture-Western, Reconstituted Complex	physical	10620507, (Europe PMC)	NA	BioGRID
PRKG1	Affinity Capture-Western	physical	12237340, (Europe PMC)	NA	BioGRID
PRPF6	Two-hybrid	physical	10848612, (Europe PMC)	NA	BioGRID
PSMD2	luminescence based mammalian interactome mapping	physical association	25036637, (Europe PMC)	0.40	IntAct
PURA	Two-hybrid	physical	16364241, (Europe PMC)	NA	BioGRID
RAF1	Affinity Capture-Western, anti tag coimmunoprecipitation, tandem affinity purification, x-ray crystallography	association, direct interaction, physical, physical association	16093354, 17979178, 20130576, 22169110, 22510884, 27703006, (Europe PMC)	0.81	BioGRID, IntAct, MINT
RALGDS	pull down	association	19075231, (Europe PMC)	0.35	IntAct
RANBP9	Affinity Capture-Western, Two-hybrid	physical	16364241, 23118896, (Europe PMC)	NA	BioGRID
RAP1A	Co-crystal Structure, Reconstituted Complex, Two-hybrid, x-ray crystallography	direct interaction, physical	10454553, 7791872, 7862125, 8756332, 9867809, (Europe PMC)	0.62	BioGRID, IntAct
RASD2	Reconstituted Complex	physical	14724584, (Europe PMC)	NA	BioGRID
RB1	Affinity Capture-Western, Biochemical Activity, Reconstituted Complex, Two-hybrid, anti bait coimmunoprecipitation	physical, physical association	10523633, 15485920, 19058874, 21139044, 9819434, (Europe PMC)	0.40	BioGRID, IntAct
RBBP8	Two-hybrid, two hybrid array	physical, physical association	21988832, (Europe PMC)	0.37	BioGRID, IntAct
RBL2	Affinity Capture-Western, Reconstituted Complex, Two-hybrid	physical	9819434, (Europe PMC)	NA	BioGRID
RCAN1	pull down	physical association	15935327, (Europe PMC)	0.40	IntAct
RFXANK	Biochemical Activity	physical	10329666, (Europe PMC)	NA	BioGRID
RHEB	Affinity Capture-Western, Reconstituted Complex, Two-hybrid, pull down	direct interaction, physical	15150271, 15854902, 19222999, 9001246, (Europe PMC)	0.44	BioGRID, IntAct, MINT
RIPK4	anti tag coimmunoprecipitation	association	26972000, (Europe PMC)	0.35	IntAct
RMDN3	Co-localization	physical	25862004, (Europe PMC)	NA	BioGRID
RPGRIP1L	Affinity Capture-MS, inference by socio-affinity scoring	physical, physical association	27173435, (Europe PMC)	0.27	BioGRID, IntAct
RRAS	Affinity Capture-Western, Two-hybrid	physical	10848612, 19805522, (Europe PMC)	NA	BioGRID
RRAS2	Reconstituted Complex, Two-hybrid, two hybrid	physical, physical association	10557073, 10783161, 12620389, (Europe PMC)	0.37	BioGRID, IntAct
SCNN1B	Affinity Capture-Western	physical	19380724, (Europe PMC)	NA	BioGRID
SFN	Affinity Capture-MS, Affinity Capture-Western, FRET, anti tag coimmunoprecipitation, biochemical, tandem affinity purification	association, physical, physical association	11697890, 15778465, 16041367, 16093354, 25852190, 26578655, (Europe PMC)	0.67	BioGRID, IntAct, MINT
SGK1	Affinity Capture-Western	physical	19380724, 20947508, (Europe PMC)	NA	BioGRID
SH3KBP1	Affinity Capture-Western	physical	24167568, (Europe PMC)	NA	BioGRID
SHOC2	Affinity Capture-Western	physical	10783161, 25022756, 26519477, (Europe PMC)	NA	BioGRID
SPATA7	Affinity Capture-MS, inference by socio-affinity scoring, tandem affinity purification	association, physical, physical association	27173435, (Europe PMC)	0.27, 0.35	BioGRID, IntAct
SPRY2	Affinity Capture-Western	physical	12717443, (Europe PMC)	NA	BioGRID
SPRY4	Affinity Capture-Western	physical	12717443, (Europe PMC)	NA	BioGRID
SRC	Affinity Capture-Western, Reconstituted Complex	physical	7517401, (Europe PMC)	NA	BioGRID
SS18L2	Affinity Capture-MS, anti tag coimmunoprecipitation	association, physical	26496610, (Europe PMC)	0.35	BioGRID, IntAct
STIP1	luminescence based mammalian interactome mapping	physical association	25036637, (Europe PMC)	0.40	IntAct
STK26	Two-hybrid	physical	11306563, (Europe PMC)	NA	BioGRID
STK3	Affinity Capture-MS, Affinity Capture-Western, Reconstituted Complex, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, peptide array, pull down	direct interaction, physical, physical association	15618521, 17889669, 20086174, 20212043, 24929361, (Europe PMC)	0.65	BioGRID, IntAct
STUB1	Affinity Capture-Western, Biochemical Activity, Reconstituted Complex	physical	15215316, 15936278, 19011619, 22350907, (Europe PMC)	NA	BioGRID
STUB1	luminescence based mammalian interactome mapping	physical association	25036637, (Europe PMC)	0.40	IntAct
SYNPO	Affinity Capture-MS, anti tag coimmunoprecipitation	association, physical	26496610, (Europe PMC)	0.35	BioGRID, IntAct
TBXA2R	Affinity Capture-Western	physical	16413928, (Europe PMC)	NA	BioGRID
TIMM50	Affinity Capture-MS, anti tag coimmunoprecipitation, two hybrid	association, physical, physical association	12620389, 25852190, (Europe PMC)	0.55	BioGRID, IntAct
TMEM63B	Affinity Capture-MS, anti tag coimmunoprecipitation	association, physical	26496610, (Europe PMC)	0.35	BioGRID, IntAct
TMEM70	Two-hybrid	physical	16364241, (Europe PMC)	NA	BioGRID
TRIM25	Affinity Capture-RNA	physical	29117863, (Europe PMC)	NA	BioGRID
TSC22D3	Affinity Capture-Western, Reconstituted Complex	physical	12391160, 19380724, (Europe PMC)	NA	BioGRID
UBE2D2	Biochemical Activity	physical	11676916, (Europe PMC)	NA	BioGRID
VAV1	Affinity Capture-Western	physical	8900182, (Europe PMC)	NA	BioGRID
VCP	Affinity Capture-MS	physical	23383273, (Europe PMC)	NA	BioGRID
VDAC1	Affinity Capture-Western	physical	12079506, (Europe PMC)	NA	BioGRID
WDR83	Affinity Capture-Western	physical	15118098, (Europe PMC)	NA	BioGRID
XIAP	Affinity Capture-Western, Biochemical Activity, Co-localization, Reconstituted Complex, Two-hybrid, proximity ligation assay	physical, physical association	16964381, 19011619, 25241761, (Europe PMC)	0.40	BioGRID, IntAct
XPO1	Affinity Capture-MS	physical	26673895, (Europe PMC)	NA	BioGRID
YWHAB	Affinity Capture-MS, Affinity Capture-Western, Reconstituted Complex, Two-hybrid, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, biochemical, two hybrid	association, physical, physical association	10620507, 10848612, 11697890, 12360521, 12620389, 16041367, 16093354, 19595761, 24255178, 25852190, 7644510, 7882972, 7935795, 8085158, 8702721, (Europe PMC)	0.93	BioGRID, IntAct, MINT
YWHAE	Affinity Capture-MS, Affinity Capture-Western, Two-hybrid, anti tag coimmunoprecipitation, biochemical, two hybrid	association, physical, physical association	11697890, 16041367, 16093354, 17979178, 19608861, 25852190, 7644510, 8702721, (Europe PMC)	0.66	BioGRID, IntAct, MINT
YWHAG	Affinity Capture-MS, Affinity Capture-Western, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, biochemical	association, physical, physical association	10433554, 10620507, 11697890, 16041367, 16093354, 17353931, 25852190, (Europe PMC)	0.67	BioGRID, IntAct, MINT
YWHAH	Affinity Capture-MS, Affinity Capture-Western, anti tag coimmunoprecipitation, biochemical, tandem affinity purification	association, physical, physical association	10620507, 11697890, 11969417, 16041367, 16093354, 17979178, 25852190, 26496610, 8702721, (Europe PMC)	0.77	BioGRID, IntAct, MINT
YWHAQ	Affinity Capture-MS, Affinity Capture-Western, Reconstituted Complex, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, biochemical, pull down	association, physical, physical association	10620507, 10757792, 11697890, 15618521, 16041367, 16093354, 17353931, 25852190, 7479742, 7760835, 8663231, (Europe PMC)	0.74	BioGRID, IntAct, MINT
YWHAZ	Affinity Capture-MS, Affinity Capture-Western, Reconstituted Complex, Two-hybrid, anti tag coimmunoprecipitation, biochemical, coimmunoprecipitation, lex-a dimerization assay, peptide array, pull down, surface plasmon resonance, tandem affinity purification, two hybrid, x-ray crystallography	association, direct interaction, physical, physical association	10611249, 10620507, 10887173, 11697890, 12861023, 14688280, 15664191, 16041367, 16093354, 16306228, 17979178, 19049963, 20052757, 20679480, 22222486, 25852190, 7628630, 7935795, 7939632, 8085158, 8601312, 9153224, 9261098, 9632690, (Europe PMC)	0.95	BioGRID, IntAct, MINT
YY1	Two-hybrid, two hybrid array	physical, physical association	21988832, (Europe PMC)	0.37	BioGRID, IntAct

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RAF1