DEPOD - human DEPhOsphorylation Database

Basic Information
Phosphatases
Pathway
Interacting Proteins
Phosphorylating Kinases

Gene Name	PTPN11 (QuickGO)	Interactive visualization of PTPN11 structures (A quick tutorial to explore the interctive visulaization) Representative structure: 3ZM0
Synonyms	PTPN11, PTP2C, SHPTP2
Protein Name	PTPN11
Alternative Name(s)	Tyrosine-protein phosphatase non-receptor type 11;3.1.3.48;Protein-tyrosine phosphatase 1D;PTP-1D;Protein-tyrosine phosphatase 2C;PTP-2C;SH-PTP2;SHP-2;Shp2;SH-PTP3;
Protein Family	Belongs to the protein-tyrosine phosphatase familyNon-receptor class 2 subfamily
EntrezGene ID	5781 (Comparitive Toxicogenomics)
UniProt AC (Human)	Q06124 (protein sequence)
Enzyme Class	3.1.3.48 (BRENDA )
Molecular Weight	68436 Dalton
Protein Length	597 amino acids (AA)
Genome Browsers	NCBI \| ENSG00000179295 (Ensembl) \| UCSC
Crosslinking annotations	Query our ID-mapping table
Orthologues	Quest For Orthologues (QFO) \| GeneTree \| eggNOG - KOG0790 \| eggNOG - COG5599
Phosphorylation Network	Visualize

Domain organization, Expression, Diseases

(show / hide)

Localization, Function, Catalytic activity and Sequence

(show / hide)

Motif information from Eukaryotic Linear Motif atlas (ELM)

(show / hide)

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

(show / hide)

GO:0000077	P:DNA damage checkpoint
GO:0000187	P:activation of MAPK activity
GO:0001784	F:phosphotyrosine residue binding
GO:0004721	F:phosphoprotein phosphatase activity
GO:0004725	F:protein tyrosine phosphatase activity
GO:0004726	F:non-membrane spanning protein tyrosine phosphatase activity
GO:0005070	F:SH3/SH2 adaptor activity
GO:0005158	F:insulin receptor binding
GO:0005634	C:nucleus
GO:0005654	C:nucleoplasm
GO:0005737	C:cytoplasm
GO:0005739	C:mitochondrion
GO:0005829	C:cytosol
GO:0006641	P:triglyceride metabolic process
GO:0007173	P:epidermal growth factor receptor signaling pathway
GO:0007229	P:integrin-mediated signaling pathway
GO:0007411	P:axon guidance
GO:0007420	P:brain development
GO:0007507	P:heart development
GO:0008543	P:fibroblast growth factor receptor signaling pathway
GO:0009755	P:hormone-mediated signaling pathway
GO:0016303	F:1-phosphatidylinositol-3-kinase activity
GO:0019221	P:cytokine-mediated signaling pathway
GO:0019904	F:protein domain specific binding
GO:0021697	P:cerebellar cortex formation
GO:0030168	P:platelet activation
GO:0030220	P:platelet formation
GO:0030971	F:receptor tyrosine kinase binding
GO:0031295	P:T cell costimulation
GO:0031748	F:D1 dopamine receptor binding
GO:0032528	P:microvillus organization
GO:0032991	C:protein-containing complex
GO:0033277	P:abortive mitotic cell cycle
GO:0033628	P:regulation of cell adhesion mediated by integrin
GO:0033629	P:negative regulation of cell adhesion mediated by integrin
GO:0035264	P:multicellular organism growth
GO:0035265	P:organ growth
GO:0035335	P:peptidyl-tyrosine dephosphorylation
GO:0035855	P:megakaryocyte development
GO:0036302	P:atrioventricular canal development
GO:0038127	P:ERBB signaling pathway
GO:0040014	P:regulation of multicellular organism growth
GO:0042445	P:hormone metabolic process
GO:0042593	P:glucose homeostasis
GO:0043254	P:regulation of protein complex assembly
GO:0043274	F:phospholipase binding
GO:0043560	F:insulin receptor substrate binding
GO:0045931	P:positive regulation of mitotic cell cycle
GO:0046676	P:negative regulation of insulin secretion
GO:0046825	P:regulation of protein export from nucleus
GO:0046887	P:positive regulation of hormone secretion
GO:0046934	F:phosphatidylinositol-4,5-bisphosphate 3-kinase activity
GO:0048008	P:platelet-derived growth factor receptor signaling pathway
GO:0048011	P:neurotrophin TRK receptor signaling pathway
GO:0048013	P:ephrin receptor signaling pathway
GO:0048609	P:multicellular organismal reproductive process
GO:0048806	P:genitalia development
GO:0048839	P:inner ear development
GO:0048873	P:homeostasis of number of cells within a tissue
GO:0050839	F:cell adhesion molecule binding
GO:0050900	P:leukocyte migration
GO:0051428	F:peptide hormone receptor binding
GO:0051463	P:negative regulation of cortisol secretion
GO:0051897	P:positive regulation of protein kinase B signaling
GO:0060020	P:Bergmann glial cell differentiation
GO:0060125	P:negative regulation of growth hormone secretion
GO:0060325	P:face morphogenesis
GO:0060338	P:regulation of type I interferon-mediated signaling pathway
GO:0061582	P:intestinal epithelial cell migration
GO:0070102	P:interleukin-6-mediated signaling pathway
GO:0070374	P:positive regulation of ERK1 and ERK2 cascade
GO:0071260	P:cellular response to mechanical stimulus
GO:0071345	P:cellular response to cytokine stimulus
GO:0071364	P:cellular response to epidermal growth factor stimulus
GO:2001275	P:positive regulation of glucose import in response to insulin stimulus

KEGG Pathway
Reactome Pathway

Pathway ID	Pathway Name	Pathway Description (KEGG)
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).
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.
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.
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.
hsa04670	Leukocyte transendothelial migration	Leukocyte migaration from the blood into tissues is vital for immune surveillance and inflammation. During this diapedesis of leukocytes, the leukocytes bind to endothelial cell adhesion molecules (CAM) and then migrate across the vascular endothelium. A leukocyte adherent to CAMs on the endothelial cells moves forward by leading-edge protrusion and retraction of its tail. In this process, alphaL /beta2 integrin activates through Vav1, RhoA, which subsequently activates the kinase p160ROCK. ROCK activation leads to MLC phosphorylation, resulting in retraction of the actin cytoskeleton. Moreover, Leukocytes activate endothelial cell signals that stimulate endothelial cell retraction during localized dissociation of the endothelial cell junctions. ICAM-1-mediated signals activate an endothelial cell calcium flux and PKC, which are required for ICAM-1 dependent leukocyte migration. VCAM-1 is involved in the opening of the endothelial passagethrough which leukocytes can extravasate. In this regard, VCAM-1 ligation induces NADPH oxidase activation and the production of reactive oxygen species (ROS) in a Rac-mediated manner, with subsequent activation of matrix metallopoteinases and loss of VE-cadherin-mediated adhesion.
hsa04722	Neurotrophin signaling pathway	Neurotrophins are a family of trophic factors involved in differentiation and survival of neural cells. The neurotrophin family consists of nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT-3), and neurotrophin 4 (NT-4). Neurotrophins exert their functions through engagement of Trk tyrosine kinase receptors or p75 neurotrophin receptor (p75NTR). Neurotrophin/Trk signaling is regulated by connecting a variety of intracellular signaling cascades, which include MAPK pathway, PI-3 kinase pathway, and PLC pathway, transmitting positive signals like enhanced survival and growth. On the other hand, p75NTR transmits both positive and nagative signals. These signals play an important role for neural development and additional higher-order activities such as learning and memory.
hsa04920	Adipocytokine signaling pathway	Increased adipocyte volume and number are positively correlated with leptin production, and negatively correlated with production of adiponectin.Leptin is an important regulator of energy intake and metabolic rate primarily by acting at hypothalamic nuclei. Leptin exerts its anorectic effects by modulating the levels of neuropeptides such as NPY, AGRP, and alpha-MSH. This leptin action is through the JAK kinase, STAT3 phosphorylation, and nuclear transcriptional effect.Adiponectin lowers plasma glucose and FFAs. These effects are partly accounted for by adiponectin-induced AMPK activation, which in turn stimulates skeletal muscle fatty acid oxidation and glucose uptake. Furthermore, activation of AMPK by adiponectin suppresses endogenous glucose production, concomitantly with inhibition of PEPCK and G6Pase expression.The proinflammatory cytokine TNFalpha has been implicated as a link between obesity and insulin resistance. TNFalpha interferes with early steps of insulin signaling. Several data have shown that TNFalpha inhibits IRS1 tyrosine phosphorylation by promoting its serine phosphorylation. Among the serine/threonine kinases activated by TNFalpha, JNK, mTOR and IKK have been shown to be involved in this phosphorylation.
hsa04931	Insulin resistance	Insulin resistance is a condition where cells become resistant to the effects of insulin. It is often found in people with health disorders, including obesity, type 2 diabetes mellitus, non-alcoholic fatty liver disease, and cardiovascular diseases. In this diagram multiple mechanisms underlying insulin resistance are shown: (a) increased phosphorylation of IRS (insulin receptor substrate) protein through serine/threonine kinases, such as JNK1 and IKKB, and protein kinase C, (b) increased IRS-1 proteasome degradation via mTOR signaling pathway, (c) decreased activation of signaling molecules including PI3K and AKT, (d) increase in activity of phosphatases including PTPs, PTEN, and PP2A. Regulatory actions such as oxidative stress, mitochondrial dysfunction, accumulation of intracellular lipid derivatives (diacylglycrol and ceramides), and inflammation (via IL-6 and TNFA) contribute to these mechanisms. Consequently, insulin resistance causes reduced GLUT4 translocation, resulting in glucose takeup and glycogen synthesis in skeletal muscle as well as increased hepatic gluconeogenesis and decreased glycogen synthesis in liver. At the bottom of the diagram, interplay between O-GlcNAcylation and serine/threonine phosphorylation is shown. Studies suggested that elevated O-GlcNAc level was correlated to high glucose-induced insulin resistance. Donor UDP-GlcNAc is induced through hexosamine biosynthesis pathway and added to proteins by O-GlcNAc transferase. Elevation of O-GlcNAc modification alters phosphorylation and function of key insulin signaling proteins including IRS-1, PI3K, PDK1, Akt and other transcription factor and cofactors, resulting in the attenuation of insulin signaling cascade.
hsa05120	Epithelial cell signaling in Helicobacter pylori infection	Two major virulence factors of H. pylori are the vacuolating cytotoxin (VacA) and the cag type-IV secretion system (T4SS) and its translocated effector protein, cytotoxin-associated antigen A (CagA).VacA binds to lipid rafts and glycosylphosphatidylinositol-anchored proteins (GPI-APs) of the target cell membrane. After insertion into the plasma membrane, VacA channels are endocytosed and eventually reach late endosomal compartments, increasing their permeability to anions with enhancement of the electrogenic vacuolar ATPase (v-ATPase) proton pump. In the presence of weak bases, osmotically active acidotropic ions will accumulate in the endosomes. This leads to water influx and vesicle swelling, an essential step in vacuole formation. In addition, it is reported that the VacA cleavage product binds to the tyrosine phosphatase receptor zeta (Ptprz) on epithelial cells and the induced signaling leads to the phosphorylation of the G protein-coupled receptor kinase-interactor 1 (Git1) and induces ulcerogenesis in mice.The other virulence factor cag T4SS mediates the translocation of the effector protein CagA, which is subsequently phosphorylated by a Src kinase. Phosphorylated CagA interacts with the protein tyrosine phosphatase SHP-2, thus stimulating its phosphatase activity. Activated SHP-2 is able to induce MAPK signalling through Ras/Raf-dependent and -independent mechanisms. Deregulation of this pathway by CagA may lead to abnormal proliferation and movement of gastric epithelial cells.
hsa05168	Herpes simplex infection	Herpes simplex virus (HSV) infections are very common worldwide, with the prevalence of HSV-1 reaching up to 80%-90%. Primary infection with HSV takes place in the mucosa, followed by the establishment of latent infection in neuronal ganglia. HSV is the main cause of herpes infections that lead to the formation of characteristic blistering lesion. HSV express multiple viral accessory proteins that interfere with host immune responses and are indispensable for viral replication. Among these proteins, the immediate early (IE) gene ICP0, ICP4, and ICP27 are essential for regulation of HSV gene expression in productive infection. On the other hand, ORF P and ORF O gene are transcribed during latency and blocks the expression of the IE genes, thus maintaining latent infection.
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.
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.
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.

Pathway ID	Pathway Name	Pathway Description (KEGG)
R-HSA-1059683	Interleukin-6 signaling.	Interleukin-6 (IL-6) is a pleiotropic cytokine with roles in processes including immune regulation, hematopoiesis, inflammation, oncogenesis, metabolic control and sleep. It is the founding member of a family of IL-6-related cytokines such as IL-11, IL-27 leukemia inhibitory factor (LIF), cilliary neurotrophic factor (CNTF) and oncostatin M. The IL-6 receptor (IL6R) consists of an alpha subunit that specifically binds IL-6 and a beta subunit, IL6RB or gp130, which is the signaling component of all the receptors for cytokines related to IL-6. IL6R alpha exists in transmembrane and soluble forms. The transmembrane form is mainly expressed by hepatocytes, neutrophils, monocytes/macrophages, and some lymphocytes. Soluble forms of IL6R (sIL6R) are also expressed by these cells. Two major mechanisms for the production of sIL6R have been proposed. Alternative splicing generates a transcript lacking the transmembrane domain by using splicing donor and acceptor sites that flank the transmembrane domain coding region. This also introduces a frameshift leading to the incorporation of 10 additional amino acids at the C terminus of sIL6R.A second mechanism for the generation of sIL6R is the proteolytic cleavage or 'shedding' of membrane-bound IL-6R. Two proteases ADAM10 and ADAM17 are thought to contribute to this (Briso et al. 2008). sIL6R can bind IL6 and stimulate cells that express gp130 but not IL6R alpha, a process that is termed trans-signaling. This explains why many cells, including hematopoietic progenitor cells, neuronal cells, endothelial cells, smooth muscle cells, and embryonic stem cells, do not respond to IL6 alone, but show a remarkable response to IL6/sIL6R. It is clear that the trans-signaling pathway is responsible for the pro-inflammatory activities of IL-6 whereas the membrane bound receptor governs regenerative and anti-inflammatory IL-6 activitiesIL6R signal transduction is mediated by two pathways:the JAK-STAT (Janus family tyrosine kinase-signal transducer and activator of transcription) pathway and the Ras-MAPK (mitogen-activated protein kinase) pathway. Negative regulators of IL-6 signaling include SOCS (suppressor of cytokine signals) and SHP2. Within the last few years different antibodies have been developed to inhibit IL-6 activity, and the first such antibodies have been introduced into the clinic for the treatment of inflammatory diseases (Kopf et al. 2010)
R-HSA-109704	PI3K Cascade.	The PI3K (Phosphatidlyinositol-3-kinase) - AKT signaling pathway stimulates cell growth and survival
R-HSA-110056	MAPK3 (ERK1) activation.	Mitogen-activated protein kinase kinase MAP2K1 (also known as MEK1) is a dual threonine and tyrosine recognition kinase that phosphorylates and activates MAPK3 (ERK1) (Ohren et al. 2004; Roskoski 2012a)
R-HSA-112411	MAPK1 (ERK2) activation.	Mitogen-activated protein kinase kinase MAP2K2 (also known as MEK2) is a dual threonine and tyrosine recognition kinase that phosphorylates and activates MAPK1 (ERK2) (Ohren et al. 2004; Roskoski 2012)
R-HSA-114604	GPVI-mediated activation cascade.	The GPVI receptor is a complex of the GPVI protein with Fc epsilon R1 gamma (FcR). The Src family kinases Fyn and Lyn constitutively associate with the GPVI-FcR complex in platelets and initiate platelet activation through phosphorylation of the immunoreceptor tyrosine-based activation motif (ITAM) in the FcR gamma chain, leading to binding and activation of the tyrosine kinase Syk. Downstream of Syk, a series of adapter molecules and effectors lead to platelet activation. The GPVI receptor signaling cascade is similar to that of T- and B-cell immune receptors, involving the formation of a signalosome composed of adapter and effector proteins. At the core of the T-cell receptor signalosome is the transmembrane adapter LAT and two cytosolic adapters SLP-76 and Gads. While LAT is essential for signalling to PLCgamma1 downstream of the T-cell receptor, the absence of LAT in platelets only impairs the activation of PLCgamma2, the response to collagen and GPVI receptor ligands remains sufficient to elicit a full aggregation response. In contrast, GPVI signalling is almost entirely abolished in the absence of SLP-76
R-HSA-1170546	Prolactin receptor signaling.	Prolactin (PRL) is a hormone secreted mainly by the anterior pituitary gland. It was originally identified by its ability to stimulate the development of the mammary gland and lactation, but is now known to have numerous and varied functions (Bole-Feysot et al. 1998). Despite this, few pathologies have been associated with abnormalities in prolactin receptor (PRLR) signaling, though roles in various forms of cancer and certain autoimmune disorders have been suggested (Goffin et al. 2002). A vast body of literature suggests effects of PRL in immune cells (Matera 1996) but PRLR KO mice have unaltered immune system development and function (Bouchard et al. 1999). In addition to the pituitary, numerous other tissues produce PRL, including the decidua and myometrium, certain cells of the immune system, brain, skin and exocrine glands such as the mammary, sweat and lacrimal glands (Ben-Jonathan et al. 1996). Pituitary PRL secretion is negatively regulated by inhibitory factors originating from the hypothalamus, the most important of which is dopamine, acting through the D2 subclass of dopamine receptors present in lactotrophs (Freeman et al. 2000). PRL-binding sites or receptors have been identified in numerous cells and tissues of adult mammals. Various forms of PRLR, generated by alternative splicing, have been reported in several species including humans (Kelly et al. 1991, Clevenger et al. 2003).PRLR is a member of the cytokine receptor superfamily. Like many other members of this family, the first step in receptor activation was generally believed to be ligand-induced dimerization whereby one molecule of PRL bound to two molecules of receptor (Elkins et al. 2000). Recent reports suggest that PRLR pre-assembles at the plasma membrane in the absence of ligand (Gadd & Clevenger 2006, Tallet et al. 2011), suggesting that ligand-induced activation involves conformational changes in preformed PRLR dimers (Broutin et al. 2010). PRLR has no intrinsic kinase activity but associates (Lebrun et al. 1994, 1995) with Janus kinase 2 (JAK2) which is activated following receptor activation (Campbell et al. 1994, Rui et al. 1994, Carter-Su et al. 2000, Barua et al. 2009). JAK2-dependent activation of JAK1 has also been reported (Neilson et al. 2007). It is generally accepted that activation of JAK2 occurs by transphosphorylation upon ligand-induced receptor activation, based on JAK activation by chimeric receptors in which various extracellular domains of cytokine or tyrosine kinase receptors were fused to the IL-2 receptor beta chain (see Ihle et al. 1994). This activation step involves the tyrosine phosphorylation of JAK2, which in turn phosphorylates PRLR on specific intracellular tyrosine residues leading to STAT5 recruitment and signaling, considered to be the most important signaling cascade for PRLR. STAT1 and STAT3 activation have also been reported (DaSilva et al. 1996) as have many other signaling pathways; signaling through MAP kinases (Shc/SOS/Grb2/Ras/Raf/MAPK) has been reported as a consequence of PRL stimuilation in many different cellular systems (see Bole-Feysot et al. 1998) though it is not clear how this signal is propagated. Other cascades non exhaustively include Src kinases, Focal adhesion kinase, phospholipase C gamma, PI3 kinase/Akt and Nek3 (Clevenger et al. 2003, Miller et al. 2007). The protein tyrosine phosphatase SHP2 is recruited to the C terminal tyrosine of PRLR and may have a regulatory role (Ali & Ali 2000). PRLR phosphotyrosines can recruit insulin receptor substrates (IRS) and other adaptor proteins to the receptor complex (Bole-Feysot et al. 1998).Female homozygous PRLR knockout mice are completely infertile and show a lack of mammary development (Ormandy et al. 1997). Hemizogotes are unable to lactate following their first pregnancy and depending on the genetic background, this phenotype can persist through subsequent pregnancies (Kelly et al. 2001)
R-HSA-1257604	PIP3 activates AKT signaling.	Signaling by AKT is one of the key outcomes of receptor tyrosine kinase (RTK) activation. AKT is activated by the cellular second messenger PIP3, a phospholipid that is generated by PI3K. In ustimulated cells, PI3K class IA enzymes reside in the cytosol as inactive heterodimers composed of p85 regulatory subunit and p110 catalytic subunit. In this complex, p85 stabilizes p110 while inhibiting its catalytic activity. Upon binding of extracellular ligands to RTKs, receptors dimerize and undergo autophosphorylation. The regulatory subunit of PI3K, p85, is recruited to phosphorylated cytosolic RTK domains either directly or indirectly, through adaptor proteins, leading to a conformational change in the PI3K IA heterodimer that relieves inhibition of the p110 catalytic subunit. Activated PI3K IA phosphorylates PIP2, converting it to PIP3; this reaction is negatively regulated by PTEN phosphatase. PIP3 recruits AKT to the plasma membrane, allowing TORC2 to phosphorylate a conserved serine residue of AKT. Phosphorylation of this serine induces a conformation change in AKT, exposing a conserved threonine residue that is then phosphorylated by PDPK1 (PDK1). Phosphorylation of both the threonine and the serine residue is required to fully activate AKT. The active AKT then dissociates from PIP3 and phosphorylates a number of cytosolic and nuclear proteins that play important roles in cell survival and metabolism. For a recent review of AKT signaling, please refer to Manning and Cantley, 2007
R-HSA-1295596	Spry regulation of FGF signaling.	Sprouty was initially characterized as a negative regulator of FGFR signaling in Drosophila. Human cells contain four genes encoding Sprouty proteins, of which Spry2 is the best studied and most widely expressed. Spry proteins modulate the duration and extent of signaling through the MAPK cascade after FGF stimulation, although the mechanism appears to depend on the particular biological context. Some studies have suggested that Sprouty binds to GRB2 and interferes with the recruitment of GRB2-SOS1 to the receptor, while others have shown that Sprouty interferes with the MAPK cascade at the level of RAF activation. In addition to modulating the MAPK pathway in response to FGF stimulation, Sprouty itself appears to be subject to complex post-translational modification that regulates its activity and stability
R-HSA-1433557	Signaling by SCF-KIT.	Stem cell factor (SCF) is a growth factor with membrane bound and soluble forms. It is expressed by fibroblasts and endothelial cells throughout the body, promoting proliferation, migration, survival and differentiation of hematopoetic progenitors, melanocytes and germ cells.(Linnekin 1999, Ronnstrand 2004, Lennartsson and Ronnstrand 2006). The receptor for SCF is KIT, a tyrosine kinase receptor (RTK) closely related to the receptors for platelet derived growth factor receptor, colony stimulating factor 1 (Linnekin 1999) and Flt3 (Rosnet et al. 1991). Four isoforms of c-Kit have been identified in humans. Alternative splicing results in isoforms of KIT differing in the presence or absence of four residues (GNNK) in the extracellular region. This occurs due to the use of an alternate 5' splice donor site. These GNNK+ and GNNK- variants are co-expressed in most tissues; the GNNK- form predominates and was more strongly tyrosine-phosphorylated and more rapidly internalized (Ronnstrand 2004). There are also splice variants that arise from alternative usage of splice acceptor site resulting in the presence or absence of a serine residue (Crosier et al., 1993). Finally, there is an alternative shorter transcript of KIT expressed in postmeiotic germ cells in the testis which encodes a truncated KIT consisting only of the second part of the kinase domain and thus lackig the extracellular and transmembrane domains as well as the first part of the kinase domain (Rossi et al. 1991). Binding of SCF homodimers to KIT results in KIT homodimerization followed by activation of its intrinsic tyrosine kinase activity. KIT stimulation activates a wide array of signalling pathways including MAPK, PI3K and JAK/STAT (Reber et al. 2006, Ronnstrand 2004). Defects of KIT in humans are associated with different genetic diseases and also in several types of cancers like mast cell leukaemia, germ cell tumours, certain subtypes of malignant melanoma and gastrointestinal tumours
R-HSA-180292	GAB1 signalosome.	GAB1 is recruited to the activated EGFR indirectly, through GRB2. GAB1 acts as an adaptor protein that enables formation of an active PIK3, through recruitment of PIK3 regulatory subunit PIK3R1 (also known as PI3Kp85), which subsequently recruits PIK3 catalytic subunit PIK3CA (also known as PI3Kp110). PIK3, in complex with EGFR, GRB2 and GAB1, catalyzes phosphorylation of PIP2 and its conversion to PIP3, which leads to the activation of the AKT signaling
R-HSA-186763	Downstream signal transduction.	The role of autophosphorylation sites on PDGF receptors are to provide docking sites for downstream signal transduction molecules which contain SH2 domains. The SH2 domain is a conserved motif of around 100 amino acids that can bind a phosphorylated tyrosine residue. These downstream molecules are activated upon binding to, or phosphorylated by, the receptor kinases intrinsic to PDGF receptors.Some of the dowstream molecules are themselves enzymes, such as phosphatidylinositol 3'-kinase (PI3K), phospholipase C (PLC-gamma), the Src family of tyrosine kinases, the tyrosine phosphatase SHP2, and a GTPase activating protein (GAP) for Ras. Others such as Grb2 are adaptor molecules which link the receptor with downstream catalytic molecules
R-HSA-210990	PECAM1 interactions.	PECAM-1/CD31 is a member of the immunoglobulin superfamily (IgSF) and has been implicated to mediate the adhesion and trans-endothelial migration of T-lymphocytes into the vascular wall, T cell activation and angiogenesis. It has six Ig homology domains within its extracellularly and an ITIM motif within its cytoplasmic region. PECAM-1 mediates cellular interactions by both homophilic and heterophilic interactions. The cytoplasmic domain of PECAM-1 contains tyrosine residues which serves as docking sites for recruitment of cytosolic signaling molecules. Under conditions of platelet activation, PECAM-1 is phosphorylated by Src kinase members. The tyrosine residues 663 and 686 are required for recruitment of the SH2 domain containing PTPs
R-HSA-210993	Tie2 Signaling.	The Tie2/Tek receptor tyrosine kinase plays a pivotal role in vascular and hematopoietic development and is expressed exclusively on endothelial lineage. Tie2 interacts with a group of ligands belonging to angiopoietin family and undergoes activation.These ligands show opposing actions, angiopoietin 1 and angiopoietin 4 stimulate the Tie2 phosphorylation and angiopoietin 2 inhibits it. Upon tyrosine phosphorylation Tie2 acts as a scaffold for various signaling proteins involved in different signal transduction cascades that can effect survival of endothelium and angiogenic sprout formation
R-HSA-2219530	Constitutive Signaling by Aberrant PI3K in Cancer.	Signaling by PI3K/AKT is frequently constitutively activated in cancer via gain-of-function mutations in one of the two PI3K subunits - PI3KCA (encoding the catalytic subunit p110alpha) or PIK3R1 (encoding the regulatory subunit p85alpha). Gain-of-function mutations activate PI3K signaling by diverse mechanisms. Mutations affecting the helical domain of PIK3CA and mutations affecting nSH2 and iSH2 domains of PIK3R1 impair inhibitory interactions between these two subunits while preserving their association. Mutations in the catalytic domain of PIK3CA enable the kinase to achieve an active conformation. PI3K complexes with gain-of-function mutations therefore produce PIP3 and activate downstream AKT in the absence of growth factors (Huang et al. 2007, Zhao et al. 2005, Miled et al. 2007, Horn et al. 2008, Sun et al. 2010, Jaiswal et al. 2009, Zhao and Vogt 2010, Urick et al. 2011)
R-HSA-2586552	Signaling by Leptin.	Leptin (LEP, OB, OBS), a circulating adipokine, and its receptor LEPR (DB, OBR) control food intake and energy balance and are implicated in obesity-related diseases (recently reviewed in Amitani et al. 2013, Dunmore and Brown 2013, Cottrell and Mercer 2012, La Cava 2012, Marroqui et al. 2012, Paz-Filho et al. 2012, Denver et al. 2011, Lee 2011, Marino et al. 2011, Morton and Schwartz 2011, Scherer and Buettner 2011, Shan and Yeo 2011, Wauman and Tavernier 2011, Dardeno et al. 2010, Bjorbaek 2009, Morris and Rui 2009, Myers et al. 2008), including cancer (Guo et al. 2012), inflammation (Newman and Gonzalez-Perez 2013, Iikuni et al. 2008), and angiogenesis (Gonzalez-Perez et al. 2013).The identification of spontaneous mutations in the leptin gene (ob or LEP) and the leptin receptor gene (Ob-R, db or LEPR) genes in mice opened up a new field in obesity research. Leptin was discovered as the product of the gene affected by the ob (obesity) mutation, which causes obesity in mice. Likewise LEPR is the product of the gene affected by the db (diabetic) mutation. Leptin binding to LEPR induces canonical (JAK2/STATs; MAPK/ERK 1/2, PI-3K/AKT) and non-canonical signaling pathways (PKC, JNK, p38 MAPK and AMPK) in diverse cell types. The binding of leptin to the long isoform of LEPR (OB-Rl) initiates a phosphorylation cascade that results in transcriptional activation of target genes by STAT5 and STAT3 and activation of the PI3K pathway(not shown here), the MAPK/ERK pathway, and the mTOR/S6K pathway. Shorter LEPR isoforms with truncated intracellular domains are unable to activate the STAT pathway, but can transduce signals by way of activation of JAK2, IRS-1 or ERKs, including MAPKs.LEPR is constitutively bound to the JAK2 kinase. Binding of LEP to LEPR causes a conformational change in LEPR that activates JAK2 autophosphorylation followed by phosphorylation of LEPR by JAK2. Phosphorylated LEPR binds STAT3, STAT5, and SHP2 which are then phosphorylated by JAK2. Phosphorylated JAK2 binds SH2B1 which then binds IRS1/2, resulting in phosphorylation of IRS1/2 by JAK2. Phosphorylated STAT3 and STAT5 dimerize and translocate to the nucleus where they activate transcription of target genes (Jovanovic et al. 2010). SHP2 activates the MAPK pathway. IRS1/2 activate the PI3K/AKT pathway which may be the activator of mTOR/S6K.Several isoforms of LEPR have been identified (reviewed in Gorska et al. 2010). The long isoform (LEPRb, OBRb) is expressed in the hypothalamus and all types of immune cells. It is the only isoform known to fully activate signaling pathways in response to leptin. Shorter isoforms (LEPRa, LEPRc, LEPRd, and a soluble isoform LEPRe) are able to interact with JAK kinases and activate other pathways, however their roles in energy homeostasis are not fully characterized
R-HSA-388841	Costimulation by the CD28 family.	Optimal activation of T-lymphocytes requires at least two signals. A primary one is delivered by the T-cell receptor (TCR) complex after antigen recognition and additional costimulatory signals are delivered by the engagement of costimulatory receptors such as CD28. The best-characterized costimulatory pathways are mediated by a set of cosignaling molecules belonging to the CD28 superfamily, including CD28, CTLA4, ICOS, PD1 and BTLA receptors. These proteins deliver both positive and negative second signals to T-cells by interacting with B7 family ligands expressed on antigen presenting cells. Different subsets of T-cells have very different requirements for costimulation. CD28 family mediated costimulation is not required for all T-cell responses in vivo, and alternative costimulatory pathways also exist. Different receptors of the CD28 family and their ligands have different regulation of expression. CD28 is constitutively expressed on naive T cells whereas CTLA4 expression is dependent on CD28/B7 engagement and the other receptor members ICOS, PD1 and BTLA are induced after initial T-cell stimulation. The positive signals induced by CD28 and ICOS molecules are counterbalanced by other members of the CD28 family, including cytotoxic T-lymphocyte associated antigen (CTLA)4, programmed cell death (PD)1, and B and T lymphocyte attenuator (BTLA), which dampen immune responses. The balance of stimulatory and inhibitory signals is crucial to maximize protective immune responses while maintaining immunological tolerance and preventing autoimmunity. The costimulatory receptors CD28, CTLA4, ICOS and PD1 are composed of single extracellular IgV-like domains, whereas BTLA has one IgC-like domain. Receptors CTLA4, CD28 and ICOS are covalent homodimers, due to an interchain disulphide linkage. The costimulatory ligands B71, B72, B7H2, B7H1 and B7DC, have a membrane proximal IgC-like domain and a membrane distal IgV-like domain that is responsible for receptor binding and dimerization. CD28 and CTLA4 have no known intrinsic enzymatic activity. Instead, engagement by their physiologic ligands B71 and B72 leads to the physical recruitment and activation of downstream T-cell effector molecules
R-HSA-389513	CTLA4 inhibitory signaling.	CTLA4 is one of the best studied inhibitory receptors of the CD28 superfamily. CTLA4 inhibits Tcell activation by reducing IL2 production and IL2 expression, and by arresting T cells at the G1 phase of the cell cycle. CTLA-4 expressed by a T cell subpopulation exerts a dominant control on the proliferation of other T cells, which limits autoreactivity. CTLA4 also blocks CD28 signals by competing for the ligands B71 and B72 in the limited space between T cells and antigenpresenting cells. Though the mechanism is obscure, CTLA4 may also propagate inhibitory signals that actively counter those produced by CD28. CTLA4 can also function in a ligand-independent manner.?CTLA-4 regulates the activation of pathogenic T cells by directly modulating T cell receptor signaling (i.e. TCR-zeta chain phosphorylation) as well as downstream biochemical signals (i.e. ERK activation). The cytoplasmic region of CTLA4 contains a tyrosine motif YVKM and a proline rich region. After TCR stimulation, it undergoes tyrosine phosphorylation by src kinases, inducing surface retention
R-HSA-389948	PD-1 signaling.	The Programmed cell death protein 1 (PD-1) is one of the negative regulators of TCR signaling. PD-1 may exert its effects on cell differentiation and survival directly by inhibiting early activation events that are positively regulated by CD28 or indirectly through IL-2. PD-1 ligation inhibits the induction of the cell survival factor Bcl-xL and the expression of transcription factors associated with effector cell function, including GATA-3, Tbet, and Eomes. PD-1 exerts its inhibitory effects by bringing phosphatases SHP-1 and SHP-2 into the immune synapse, leading to dephosphorylation of CD3-zeta chain, PI3K and AKT
R-HSA-391160	Signal regulatory protein family interactions.	Signal regulatory protein alpha (SIRPA, SHPS1, CD172a) is a transmembrane protein expressed mostly on myeloid cells. CD47, a widely expressed transmembrane protein, is a ligand for SIRP alpha, with the two proteins constituting a cell-cell communication system. The interaction of SIRPA with CD47 is important for the regulation of migration and phagocytosis. SIRPA functions as a docking protein to recruit and activate PTPN6 (SHP-1) or PTPN11 (SHP-2) at the cell membrane in response to extracellular stimuli. SIRPA also binds other intracellular proteins including the adaptor molecules Src kinase-associated protein (SKAP2 SKAP55hom/R), Fyn-binding protein/SLP-76-associated phosphoprotein (FYB/SLAP-130) and the tyrosine kinase PYK2. SIRPA also binds the extracellular proteins, surfactant-A (SP-A) and surfactant-D (SP-D). The SIRP family members SIRPB and SIRPG show high sequence similarity and similar extracellular structural topology, including three Ig domains, but their ligand binding topology might differ. SIRPB is expressed on myeloid cells, including monocytes, granulocytes and DCs. It has no known natural ligand. SIRPG can bind CD47 but with lower affinity than SIRPA
R-HSA-418886	Netrin mediated repulsion signals.	Unc5 netrin receptors mediate repellent responses to netrin. Four Unc5 members have been found in humans: Unc5A, B, C and D. Different studies have suggested that long-range repulsion to netrin requires the cooperation of Unc5 and DCC, but that Unc5 without DCC is sufficient for short-range repulsion. The binding of netrin to Unc5 triggers the phosphorylation of Unc5 in its ZU-5 domain. Several proteins have been proposed to interact with Unc5 family members in mediating a repellent response, including tyrosine phosphatase Shp2, the F-actin anti-capping protein Mena, and ankyrin
R-HSA-432142	Platelet sensitization by LDL.	Physiological concentrations (1g/L) of Low density lipoprotein (LDL) enhance platelet aggregation responses initiated by thrombin, collagen, and ADP. This enhancement involves the rapid phosphorylation of p38 mitogen-activated protein kinase (p38MAPK) at Thr180 and Tyr182. The receptor for LDL is ApoER2, a splice variant of the classical ApoE receptor. ApoER2 stimulation leads to association of the Src family kinase Fgr which is probably responsible for subsequent phosphorylation of p38MAPK. This stimulation is transient because LDL also increases the activity of PECAM-1, which stimulates phosphatases that dephosphorylate p38MAPK
R-HSA-512988	Interleukin-3, Interleukin-5 and GM-CSF signaling.	The Interleukin-3 (IL-3), IL-5 and Granulocyte-macrophage colony stimulating factor (GM-CSF) receptors form a family of heterodimeric receptors that have specific alpha chains but share a common beta subunit, often referred to as the common beta (Bc). Both subunits contain extracellular conserved motifs typical of the cytokine receptor superfamily. The cytoplasmic domains have limited similarity with other cytokine receptors and lack detectable catalytic domains such as tyrosine kinase domains. IL-3 is a 20-26 kDa product of CD4+ T cells that acts on the most immature marrow progenitors. IL-3 is capable of inducing the growth and differentiation of multi-potential hematopoietic stem cells, neutrophils, eosinophils, megakaryocytes, macrophages, lymphoid and erythroid cells. IL-3 has been used to support the proliferation of murine cell lines with properties of multi-potential progenitors, immature myeloid as well as T and pre-B lymphoid cells (Miyajima et al. 1992). IL-5 is a hematopoietic growth factor responsible for the maturation and differentiation of eosinophils. It was originally defined as a T-cell-derived cytokine that triggers activated B cells for terminal differentiation into antibody-secreting plasma cells. It also promotes the generation of cytotoxic T-cells from thymocytes. IL-5 induces the expression of IL-2 receptors (Kouro & Takatsu 2009). GM-CSF is produced by cells (T-lymphocytes, tissue macrophages, endothelial cells, mast cells) found at sites of inflammatory responses. It stimulates the growth and development of progenitors of granulocytes and macrophages, and the production and maturation of dendritic cells. It stimulates myeloblast and monoblast differentiation, synergises with Epo in the proliferation of erythroid and megakaryocytic progenitor cells, acts as an autocrine mediator of growth for some types of acute myeloid leukemia, is a strong chemoattractant for neutrophils and eosinophils. It enhances the activity of neutrophils and macrophages. Under steady-state conditions GM-CSF is not essential for the production of myeloid cells, but it is required for the proper development of alveolar macrophages, otherwise, pulmonary alvelolar proteinosis (PAP) develops. A growing body of evidence suggests that GM-CSF plays a key role in emergency hematopoiesis (predominantly myelopoiesis) in response to infection, including the production of granulocytes and macrophages in the bone marrow and their maintenance, survival, and functional activation at sites of injury or insult (Hercus et al. 2009). All three receptors have alpha chains that bind their specific ligands with low affinity (de Groot et al. 1998). Bc then associates with the alpha chain forming a high affinity receptor (Geijsen et al. 2001), though the in vivo receptor is likely be a higher order multimer as recently demonstrated for the GM-CSF receptor (Hansen et al. 2008). The receptor chains lack intrinsic kinase activity, instead they interact with and activate signaling kinases, notably Janus Kinase 2 (JAK2). These phosphorylate the common beta subunit, allowing recruitment of signaling molecules such as Shc, the phosphatidylinositol 3-kinases (PI3Ks), and the Signal Transducers and Activators of Transcription (STATs). The cytoplasmic domain of Bc has two distinct functional domains: the membrane proximal region mediates the induction of proliferation-associated genes such as c-myc, pim-1 and oncostatin M. This region binds multiple signal-transducing proteins including JAK2 (Quelle et al. 1994), STATs, c-Src and PI3 kinase (Rao and Mufson, 1995). The membrane distal domain is required for cytokine-induced growth inhibition and is necessary for the viability of hematopoietic cells (Inhorn et al. 1995). This region interacts with signal-transducing proteins such as Shc (Inhorn et al. 1995) and SHP and mediates the transcriptional activation of c-fos, c-jun, c-Raf and p70S6K (Reddy et al. 2000).Figure reproduced by permission from Macmillan Publishers Ltd: Leukemia, WL Blalock et al. 13:1109-1166, copyright 1999. Note that residue numbering in this diagram refers to the mature Common beta chain with signal peptide removed
R-HSA-5654689	PI-3K cascade:FGFR1.	The ability of growth factors to protect from apoptosis is primarily due to the activation of the AKT survival pathway. P-I-3-kinase dependent activation of PDK leads to the activation of AKT which in turn affects the activity or expression of pro-apoptotic factors, which contribute to protection from apoptosis. AKT activation also blocks the activity of GSK-3b which could lead to additional antiapoptotic signals
R-HSA-5654693	FRS-mediated FGFR1 signaling.	The FRS family of scaffolding adaptor proteins has two members, FRS2 (also known as FRS2 alpha) and FRS3 (also known as FRS2beta or SNT-2). Activation of FGFR tyrosine kinase allows FRS proteins to become phosphorylated on tyrosine residues and then bind to the adaptor GRB2 and the tyrosine phosphatase PPTN11/SHP2. Subsequently, PPTN11 activates the RAS-MAP kinase pathway and GRB2 activates the RAS-MAP kinase , PI-3-kinase and ubiquitinations/degradation pathways by binding to SOS, GAB1 and CBL, respectively, via the SH3 domains of GRB2. FRS2 acts as a central mediator in FGF signaling mainly because it induces sustained levels of activation of ERK with ubiquitous expression
R-HSA-5654695	PI-3K cascade:FGFR2.	The ability of growth factors to protect from apoptosis is primarily due to the activation of the AKT survival pathway. P-I-3-kinase dependent activation of PDK leads to the activation of AKT which in turn affects the activity or expression of pro-apoptotic factors, which contribute to protection from apoptosis. AKT activation also blocks the activity of GSK-3b which could lead to additional antiapoptotic signals
R-HSA-5654700	FRS-mediated FGFR2 signaling.	The FRS family of scaffolding adaptor proteins has two members, FRS2 (also known as FRS2 alpha) and FRS3 (also known as FRS2beta or SNT-2). Activation of FGFR tyrosine kinase allows FRS proteins to become phosphorylated on tyrosine residues and then bind to the adaptor GRB2 and the tyrosine phosphatase PPTN11/SHP2. Subsequently, PPTN11 activates the RAS-MAP kinase pathway and GRB2 activates the RAS-MAP kinase , PI-3-kinase and ubiquitinations/degradation pathways by binding to SOS, GAB1 and CBL, respectively, via the SH3 domains of GRB2. FRS2 acts as a central mediator in FGF signaling mainly because it induces sustained levels of activation of ERK with ubiquitous expression
R-HSA-5654706	FRS-mediated FGFR3 signaling.	The FRS family of scaffolding adaptor proteins has two members, FRS2 (also known as FRS2 alpha) and FRS3 (also known as FRS2beta or SNT-2). Activation of FGFR tyrosine kinase allows FRS proteins to become phosphorylated on tyrosine residues and then bind to the adaptor GRB2 and the tyrosine phosphatase PPTN11/SHP2. Subsequently, PPTN11 activates the RAS-MAP kinase pathway and GRB2 activates the RAS-MAP kinase , PI-3-kinase and ubiquitinations/degradation pathways by binding to SOS, GAB1 and CBL, respectively, via the SH3 domains of GRB2. FRS2 acts as a central mediator in FGF signaling mainly because it induces sustained levels of activation of ERK with ubiquitous expression
R-HSA-5654710	PI-3K cascade:FGFR3.	The ability of growth factors to protect from apoptosis is primarily due to the activation of the AKT survival pathway. P-I-3-kinase dependent activation of PDK leads to the activation of AKT which in turn affects the activity or expression of pro-apoptotic factors, which contribute to protection from apoptosis. AKT activation also blocks the activity of GSK-3b which could lead to additional antiapoptotic signals
R-HSA-5654712	FRS-mediated FGFR4 signaling.	The FRS family of scaffolding adaptor proteins has two members, FRS2 (also known as FRS2 alpha) and FRS3 (also known as FRS2beta or SNT-2). Activation of FGFR tyrosine kinase allows FRS proteins to become phosphorylated on tyrosine residues and then bind to the adaptor GRB2 and the tyrosine phosphatase PPTN11/SHP2. Subsequently, PPTN11 activates the RAS-MAP kinase pathway and GRB2 activates the RAS-MAP kinase , PI-3-kinase and ubiquitinations/degradation pathways by binding to SOS, GAB1 and CBL, respectively, via the SH3 domains of GRB2. FRS2 acts as a central mediator in FGF signaling mainly because it induces sustained levels of activation of ERK with ubiquitous expression
R-HSA-5654720	PI-3K cascade:FGFR4.	The ability of growth factors to protect from apoptosis is primarily due to the activation of the AKT survival pathway. P-I-3-kinase dependent activation of PDK leads to the activation of AKT which in turn affects the activity or expression of pro-apoptotic factors, which contribute to protection from apoptosis. AKT activation also blocks the activity of GSK-3b which could lead to additional antiapoptotic signals
R-HSA-5654726	Negative regulation of FGFR1 signaling.	Once activated, the FGFR signaling pathway is regulated by numerous negative feedback mechanisms. These include downregulation of receptors through CBL-mediated ubiquitination and endocytosis, ERK-mediated inhibition of FRS2-tyrosine phosphorylation and the attenuation of ERK signaling through the action of dual-specificity phosphatases, IL17RD/SEF, Sprouty and Spred proteins. A number of these inhibitors are themselves transcriptional targets of the activated FGFR pathway
R-HSA-5654727	Negative regulation of FGFR2 signaling.	Once activated, the FGFR signaling pathway is regulated by numerous negative feedback mechanisms. These include downregulation of receptors through CBL-mediated ubiquitination and endocytosis, ERK-mediated inhibition of FRS2-tyrosine phosphorylation and the attenuation of ERK signaling through the action of dual-specificity phosphatases, IL17RD/SEF, Sprouty and Spred proteins. A number of these inhibitors are themselves transcriptional targets of the activated FGFR pathway
R-HSA-5654732	Negative regulation of FGFR3 signaling.	Once activated, the FGFR signaling pathway is regulated by numerous negative feedback mechanisms. These include downregulation of receptors through CBL-mediated ubiquitination and endocytosis, ERK-mediated inhibition of FRS2-tyrosine phosphorylation and the attenuation of ERK signaling through the action of dual-specificity phosphatases, IL17RD/SEF, Sprouty and Spred proteins. A number of these inhibitors are themselves transcriptional targets of the activated FGFR pathway
R-HSA-5654733	Negative regulation of FGFR4 signaling.	Once activated, the FGFR signaling pathway is regulated by numerous negative feedback mechanisms. These include downregulation of receptors through CBL-mediated ubiquitination and endocytosis, ERK-mediated inhibition of FRS2-tyrosine phosphorylation and the attenuation of ERK signaling through the action of dual-specificity phosphatases, IL17RD/SEF, Sprouty and Spred proteins. A number of these inhibitors are themselves transcriptional targets of the activated FGFR pathway
R-HSA-6811558	PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling.	Phosphatidylinositol-5-phosphate (PI5P) may modulate PI3K/AKT signaling in several ways. PI5P is used as a substrate for production of phosphatidylinositol-4,5-bisphosphate, PI(4,5)P2 (Rameh et al. 1997, Clarke et al. 2008, Clarke et al. 2010, Clarke and Irvine 2013, Clarke et al. 2015), which serves as a substrate for activated PI3K, resulting in the production of PIP3 (Mandelker et al. 2009, Burke et al. 2011). The majority of PI(4,5)P2 in the cell, however, is produced from the phosphatidylinositol-4-phosphate (PI4P) substrate (Zhang et al. 1997, Di Paolo et al. 2002, Oude Weernink et al. 2004, Halstead et al. 2006, Oude Weernink et al. 2007). PIP3 is necessary for the activating phosphorylation of AKT. AKT1 can be deactivated by the protein phosphatase 2A (PP2A) complex that contains a regulatory subunit B56-beta (PPP2R5B) or B56-gamma (PPP2R5C). PI5P inhibits AKT1 dephosphorylation by PP2A through an unknown mechanism (Ramel et al. 2009). Increased PI5P levels correlate with inhibitory phosphorylation(s) of the PP2A complex. MAPK1 (ERK2) and MAPK3 (ERK1) are involved in inhibitory phosphorylation of PP2A, in a process that involves IER3 (IEX-1) (Letourneux et al. 2006, Rocher et al. 2007). It is uncertain, however, whether PI5P is in any way involved in ERK-mediated phosphorylation of PP2A or if it regulates another PP2A kinase
R-HSA-877312	Regulation of IFNG signaling.	At least three different classes of negative regulators exist to control the extent of INFG stimulation and signaling. These include the feedback inhibitors belonging to protein family suppressors of cytokine signaling (SOCS), the Scr-homology 2 (SH2)-containing protein tyrosine phosphatases (SHPs), and the protein inhibitors of activated STATs (PIAS). The induction of these regulators seems to be able to stop further signal transduction by inhibiting various steps in IFNG cascade
R-HSA-8853659	RET signaling.	The RET proto-oncogene encodes a receptor tyrosine kinase expressed primarily in urogenital precursor cells, spermatogonocytes, dopaminergic neurons, motor neurons and neural crest progenitors and derived cells. It is essential for kidney genesis, spermatogonial self-renewal and survivial, specification, migration, axonal growth and axon guidance of developing enteric neurons, motor neurons, parasympathetic neurons and somatosensory neurons (Schuchardt et al. 1994, Enomoto et al. 2001, Naughton et al. 2006, Kramer et al. 2006, Luo et al. 2006, 2009). RET was identified as the causative gene for human papillary thyroid carcinoma (Grieco et al. 1990), multiple endocrine neoplasia (MEN) type 2A (Mulligan et al. 1993), type 2B (Hofstra et al. 1994, Carlson et al. 1994), and Hirschsprung's disease (Romeo et al. 1994, Edery et al. 1994). RET contains a cadherin-related motif and a cysteine-rich domain in the extracellular domain (Takahashi et al. 1988). It is the receptor for members of the glial cell-derived neurotrophic factor (GDNF) family of ligands, GDNF (Lin et al. 1993), neurturin (NRTN) (Kotzbauer et al. 1996), artemin (ARTN) (Baloh et al. 1998), and persephin (PSPN) (Milbrandt et al. 1998), which form a family of neurotrophic factors. To stimulate RET, these ligands need a glycosylphosphatidylinositol (GPI)-anchored co-receptor, collectively termed GDNF family receptor-alpha (GFRA) (Treanor et al. 1996, Jing et al. 1996). The four members of this family have different, overlapping ligand preferences. GFRA1, GFRA2, GFRA3, and GFRA4 preferentially bind GDNF, NRTN, ARTN and PSPN, respectively (Jing et al. 1996, 1997, Creedon et al. 1997, Baloh et al. 1997, 1998, Masure et al. 2000). The GFRA co-receptor can come from the same cell as RET, or from a different cell. When the co-receptor is produced by the same cell as RET, it is termed cis signaling. When the co-receptor is produced by another cell, it is termed trans signaling. Cis and trans activation has been proposed to diversify RET signaling, either by recruiting different downstream effectors or by changing the kinetics or efficacy of kinase activation (Tansey et al. 2000, Paratcha et al. 2001). Whether cis and trans signaling has significant differences in vivo is unresolved (Fleming et al. 2015). Different GDNF family members could activate similar downstream signaling pathways since all GFRAs bind to and activate the same tyrosine kinase and induce coordinated phosphorylation of the same four RET tyrosines (Tyr905, Tyr1015, Tyr1062, and Tyr1096) with similar kinetics (Coulpier et al. 2002). However the exact RET signaling pathways in different types of cells and neurons remain to be determined
R-HSA-8854691	Interleukin-20 family signaling.	The interleukin 20 (IL20) subfamily comprises IL19, IL20, IL22, IL24 and IL26. They are members of the larger IL10 family, but have been grouped together based on their usage of common receptor subunits and similarities in their target cell profiles and biological functions. Members of the IL20 subfamily facilitate the communication between leukocytes and epithelial cells, thereby enhancing innate defence mechanisms and tissue repair processes at epithelial surfaces. Much of the understanding of this group of cytokines is based on IL22, which is the most studied member (Rutz et al. 2014, Akdis M et al. 2016, Longsdon et al. 2012)
R-HSA-8865999	MET activates PTPN11.	PTPN11 (SHP2), recruited to activated MET receptor through GAB1, is phosphorylated in response to HGF treatment, although phosphorylation sites and direct MET involvement have not been examined (Schaeper et al. 2000, Duan et al. 2006). Phosphorylation of PTPN11 in response to HGF treatment is required for the recruitment and activation of sphingosine kinase SPHK1, which may play a role in HGF-induced cell scattering (Duan et al. 2006). While PTPN11 promotes MAPK3/1 (ERK1/2) signaling downstream of MET, it can also dephosphorylate MET on unidentified tyrosine residues (Furcht et al. 2014)
R-HSA-8934593	Regulation of RUNX1 Expression and Activity.	At the level of transcription, expression of the RUNX1 transcription factor is regulated by two alternative promoters: a distal promoter, P1, and a proximal promoter, P2. P1 is more than 7 kb upstream of P2 (Ghozi et al. 1996). In mice, the Runx1 gene is preferentially transcribed from the proximal P2 promoter during generation of hematopoietic cells from hemogenic endothelium. In fully committed hematopoietic progenitors, the Runx1 gene is preferentially transcribed from the distal P1 promoter (Sroczynska et al. 2009, Bee et al. 2010). In human T cells, RUNX1 is preferentially transcribed from P1 throughout development, while developing natural killer cells transcribe RUNX1 predominantly from P2. Developing B cells transcribe low levels of RUNX1 from both promoters (Telfer and Rothenberg 2001).RUNX1 mRNAs transcribed from alternative promoters differ in their 5'UTRs and splicing isoforms of RUNX1 have also been described. The function of alternative splice isoforms and alternative 5'UTRs has not been fully elucidated (Challen and Goodell 2010, Komeno et al. 2014).During zebrafish hematopoiesis, RUNX1 expression increases in response to NOTCH signaling, but direct transcriptional regulation of RUNX1 by NOTCH has not been demonstrated (Burns et al. 2005). RUNX1 transcription also increases in response to WNT signaling. BothTCF7 and TCF4 bind the RUNX1 promoter (Wu et al. 2012, Hoverter et al. 2012), and RUNX1 transcription driven by the TCF binding element (TBE) in response to WNT3A treatment is inhibited by the dominant-negative mutant of TCF4 (Medina et al. 2016). In developing mouse ovary, Runx1 expression is positively regulated by Wnt4 signaling (Naillat et al. 2015).Studies in mouse hematopoietic stem and progenitor cells imply that RUNX1 may be a direct transcriptional target of HOXB4 (Oshima et al. 2011).Conserved cis-regulatory elements were recently identified in intron 5 of RUNX1. The RUNX1 breakpoints observed in acute myeloid leukemia (AML) with translocation (8;21), which result in expression of a fusion RUNX1-ETO protein, cluster in intron 5, in proximity to these not yet fully characterized cis regulatory elements (Rebolledo-Jaramillo et al. 2014).At the level of translation, RUNX1 expression is regulated by various microRNAs which bind to the 3'UTR of RUNX1 mRNA and inhibit its translation through endonucleolytic and/or nonendonucleolytic mechanisms. MicroRNAs that target RUNX1 include miR-378 (Browne et al. 2016), miR-302b (Ge et al. 2014), miR-18a (Miao et al. 2015), miR-675 (Zhuang et al. 2014), miR-27a (Ben-Ami et al. 2009), miR-17, miR-20a, miR106 (Fontana et al. 2007) and miR-215 (Li et al. 2016).At the posttranslational level, RUNX1 activity is regulated by postranslational modifications and binding to co-factors. SRC family kinases phosphorylate RUNX1 on multiple tyrosine residues in the negative regulatory domain, involved in autoinhibition of RUNX1. RUNX1 tyrosine phosphorylation correlates with reduced binding of RUNX1 to GATA1 and increased binding of RUNX1 to the SWI/SNF complex, leading to inhibition of RUNX1-mediated differentiation of T-cells and megakaryocytes. SHP2 (PTPN11) tyrosine phosphatase binds to RUNX1 and dephosphorylates it (Huang et al. 2012).Formation of the complex with CBFB is necessary for the transcriptional activity of RUNX1 (Wang et al. 1996). Binding of CCND3 and probably other two cyclin D family members, CCND1 and CCND2, to RUNX1 inhibits its association with CBFB (Peterson et al. 2005), while binding to CDK6 interferes with binding of RUNX1 to DNA without affecting formation of the RUNX1:CBFB complex. Binding of RUNX1 to PML plays a role in subnuclear targeting of RUNX1 (Nguyen et al. 2005).RUNX1 activity and protein levels vary during the cell cycle. RUNX1 protein levels increase from G1 to S and from S to G2 phases, with no increase in RUNX1 mRNA levels. CDK1-mediated phosphorylation of RUNX1 at the G2/M transition is implicated in reduction of RUNX1 transactivation potency and may promote RUNX1 protein degradation by the anaphase promoting complex (reviewed by Friedman 2009)
R-HSA-9008059	Interleukin-37 signaling.	Interleukins (IL) are immunomodulatory proteins that elicit a wide array of responses in cells and tissues. Interleukin 37 (IL37), also known as IL 1F7, is a member of the IL 1 family (Sharma et al. 2008). Isoform b of IL37 (referred just as IL37) is synthesized as a precursor that requires processing (primarily by caspase 1) to attain full receptor agonist or antagonist function (Kumar et al. 2002). Both full length and processed IL37 can bind to the IL 18 binding protein (IL 18BP) and the Interleukin 18 receptor 1 (IL 18R1) (Shi et al. 2003). Upon binding to the IL18R1, IL37 recruits Single Ig IL 1 related receptor (SIGIRR) (Nold-Petry et al. 2015). The IL37:IL18R1 complex can activate phosphorylation of Signal transducer and activator of transcription 3 (STAT3), Tyrosine protein kinase Mer and Phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase and dual specificity protein phosphatase PTEN and can also inhibit Nuclear factor NF kappa B p105 subunit (NFKB) (Nold-Petry et al. 2015). Processed IL37 can be secreted from the cytosol to the extracellular space or translocated into the nucleus (Bulau et al. 2014). Full length IL37 can also be secreted from the cytosol to the extracellular space (Bulau et al. 2014). Processed IL37 can bind with Mothers against decapentaplegic homolog 3 (SMAD3) in the cytosol and then translocate to the nucleus, where it facilitates transcription of Tyrosine protein phosphatase non receptors (PTPNs) (Nold et al. 2010, Luo et al. 2017). These events ultimately lead to suppression of cytokine production in several types of immune cells resulting in reduced inflammation
R-HSA-9028731	Activated NTRK2 signals through FRS2 and FRS3.	Adapter proteins FRS2 and FRS3 can both bind to the cytoplasmic tail of activated NTRK2 (TRKB) receptor, which is followed by NTRK2-mediated phosphorylation of FRS2 and FRS3. NTRK2 signaling through FRS3 has been poorly characterized (Easton et al. 1999, Yuen and Mobley 1999, Dixon et al. 2006, Zeng et al. 2014). Phosphorylated FRS2 is known to recruit GRB2 (presumably in complex with SOS1) and PTPN11 (SHP2) to activated NTRK2, leading to augmentation of RAS signaling (Easton et al. 1999, Easton 2006)
R-HSA-909733	Interferon alpha/beta signaling.	Type I interferons (IFNs) are composed of various genes including IFN alpha (IFNA), beta (IFNB), omega, epsilon, and kappa. In humans the IFNA genes are composed of more than 13 subfamily genes, whereas there is only one IFNB gene. The large family of IFNA/B proteins all bind to a single receptor which is composed of two distinct chains: IFNAR1 and IFNAR2. The IFNA/B stimulation of the IFNA receptor complex leads to the formation of two transcriptional activator complexes: IFNA-activated-factor (AAF), which is a homodimer of STAT1 and IFN-stimulated gene factor 3 (ISGF3), which comprises STAT1, STAT2 and a member of the IRF family, IRF9/P48. AAF mediates activation of the IRF-1 gene by binding to GAS (IFNG-activated site), whereas ISGF3 activates several IFN-inducible genes including IRF3 and IRF7
R-HSA-912694	Regulation of IFNA signaling.	There are several proteins and mechanisms involved in controlling the extent of ligand stimulation of IFNA/B signaling. These mechanisms can effect every step of the IFNA/B cascade. Dephosphorylation of JAK and STAT by SHP protein phosphatases, inhibition of STAT function in the nucleus by protein inhibitors of activated STATs (PIAS) proteins, inhibition of tyrosine kinase activity of JAKs by SOCS as well as inhibition of JAK and IFNAR2 interaction by UBP43 are few of the negative regulation mechanisms in controling type I IFN signaling
R-HSA-936964	Activation of IRF3/IRF7 mediated by TBK1/IKK epsilon.	Cell stimulation with viral ds RNA leads to the activation of two IKK-related serine/threonine kinases, TBK1 and IKK-i which directly phosphorylate IRF3 and IRF7 promoting their dimerization and translocation into the nucleus. Although both kinases show structural and functional similarities, it seems that TBK1 and IKK-i differ in their regulation of downstream signaling events of TLR3. IRF3 activation and IFN-b production by poly(I:C) are decreased in TBK1-deficient mouse fibroblasts, whereas normal activation was observed in the IKK-i-deficient fibroblasts. However, in double-deficient mouse fibroblasts, the activation of IRF3 is completely abolished, suggesting a partially redundant functions of TBK1 and IKK-i (Hemmi et al. 2004). TLR3 recruits and activates PI3 kinase (PI3K), which activates the downstream kinase, Akt, leading to full phosphorylation and activation of IRF-3 [Sarkar SN et al 2004]. When PI3K is not recruited to TLR3 or its activity is blocked, IRF-3 is only partially phosphorylated and fails to bind the promoter of the target gene

BioGRID
IntAct
MINT
ALL

Visualize Download

Interacting partner	Detection method	Interaction type	PubMed IDs	Interaction Score	Source
BCAR1	Affinity Capture-Western	physical	9188452, (Europe PMC)	NA	BioGRID
BEX1	Two-hybrid	physical	27229929, (Europe PMC)	NA	BioGRID
BEX2	Two-hybrid	physical	27229929, (Europe PMC)	NA	BioGRID
BLZF1	Two-hybrid	physical	27229929, (Europe PMC)	NA	BioGRID
BTLA	Affinity Capture-Western, coimmunoprecipitation	association, physical	12796776, 14652006, (Europe PMC)	0.35	BioGRID, IntAct, MINT
C9orf62	Two-hybrid	physical	27229929, (Europe PMC)	NA	BioGRID
CAV1	Affinity Capture-Western, coimmunoprecipitation, cosedimentation through density gradient	colocalization, physical, physical association	12176037, (Europe PMC)	0.50	BioGRID, IntAct, MINT
CBL	Affinity Capture-Western	physical	11157475, 17330819, 18519587, (Europe PMC)	NA	BioGRID
CBLB	Affinity Capture-Western	physical	17330819, (Europe PMC)	NA	BioGRID
CD274	Affinity Capture-Western	physical	11224527, (Europe PMC)	NA	BioGRID
CD33	Affinity Capture-Western, Reconstituted Complex, anti bait coimmunoprecipitation, coimmunoprecipitation, pull down	association, physical, physical association	10206955, 17947393, (Europe PMC)	0.68	BioGRID, IntAct, MINT
CD84	Affinity Capture-Western	physical	11689425, (Europe PMC)	NA	BioGRID
CDC73	Affinity Capture-Western	physical	21726809, (Europe PMC)	NA	BioGRID
CDH5	Affinity Capture-Western	physical	10681592, (Europe PMC)	NA	BioGRID
CEACAM1	Affinity Capture-Western, Reconstituted Complex	physical	9867848, (Europe PMC)	NA	BioGRID
CHRAC1	Co-fractionation	physical	22863883, (Europe PMC)	NA	BioGRID
COP1	Affinity Capture-Western	physical	23269672, (Europe PMC)	NA	BioGRID
CRK	Affinity Capture-MS, Affinity Capture-Western	physical	10464310, 19380743, (Europe PMC)	NA	BioGRID
CRKL	Affinity Capture-Western, proximity ligation assay	physical, physical association	23397142, 9344843, (Europe PMC)	0.40	BioGRID, IntAct
CSF2RB	Affinity Capture-Western, Reconstituted Complex, pull down	association, physical	9162089, 9973406, (Europe PMC)	0.53	BioGRID, IntAct, MINT
CSF2RBP1	Affinity Capture-Western	physical	9361008, (Europe PMC)	NA	BioGRID
CSF3R	Far Western	physical	9824671, (Europe PMC)	NA	BioGRID
CTDSP1	Two-hybrid	physical	27229929, (Europe PMC)	NA	BioGRID
CTNNB1	Affinity Capture-Western	physical	10681592, (Europe PMC)	NA	BioGRID
CTR9	Affinity Capture-Western, Proximity Label-MS	physical	21726809, 27880917, (Europe PMC)	NA	BioGRID
CXCR4	Affinity Capture-Western	physical	11157475, (Europe PMC)	NA	BioGRID
CYP1A1	Affinity Capture-MS	physical	26186194, 28514442, (Europe PMC)	NA	BioGRID
DMRTC1	Two-hybrid	physical	27229929, (Europe PMC)	NA	BioGRID
DNM2	Affinity Capture-Western	physical	21996738, (Europe PMC)	NA	BioGRID
DUSP13	Affinity Capture-MS	physical	27432908, (Europe PMC)	NA	BioGRID
EFHD2	Co-fractionation	physical	22863883, (Europe PMC)	NA	BioGRID
EGFR	Affinity Capture-MS, Affinity Capture-Western, Biochemical Activity, Protein-peptide, Two-hybrid, protein array, pull down	direct interaction, physical, physical association	16273093, 16729043, 20473329, 28065597, 7673163, 8959326, 9756944, (Europe PMC)	0.61	BioGRID, IntAct, MINT
ELAVL1	Affinity Capture-RNA	physical	19322201, (Europe PMC)	NA	BioGRID
EPHA1	Two-hybrid	physical	28065597, (Europe PMC)	NA	BioGRID
EPHA2	Affinity Capture-Western, Two-hybrid, anti bait coimmunoprecipitation	physical, physical association	10655584, 28065597, (Europe PMC)	0.40	BioGRID, IntAct
EPOR	Affinity Capture-Western, Reconstituted Complex	physical	7534299, 8639815, (Europe PMC)	NA	BioGRID
ERBB2	Affinity Capture-MS, Affinity Capture-Western, Protein-peptide, Two-hybrid, protein array	direct interaction, physical	16273093, 16729043, 28065597, 8959326, 9756944, (Europe PMC)	0.44	BioGRID, IntAct, MINT
ERBB3	Affinity Capture-Western, Two-hybrid	physical	28065597, 9756944, (Europe PMC)	NA	BioGRID
ERBB4	Affinity Capture-MS, Biochemical Activity, Two-hybrid, pull down	physical, physical association	16729043, 28065597, (Europe PMC)	0.40	BioGRID, IntAct, MINT
FAM71E1	Two-hybrid	physical	27229929, (Europe PMC)	NA	BioGRID
FASN	Affinity Capture-Western	physical	23269672, (Europe PMC)	NA	BioGRID
FCGR2A	Affinity Capture-MS	physical	26186194, 28514442, (Europe PMC)	NA	BioGRID
FCGR2B	Affinity Capture-Western, pull down	association, physical	10382761, (Europe PMC)	0.35	BioGRID, IntAct, MINT
FCRL3	Reconstituted Complex	physical	12051764, (Europe PMC)	NA	BioGRID
FGB	Affinity Capture-MS	physical	28514442, (Europe PMC)	NA	BioGRID
FGFR2	Two-hybrid	physical	28065597, (Europe PMC)	NA	BioGRID
FGFR4	Two-hybrid	physical	28065597, (Europe PMC)	NA	BioGRID
FLT1	Co-localization, proximity ligation assay	physical, physical association	23397142, 25241761, (Europe PMC)	0.40	BioGRID, IntAct
FRS2	Affinity Capture-Western, Far Western, Protein-peptide, Two-hybrid, coimmunoprecipitation, far western blotting	association, physical	10650943, 11360177, 22974441, 25159185, 9632781, (Europe PMC)	0.46	BioGRID, IntAct, MINT
FSD1	Affinity Capture-MS	physical	26186194, 28514442, (Europe PMC)	NA	BioGRID
FYN	Affinity Capture-Western	physical	10212213, 11157475, (Europe PMC)	NA	BioGRID
GAB1	Affinity Capture-Western, Far Western, Two-hybrid, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, coimmunoprecipitation, far western blotting, fluorescence polarization spectroscopy, phosphatase assay, surface plasmon resonance, two hybrid	association, dephosphorylation reaction, direct interaction, physical, physical association	11323411, 11453982, 11940581, 12855672, 14665621, 14701753, 14982882, 15574420, 20308328, 20473329, 23612964, 24728074, 9658397, 9804835, (Europe PMC)	0.95	BioGRID, IntAct, MINT
GAB2	Affinity Capture-Western, Two-hybrid, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, pull down	association, physical	10391903, 10871282, 11334882, 11782427, 12135708, 14982882, 15170389, 15356145, 16253990, 16371368, 19172738, 19909739, (Europe PMC)	0.64	BioGRID, IntAct, MINT
GAB3	Affinity Capture-Western	physical	11739737, (Europe PMC)	NA	BioGRID
GAREM2	Affinity Capture-Western	physical	24003223, (Europe PMC)	NA	BioGRID
GHR	Reconstituted Complex	physical	10976913, 9632636, (Europe PMC)	NA	BioGRID
GOLGA2	Two-hybrid	physical	27229929, (Europe PMC)	NA	BioGRID
GPX7	Affinity Capture-MS	physical	28514442, (Europe PMC)	NA	BioGRID
GRASP	Affinity Capture-Western	physical	15173175, (Europe PMC)	NA	BioGRID
GRB2	Affinity Capture-MS, Affinity Capture-Western, Far Western, Reconstituted Complex, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, pull down, tandem affinity purification	association, physical, physical association	10080542, 10212213, 10747947, 12577067, 16371368, 19380743, 20473329, 21706016, 28514442, 7523381, 7534299, 8041791, 8702859, 8959326, 8995399, 9361008, 9362449, 9632781, 9824671, (Europe PMC)	0.74	BioGRID, IntAct
GSK3B	Co-fractionation	physical	22939629, (Europe PMC)	NA	BioGRID
GTF2A2	Two-hybrid	physical	27229929, (Europe PMC)	NA	BioGRID
GTF2E2	Affinity Capture-MS	physical	28514442, (Europe PMC)	NA	BioGRID
HDAC6	Affinity Capture-Western	physical	26775640, (Europe PMC)	NA	BioGRID
HIST1H2BG	Proximity Label-MS	physical	25281560, (Europe PMC)	NA	BioGRID
IGF1R	Affinity Capture-Western, Reconstituted Complex, Two-hybrid, beta galactosidase complementation, pull down, two hybrid	association, physical, physical association	10082579, 28065597, 7642582, 8895367, (Europe PMC)	0.62	BioGRID, IntAct, MINT
IL4R	Reconstituted Complex	physical	11714803, (Europe PMC)	NA	BioGRID
IL6ST	Affinity Capture-Western, Reconstituted Complex	physical	10777583, 10946280, 12403768, 9388212, (Europe PMC)	NA	BioGRID
INPP5D	Affinity Capture-Western	physical	11157475, 9110989, (Europe PMC)	NA	BioGRID
INSR	Affinity Capture-Western, Reconstituted Complex, pull down	association, physical, physical association	7493946, 8135823, 9593725, (Europe PMC)	0.56	BioGRID, IntAct, MINT
IQCB1	Affinity Capture-MS, anti tag coimmunoprecipitation	association, physical	21565611, (Europe PMC)	0.35	BioGRID, IntAct
IRS1	Affinity Capture-Western, Biochemical Activity, Protein-peptide, Reconstituted Complex, surface plasmon resonance	association, physical	11781100, 22974441, 7513703, 8505282, 9756938, (Europe PMC)	0.35	BioGRID, IntAct, MINT
IRS2	Affinity Capture-Western	physical	8910607, (Europe PMC)	NA	BioGRID
JAK1	Affinity Capture-Western, Biochemical Activity, Reconstituted Complex	physical	12403768, 8995399, (Europe PMC)	NA	BioGRID
JAK2	Affinity Capture-Western, Biochemical Activity, Reconstituted Complex	physical	8639815, 8912646, 8995399, (Europe PMC)	NA	BioGRID
KDR	Affinity Capture-Western, Far Western, Two-hybrid	physical	16339483, 28065597, (Europe PMC)	NA	BioGRID
KIT	Affinity Capture-Western, Protein-peptide, Reconstituted Complex, fluorescence polarization spectroscopy	direct interaction, physical	12444928, 24728074, 7523381, 9528781, (Europe PMC)	0.44	BioGRID, IntAct
LAIR1	Affinity Capture-Western	physical	10903717, 9285412, (Europe PMC)	NA	BioGRID
LEO1	Affinity Capture-Western	physical	21726809, (Europe PMC)	NA	BioGRID
LGALS3	Affinity Capture-MS	physical	26186194, 28514442, (Europe PMC)	NA	BioGRID
LGALS9	Affinity Capture-MS	physical	26186194, 28514442, (Europe PMC)	NA	BioGRID
LINC00673	Affinity Capture-RNA	physical	27213290, (Europe PMC)	NA	BioGRID
LINC01558	Two-hybrid	physical	27229929, (Europe PMC)	NA	BioGRID
LNX1	Two-hybrid, two hybrid array, validated two hybrid	physical, physical association	25814554, (Europe PMC)	0.49	BioGRID, IntAct
LRRK1	Affinity Capture-MS	physical	20697350, (Europe PMC)	NA	BioGRID
LUM	Affinity Capture-MS	physical	28514442, (Europe PMC)	NA	BioGRID
LY9	Affinity Capture-Western	physical	11689425, (Europe PMC)	NA	BioGRID
MAP2K1	Co-fractionation	physical	26344197, (Europe PMC)	NA	BioGRID
MAP3K5	Affinity Capture-Western, Biochemical Activity	physical	19287004, (Europe PMC)	NA	BioGRID
MAPK14	Co-fractionation	physical	22863883, (Europe PMC)	NA	BioGRID
MED21	Affinity Capture-MS	physical	28514442, (Europe PMC)	NA	BioGRID
MPIG6B	Affinity Capture-Western	physical	11544253, (Europe PMC)	NA	BioGRID
MPZL1	Affinity Capture-MS, Affinity Capture-Western, anti bait coimmunoprecipitation, coimmunoprecipitation	association, physical, physical association	10681522, 28514442, 9792637, (Europe PMC)	0.56	BioGRID, IntAct, MINT
MTPN	Co-fractionation	physical	22863883, (Europe PMC)	NA	BioGRID
NOSIP	Affinity Capture-MS	physical	28514442, (Europe PMC)	NA	BioGRID
NSUN5	Two-hybrid	physical	27229929, (Europe PMC)	NA	BioGRID
NSUN5P2	Two-hybrid	physical	27229929, (Europe PMC)	NA	BioGRID
NTRK1	Affinity Capture-MS	physical	25921289, (Europe PMC)	NA	BioGRID
NXT2	Affinity Capture-MS	physical	28514442, (Europe PMC)	NA	BioGRID
ORMDL3	Two-hybrid	physical	27229929, (Europe PMC)	NA	BioGRID
OVCA2	Affinity Capture-MS	physical	26186194, 28514442, (Europe PMC)	NA	BioGRID
OXCT1	Co-fractionation	physical	22863883, (Europe PMC)	NA	BioGRID
PAF1	Affinity Capture-Western, Proximity Label-MS	physical	21726809, 27880917, (Europe PMC)	NA	BioGRID
PDCD1	Affinity Capture-MS, anti tag coimmunoprecipitation, coimmunoprecipitation, confocal microscopy	association, colocalization, physical, physical association	15240681, 28046066, 28514442, (Europe PMC)	0.60	BioGRID, IntAct, MINT
PDGFRA	Affinity Capture-Western, Biochemical Activity	physical	21996738, 8959326, (Europe PMC)	NA	BioGRID
PDGFRB	Reconstituted Complex, Two-hybrid, affinity technology, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, enzymatic study, experimental interaction detection, proximity ligation assay, surface plasmon resonance, x-ray crystallography	association, physical, physical association	11266449, 12614164, 23397142, 7530043, 7688466, 7691811, 8119896, 8183548, 8538796, (Europe PMC)	0.91	BioGRID, IntAct, MINT
PECAM1	Affinity Capture-Western, Far Western, Reconstituted Complex, lambda phage display, pull down, surface plasmon resonance	association, physical	10350061, 10704309, 10801826, 9054388, 9312087, 9774457, (Europe PMC)	0.69	BioGRID, IntAct, MINT
PIK3R1	Affinity Capture-Western	physical	10962556, 11593409, 16371368, 9361008, 9886492, 9918857, (Europe PMC)	NA	BioGRID
PIK3R2	Affinity Capture-MS, tandem affinity purification	association, physical	19380743, (Europe PMC)	0.35	BioGRID, IntAct
PILRA	Affinity Capture-Western	physical	10903717, (Europe PMC)	NA	BioGRID
PLCG2	Affinity Capture-Western	physical	12135708, (Europe PMC)	NA	BioGRID
PLEKHA4	Two-hybrid	physical	27229929, (Europe PMC)	NA	BioGRID
PNCK	Two-hybrid	physical	27229929, (Europe PMC)	NA	BioGRID
POU2AF1	Two-hybrid	physical	27229929, (Europe PMC)	NA	BioGRID
PPIF	Co-fractionation	physical	22939629, (Europe PMC)	NA	BioGRID
PRLR	Affinity Capture-Western	physical	10991949, (Europe PMC)	NA	BioGRID
PRPF19	Affinity Capture-Western	physical	27213290, (Europe PMC)	NA	BioGRID
PTK2	Affinity Capture-Western	physical	10082579, 21726809, (Europe PMC)	NA	BioGRID
PTK2B	Affinity Capture-Western, Biochemical Activity, Far Western	physical	10880513, (Europe PMC)	NA	BioGRID
PTK7	Two-hybrid	physical	28065597, (Europe PMC)	NA	BioGRID
PTPN11	Affinity Capture-MS, Two-hybrid	physical	27432908, 9847309, (Europe PMC)	NA	BioGRID
PTPN6	Affinity Capture-MS	physical	27432908, (Europe PMC)	NA	BioGRID
RANGRF	Two-hybrid	physical	27229929, (Europe PMC)	NA	BioGRID
ROR2	Two-hybrid	physical	28065597, (Europe PMC)	NA	BioGRID
ROS1	Two-hybrid	physical	11266449, (Europe PMC)	NA	BioGRID
RPIA	Two-hybrid, two hybrid, two hybrid array, two hybrid prey pooling approach, validated two hybrid	physical, physical association	21516116, 25416956, (Europe PMC)	0.67	BioGRID, IntAct, MINT
RTF1	Affinity Capture-Western	physical	21726809, (Europe PMC)	NA	BioGRID
SELE	Affinity Capture-Western, coimmunoprecipitation	association, physical	11602579, (Europe PMC)	0.35	BioGRID, IntAct, MINT
SERF2	Two-hybrid	physical	27229929, (Europe PMC)	NA	BioGRID
SERPINF1	Two-hybrid	physical	27229929, (Europe PMC)	NA	BioGRID
SIGLEC11	Affinity Capture-Western	physical	11986327, (Europe PMC)	NA	BioGRID
SIGLEC5	Affinity Capture-MS	physical	28514442, (Europe PMC)	NA	BioGRID
SIGLEC7	Affinity Capture-Western	physical	15703304, (Europe PMC)	NA	BioGRID
SIGLEC9	Affinity Capture-Western	physical	15703304, (Europe PMC)	NA	BioGRID
SIRPA	Affinity Capture-Western	physical	10962556, 20473329, (Europe PMC)	NA	BioGRID
SIT1	Affinity Capture-Western, coimmunoprecipitation, competition binding	association, physical	10209036, (Europe PMC)	0.46	BioGRID, IntAct, MINT
SLAMF1	Affinity Capture-Western, coimmunoprecipitation, pull down	association, physical	11313386, 11689425, 11806999, (Europe PMC)	0.46	BioGRID, IntAct, MINT
SLAMF6	Affinity Capture-Western, anti bait coimmunoprecipitation	association, physical	11489943, (Europe PMC)	0.35	BioGRID, IntAct
SLC38A1	Two-hybrid	physical	27229929, (Europe PMC)	NA	BioGRID
SLN	Two-hybrid	physical	27229929, (Europe PMC)	NA	BioGRID
SNRNP27	Affinity Capture-MS	physical	28514442, (Europe PMC)	NA	BioGRID
SOCS1	Affinity Capture-Western	physical	14522994, (Europe PMC)	NA	BioGRID
SOCS3	Affinity Capture-Western, Reconstituted Complex	physical	10777583, 12403768, 17138568, (Europe PMC)	NA	BioGRID
SOS1	Affinity Capture-Western	physical	16371368, 20473329, 9344843, 9632781, (Europe PMC)	NA	BioGRID
SRC	Biochemical Activity, phosphatase assay	dephosphorylation reaction, physical	20308328, 8959326, (Europe PMC)	0.44	BioGRID, IntAct, MINT
SRSF10	Two-hybrid	physical	27229929, (Europe PMC)	NA	BioGRID
STAMBP	Co-fractionation	physical	26344197, (Europe PMC)	NA	BioGRID
STAT1	Two-hybrid	physical	27229929, (Europe PMC)	NA	BioGRID
STAT3	Affinity Capture-Western	physical	11594781, 26775640, (Europe PMC)	NA	BioGRID
STAT5A	Affinity Capture-Western, Biochemical Activity, Reconstituted Complex	physical	10617656, 12060651, (Europe PMC)	NA	BioGRID
STAT5B	Biochemical Activity, Reconstituted Complex	physical	10617656, (Europe PMC)	NA	BioGRID
SYNCRIP	Two-hybrid	physical	9847309, (Europe PMC)	NA	BioGRID
TCEAL1	Affinity Capture-MS	physical	26186194, 28514442, (Europe PMC)	NA	BioGRID
TEK	Two-hybrid	physical	28065597, (Europe PMC)	NA	BioGRID
THEMIS	Affinity Capture-MS, pull down	association, physical	25535246, 28514442, (Europe PMC)	0.35	BioGRID, IntAct, MINT
TLK1	Two-hybrid, two hybrid array, two hybrid prey pooling approach	physical, physical association	27229929, (Europe PMC)	0.49	BioGRID, IntAct
TMEM220	Affinity Capture-MS	physical	28514442, (Europe PMC)	NA	BioGRID
TREML1	Affinity Capture-Western	physical	15128762, (Europe PMC)	NA	BioGRID
TRIM25	Affinity Capture-RNA	physical	29117863, (Europe PMC)	NA	BioGRID
TRIM32	Two-hybrid, two hybrid array, two hybrid prey pooling approach, validated two hybrid	physical, physical association	25416956, 27229929, (Europe PMC)	0.56	BioGRID, IntAct
TRMT2B	Two-hybrid	physical	27229929, (Europe PMC)	NA	BioGRID
TXNIP	Co-crystal Structure, Reconstituted Complex	physical	26527736, 26919541, (Europe PMC)	NA	BioGRID
VCAM1	Affinity Capture-MS, cross-linking study	association, physical	19738201, 22623428, (Europe PMC)	0.53	BioGRID, IntAct
WDR61	Affinity Capture-Western	physical	21726809, (Europe PMC)	NA	BioGRID

Visualize Download

Interacting partner	Detection method	Interaction type	PubMed IDs	Interaction Score	Source
AR	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
BTLA	Affinity Capture-Western, coimmunoprecipitation	association, physical	12796776, 14652006, (Europe PMC)	0.35	BioGRID, IntAct, MINT
CAT	anti bait coimmunoprecipitation, pull down	direct interaction, physical association	15556604, (Europe PMC)	0.54	IntAct, MINT
CAV1	Affinity Capture-Western, coimmunoprecipitation, cosedimentation through density gradient	colocalization, physical, physical association	12176037, (Europe PMC)	0.50	BioGRID, IntAct, MINT
CCKBR	anti tag coimmunoprecipitation, pull down, surface plasmon resonance	association, physical association	16963136, (Europe PMC)	0.62	IntAct, MINT
CD244	pull down, surface plasmon resonance	association, direct interaction	24642916, (Europe PMC)	0.52	IntAct
CD300A	anti bait coimmunoprecipitation	association	11489943, (Europe PMC)	0.35	IntAct
CD33	Affinity Capture-Western, Reconstituted Complex, anti bait coimmunoprecipitation, coimmunoprecipitation, pull down	association, physical, physical association	10206955, 17947393, (Europe PMC)	0.68	BioGRID, IntAct, MINT
CRKL	Affinity Capture-Western, proximity ligation assay	physical, physical association	23397142, 9344843, (Europe PMC)	0.40	BioGRID, IntAct
CSF2RB	Affinity Capture-Western, Reconstituted Complex, pull down	association, physical	9162089, 9973406, (Europe PMC)	0.53	BioGRID, IntAct, MINT
DDR1	anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, coimmunoprecipitation	association, physical association	16337946, (Europe PMC)	0.58	IntAct, MINT
DOK1	coimmunoprecipitation	association	15546884, (Europe PMC)	0.35	IntAct, MINT
EGFR	Affinity Capture-MS, Affinity Capture-Western, Biochemical Activity, Protein-peptide, Two-hybrid, protein array, pull down	direct interaction, physical, physical association	16273093, 16729043, 20473329, 28065597, 7673163, 8959326, 9756944, (Europe PMC)	0.61	BioGRID, IntAct, MINT
EPHA2	Affinity Capture-Western, Two-hybrid, anti bait coimmunoprecipitation	physical, physical association	10655584, 28065597, (Europe PMC)	0.40	BioGRID, IntAct
ERBB2	Affinity Capture-MS, Affinity Capture-Western, Protein-peptide, Two-hybrid, protein array	direct interaction, physical	16273093, 16729043, 28065597, 8959326, 9756944, (Europe PMC)	0.44	BioGRID, IntAct, MINT
ERBB4	Affinity Capture-MS, Biochemical Activity, Two-hybrid, pull down	physical, physical association	16729043, 28065597, (Europe PMC)	0.40	BioGRID, IntAct, MINT
FCGR2B	Affinity Capture-Western, pull down	association, physical	10382761, (Europe PMC)	0.35	BioGRID, IntAct, MINT
FLT1	Co-localization, proximity ligation assay	physical, physical association	23397142, 25241761, (Europe PMC)	0.40	BioGRID, IntAct
FLT3	coimmunoprecipitation, competition binding	association	16684964, (Europe PMC)	0.46	IntAct, MINT
FRS2	Affinity Capture-Western, Far Western, Protein-peptide, Two-hybrid, coimmunoprecipitation, far western blotting	association, physical	10650943, 11360177, 22974441, 25159185, 9632781, (Europe PMC)	0.46	BioGRID, IntAct, MINT
FRS3	two hybrid	physical association	11432792, (Europe PMC)	0.37	IntAct, MINT
GAB1	Affinity Capture-Western, Far Western, Two-hybrid, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, coimmunoprecipitation, far western blotting, fluorescence polarization spectroscopy, phosphatase assay, surface plasmon resonance, two hybrid	association, dephosphorylation reaction, direct interaction, physical, physical association	11323411, 11453982, 11940581, 12855672, 14665621, 14701753, 14982882, 15574420, 20308328, 20473329, 23612964, 24728074, 9658397, 9804835, (Europe PMC)	0.95	BioGRID, IntAct, MINT
GAB2	Affinity Capture-Western, Two-hybrid, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, pull down	association, physical	10391903, 10871282, 11334882, 11782427, 12135708, 14982882, 15170389, 15356145, 16253990, 16371368, 19172738, 19909739, (Europe PMC)	0.64	BioGRID, IntAct, MINT
GRB2	Affinity Capture-MS, Affinity Capture-Western, Far Western, Reconstituted Complex, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, pull down, tandem affinity purification	association, physical, physical association	10080542, 10212213, 10747947, 12577067, 16371368, 19380743, 20473329, 21706016, 28514442, 7523381, 7534299, 8041791, 8702859, 8959326, 8995399, 9361008, 9362449, 9632781, 9824671, (Europe PMC)	0.74	BioGRID, IntAct
HOXA10	genetic interference	genetic interaction	19022774, (Europe PMC)	0.17	IntAct, MINT
IGF1R	Affinity Capture-Western, Reconstituted Complex, Two-hybrid, beta galactosidase complementation, pull down, two hybrid	association, physical, physical association	10082579, 28065597, 7642582, 8895367, (Europe PMC)	0.62	BioGRID, IntAct, MINT
INSR	Affinity Capture-Western, Reconstituted Complex, pull down	association, physical, physical association	7493946, 8135823, 9593725, (Europe PMC)	0.56	BioGRID, IntAct, MINT
IQCB1	Affinity Capture-MS, anti tag coimmunoprecipitation	association, physical	21565611, (Europe PMC)	0.35	BioGRID, IntAct
IRS1	Affinity Capture-Western, Biochemical Activity, Protein-peptide, Reconstituted Complex, surface plasmon resonance	association, physical	11781100, 22974441, 7513703, 8505282, 9756938, (Europe PMC)	0.35	BioGRID, IntAct, MINT
ITGB3	coimmunoprecipitation	association	12791772, (Europe PMC)	0.35	IntAct, MINT
KIR2DL1	lex-a dimerization assay, two hybrid	physical association	9751747, (Europe PMC)	0.49	IntAct, MINT
KIR2DL3	pull down, surface plasmon resonance	association	8648092, (Europe PMC)	0.46	IntAct, MINT
KIT	Affinity Capture-Western, Protein-peptide, Reconstituted Complex, fluorescence polarization spectroscopy	direct interaction, physical	12444928, 24728074, 7523381, 9528781, (Europe PMC)	0.44	BioGRID, IntAct
KSR1	anti tag coimmunoprecipitation	association	27086506, (Europe PMC)	0.35	IntAct
LEPR	anti tag coimmunoprecipitation, surface plasmon resonance	association	11342028, 9600917, (Europe PMC)	0.53	IntAct, MINT
LNX1	Two-hybrid, two hybrid array, validated two hybrid	physical, physical association	25814554, (Europe PMC)	0.49	BioGRID, IntAct
MAPK3	proximity ligation assay	physical association	23397142, (Europe PMC)	0.40	IntAct
MET	anti bait coimmunoprecipitation, fluorescence polarization spectroscopy	direct interaction, physical association	18579758, 24728074, (Europe PMC)	0.61	IntAct, MINT
MPIG6B	coimmunoprecipitation	association	11544253, (Europe PMC)	0.35	IntAct, MINT
MPZL1	Affinity Capture-MS, Affinity Capture-Western, anti bait coimmunoprecipitation, coimmunoprecipitation	association, physical, physical association	10681522, 28514442, 9792637, (Europe PMC)	0.56	BioGRID, IntAct, MINT
NEB	two hybrid fragment pooling approach	physical association	23414517, (Europe PMC)	0.37	IntAct
PDCD1	Affinity Capture-MS, anti tag coimmunoprecipitation, coimmunoprecipitation, confocal microscopy	association, colocalization, physical, physical association	15240681, 28046066, 28514442, (Europe PMC)	0.60	BioGRID, IntAct, MINT
PDGFRB	Reconstituted Complex, Two-hybrid, affinity technology, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, enzymatic study, experimental interaction detection, proximity ligation assay, surface plasmon resonance, x-ray crystallography	association, physical, physical association	11266449, 12614164, 23397142, 7530043, 7688466, 7691811, 8119896, 8183548, 8538796, (Europe PMC)	0.91	BioGRID, IntAct, MINT
PECAM1	Affinity Capture-Western, Far Western, Reconstituted Complex, lambda phage display, pull down, surface plasmon resonance	association, physical	10350061, 10704309, 10801826, 9054388, 9312087, 9774457, (Europe PMC)	0.69	BioGRID, IntAct, MINT
PIK3R2	Affinity Capture-MS, tandem affinity purification	association, physical	19380743, (Europe PMC)	0.35	BioGRID, IntAct
PLCG1	pull down	physical association	9020117, (Europe PMC)	0.40	IntAct, MINT
PXN	anti bait coimmunoprecipitation, proximity ligation assay	association, physical association	14665621, 23397142, (Europe PMC)	0.64	IntAct, MINT
RPIA	Two-hybrid, two hybrid, two hybrid array, two hybrid prey pooling approach, validated two hybrid	physical, physical association	21516116, 25416956, (Europe PMC)	0.67	BioGRID, IntAct, MINT
SELE	Affinity Capture-Western, coimmunoprecipitation	association, physical	11602579, (Europe PMC)	0.35	BioGRID, IntAct, MINT
SGCG	proximity ligation assay	physical association	23414517, (Europe PMC)	0.40	IntAct
SIT1	Affinity Capture-Western, coimmunoprecipitation, competition binding	association, physical	10209036, (Europe PMC)	0.46	BioGRID, IntAct, MINT
SLAMF1	Affinity Capture-Western, coimmunoprecipitation, pull down	association, physical	11313386, 11689425, 11806999, (Europe PMC)	0.46	BioGRID, IntAct, MINT
SLAMF6	Affinity Capture-Western, anti bait coimmunoprecipitation	association, physical	11489943, (Europe PMC)	0.35	BioGRID, IntAct
SLC4A1	coimmunoprecipitation	association	12070037, (Europe PMC)	0.35	IntAct, MINT
SRC	Biochemical Activity, phosphatase assay	dephosphorylation reaction, physical	20308328, 8959326, (Europe PMC)	0.44	BioGRID, IntAct, MINT
THEMIS	Affinity Capture-MS, pull down	association, physical	25535246, 28514442, (Europe PMC)	0.35	BioGRID, IntAct, MINT
TLK1	Two-hybrid, two hybrid array, two hybrid prey pooling approach	physical, physical association	27229929, (Europe PMC)	0.49	BioGRID, IntAct
TNFRSF1A	pull down	association	11786908, (Europe PMC)	0.35	IntAct, MINT
TRIM32	Two-hybrid, two hybrid array, two hybrid prey pooling approach, validated two hybrid	physical, physical association	25416956, 27229929, (Europe PMC)	0.56	BioGRID, IntAct
VCAM1	Affinity Capture-MS, cross-linking study	association, physical	19738201, 22623428, (Europe PMC)	0.53	BioGRID, IntAct

Visualize Download

Interacting partner	Detection method	Interaction type	PubMed IDs	Interaction Score	Source
CAT	anti bait coimmunoprecipitation, pull down	direct interaction, physical association	15556604, (Europe PMC)	0.54	IntAct, MINT
CAV1	Affinity Capture-Western, coimmunoprecipitation, cosedimentation through density gradient	colocalization, physical, physical association	12176037, (Europe PMC)	0.50	BioGRID, IntAct, MINT
CCKBR	anti tag coimmunoprecipitation, pull down, surface plasmon resonance	association, physical association	16963136, (Europe PMC)	0.62	IntAct, MINT
CD33	Affinity Capture-Western, Reconstituted Complex, anti bait coimmunoprecipitation, coimmunoprecipitation, pull down	association, physical, physical association	10206955, 17947393, (Europe PMC)	0.68	BioGRID, IntAct, MINT
CSF2RB	Affinity Capture-Western, Reconstituted Complex, pull down	association, physical	9162089, 9973406, (Europe PMC)	0.53	BioGRID, IntAct, MINT
DDR1	anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, coimmunoprecipitation	association, physical association	16337946, (Europe PMC)	0.58	IntAct, MINT
DOK1	coimmunoprecipitation	association	15546884, (Europe PMC)	0.35	IntAct, MINT
EGFR	Affinity Capture-MS, Affinity Capture-Western, Biochemical Activity, Protein-peptide, Two-hybrid, protein array, pull down	direct interaction, physical, physical association	16273093, 16729043, 20473329, 28065597, 7673163, 8959326, 9756944, (Europe PMC)	0.61	BioGRID, IntAct, MINT
ERBB2	Affinity Capture-MS, Affinity Capture-Western, Protein-peptide, Two-hybrid, protein array	direct interaction, physical	16273093, 16729043, 28065597, 8959326, 9756944, (Europe PMC)	0.44	BioGRID, IntAct, MINT
ERBB4	Affinity Capture-MS, Biochemical Activity, Two-hybrid, pull down	physical, physical association	16729043, 28065597, (Europe PMC)	0.40	BioGRID, IntAct, MINT
FCGR2B	Affinity Capture-Western, pull down	association, physical	10382761, (Europe PMC)	0.35	BioGRID, IntAct, MINT
FLT3	coimmunoprecipitation, competition binding	association	16684964, (Europe PMC)	0.46	IntAct, MINT
FRS2	Affinity Capture-Western, Far Western, Protein-peptide, Two-hybrid, coimmunoprecipitation, far western blotting	association, physical	10650943, 11360177, 22974441, 25159185, 9632781, (Europe PMC)	0.46	BioGRID, IntAct, MINT
FRS3	two hybrid	physical association	11432792, (Europe PMC)	0.37	IntAct, MINT
GAB1	Affinity Capture-Western, Far Western, Two-hybrid, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, coimmunoprecipitation, far western blotting, fluorescence polarization spectroscopy, phosphatase assay, surface plasmon resonance, two hybrid	association, dephosphorylation reaction, direct interaction, physical, physical association	11323411, 11453982, 11940581, 12855672, 14665621, 14701753, 14982882, 15574420, 20308328, 20473329, 23612964, 24728074, 9658397, 9804835, (Europe PMC)	0.95	BioGRID, IntAct, MINT
GAB2	Affinity Capture-Western, Two-hybrid, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, pull down	association, physical	10391903, 10871282, 11334882, 11782427, 12135708, 14982882, 15170389, 15356145, 16253990, 16371368, 19172738, 19909739, (Europe PMC)	0.64	BioGRID, IntAct, MINT
HOXA10	genetic interference	genetic interaction	19022774, (Europe PMC)	0.17	IntAct, MINT
IGF1R	Affinity Capture-Western, Reconstituted Complex, Two-hybrid, beta galactosidase complementation, pull down, two hybrid	association, physical, physical association	10082579, 28065597, 7642582, 8895367, (Europe PMC)	0.62	BioGRID, IntAct, MINT
INSR	Affinity Capture-Western, Reconstituted Complex, pull down	association, physical, physical association	7493946, 8135823, 9593725, (Europe PMC)	0.56	BioGRID, IntAct, MINT
IRS1	Affinity Capture-Western, Biochemical Activity, Protein-peptide, Reconstituted Complex, surface plasmon resonance	association, physical	11781100, 22974441, 7513703, 8505282, 9756938, (Europe PMC)	0.35	BioGRID, IntAct, MINT
ITGB3	coimmunoprecipitation	association	12791772, (Europe PMC)	0.35	IntAct, MINT
KIR2DL1	lex-a dimerization assay, two hybrid	physical association	9751747, (Europe PMC)	0.49	IntAct, MINT
KIR2DL3	pull down, surface plasmon resonance	association	8648092, (Europe PMC)	0.46	IntAct, MINT
LEPR	anti tag coimmunoprecipitation, surface plasmon resonance	association	11342028, 9600917, (Europe PMC)	0.53	IntAct, MINT
MET	anti bait coimmunoprecipitation, fluorescence polarization spectroscopy	direct interaction, physical association	18579758, 24728074, (Europe PMC)	0.61	IntAct, MINT
MPIG6B	coimmunoprecipitation	association	11544253, (Europe PMC)	0.35	IntAct, MINT
MPZL1	Affinity Capture-MS, Affinity Capture-Western, anti bait coimmunoprecipitation, coimmunoprecipitation	association, physical, physical association	10681522, 28514442, 9792637, (Europe PMC)	0.56	BioGRID, IntAct, MINT
PDCD1	Affinity Capture-MS, anti tag coimmunoprecipitation, coimmunoprecipitation, confocal microscopy	association, colocalization, physical, physical association	15240681, 28046066, 28514442, (Europe PMC)	0.60	BioGRID, IntAct, MINT
PDGFRB	Reconstituted Complex, Two-hybrid, affinity technology, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, enzymatic study, experimental interaction detection, proximity ligation assay, surface plasmon resonance, x-ray crystallography	association, physical, physical association	11266449, 12614164, 23397142, 7530043, 7688466, 7691811, 8119896, 8183548, 8538796, (Europe PMC)	0.91	BioGRID, IntAct, MINT
PECAM1	Affinity Capture-Western, Far Western, Reconstituted Complex, lambda phage display, pull down, surface plasmon resonance	association, physical	10350061, 10704309, 10801826, 9054388, 9312087, 9774457, (Europe PMC)	0.69	BioGRID, IntAct, MINT
PLCG1	pull down	physical association	9020117, (Europe PMC)	0.40	IntAct, MINT
PXN	anti bait coimmunoprecipitation, proximity ligation assay	association, physical association	14665621, 23397142, (Europe PMC)	0.64	IntAct, MINT
RPIA	Two-hybrid, two hybrid, two hybrid array, two hybrid prey pooling approach, validated two hybrid	physical, physical association	21516116, 25416956, (Europe PMC)	0.67	BioGRID, IntAct, MINT
SELE	Affinity Capture-Western, coimmunoprecipitation	association, physical	11602579, (Europe PMC)	0.35	BioGRID, IntAct, MINT
SIT1	Affinity Capture-Western, coimmunoprecipitation, competition binding	association, physical	10209036, (Europe PMC)	0.46	BioGRID, IntAct, MINT
SLAMF1	Affinity Capture-Western, coimmunoprecipitation, pull down	association, physical	11313386, 11689425, 11806999, (Europe PMC)	0.46	BioGRID, IntAct, MINT
SLC4A1	coimmunoprecipitation	association	12070037, (Europe PMC)	0.35	IntAct, MINT
SRC	Biochemical Activity, phosphatase assay	dephosphorylation reaction, physical	20308328, 8959326, (Europe PMC)	0.44	BioGRID, IntAct, MINT
THEMIS	Affinity Capture-MS, pull down	association, physical	25535246, 28514442, (Europe PMC)	0.35	BioGRID, IntAct, MINT
TNFRSF1A	pull down	association	11786908, (Europe PMC)	0.35	IntAct, MINT

Visualize Download

Interacting partner	Detection method	Interaction type	PubMed IDs	Interaction Score	Source
ANXA1	anti bait coimmunoprecipitation	association	23754495, (Europe PMC)	0.35	IntAct
AR	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
BCAR1	Affinity Capture-Western	physical	9188452, (Europe PMC)	NA	BioGRID
BEX1	Two-hybrid	physical	27229929, (Europe PMC)	NA	BioGRID
BEX2	Two-hybrid	physical	27229929, (Europe PMC)	NA	BioGRID
BLZF1	Two-hybrid	physical	27229929, (Europe PMC)	NA	BioGRID
BTLA	Affinity Capture-Western, coimmunoprecipitation	association, physical	12796776, 14652006, (Europe PMC)	0.35	BioGRID, IntAct, MINT
C9orf62	Two-hybrid	physical	27229929, (Europe PMC)	NA	BioGRID
CAT	anti bait coimmunoprecipitation, pull down	direct interaction, physical association	15556604, (Europe PMC)	0.54	IntAct, MINT
CAV1	Affinity Capture-Western, coimmunoprecipitation, cosedimentation through density gradient	colocalization, physical, physical association	12176037, (Europe PMC)	0.50	BioGRID, IntAct, MINT
CBL	Affinity Capture-Western	physical	11157475, 17330819, 18519587, (Europe PMC)	NA	BioGRID
CBLB	Affinity Capture-Western	physical	17330819, (Europe PMC)	NA	BioGRID
CCKBR	anti tag coimmunoprecipitation, pull down, surface plasmon resonance	association, physical association	16963136, (Europe PMC)	0.62	IntAct, MINT
CD244	pull down, surface plasmon resonance	association, direct interaction	24642916, (Europe PMC)	0.52	IntAct
CD274	Affinity Capture-Western	physical	11224527, (Europe PMC)	NA	BioGRID
CD300A	anti bait coimmunoprecipitation	association	11489943, (Europe PMC)	0.35	IntAct
CD33	Affinity Capture-Western, Reconstituted Complex, anti bait coimmunoprecipitation, coimmunoprecipitation, pull down	association, physical, physical association	10206955, 17947393, (Europe PMC)	0.68	BioGRID, IntAct, MINT
CD84	Affinity Capture-Western	physical	11689425, (Europe PMC)	NA	BioGRID
CDC73	Affinity Capture-Western	physical	21726809, (Europe PMC)	NA	BioGRID
CDH5	Affinity Capture-Western	physical	10681592, (Europe PMC)	NA	BioGRID
CEACAM1	Affinity Capture-Western, Reconstituted Complex	physical	9867848, (Europe PMC)	NA	BioGRID
CHRAC1	Co-fractionation	physical	22863883, (Europe PMC)	NA	BioGRID
COP1	Affinity Capture-Western	physical	23269672, (Europe PMC)	NA	BioGRID
CRK	Affinity Capture-MS, Affinity Capture-Western	physical	10464310, 19380743, (Europe PMC)	NA	BioGRID
CRKL	Affinity Capture-Western, proximity ligation assay	physical, physical association	23397142, 9344843, (Europe PMC)	0.40	BioGRID, IntAct
CSF2RB	Affinity Capture-Western, Reconstituted Complex, pull down	association, physical	9162089, 9973406, (Europe PMC)	0.53	BioGRID, IntAct, MINT
CSF2RBP1	Affinity Capture-Western	physical	9361008, (Europe PMC)	NA	BioGRID
CSF3R	Far Western	physical	9824671, (Europe PMC)	NA	BioGRID
CTDSP1	Two-hybrid	physical	27229929, (Europe PMC)	NA	BioGRID
CTNNB1	Affinity Capture-Western	physical	10681592, (Europe PMC)	NA	BioGRID
CTR9	Affinity Capture-Western, Proximity Label-MS	physical	21726809, 27880917, (Europe PMC)	NA	BioGRID
CXCR4	Affinity Capture-Western	physical	11157475, (Europe PMC)	NA	BioGRID
CYP1A1	Affinity Capture-MS	physical	26186194, 28514442, (Europe PMC)	NA	BioGRID
DDR1	anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, coimmunoprecipitation	association, physical association	16337946, (Europe PMC)	0.58	IntAct, MINT
DMRTC1	Two-hybrid	physical	27229929, (Europe PMC)	NA	BioGRID
DNM2	Affinity Capture-Western	physical	21996738, (Europe PMC)	NA	BioGRID
DOK1	coimmunoprecipitation	association	15546884, (Europe PMC)	0.35	IntAct, MINT
DUSP13	Affinity Capture-MS	physical	27432908, (Europe PMC)	NA	BioGRID
EFHD2	Co-fractionation	physical	22863883, (Europe PMC)	NA	BioGRID
EGFR	Affinity Capture-MS, Affinity Capture-Western, Biochemical Activity, Protein-peptide, Two-hybrid, protein array, pull down	direct interaction, physical, physical association	16273093, 16729043, 20473329, 28065597, 7673163, 8959326, 9756944, (Europe PMC)	0.61	BioGRID, IntAct, MINT
ELAVL1	Affinity Capture-RNA	physical	19322201, (Europe PMC)	NA	BioGRID
EPHA1	Two-hybrid	physical	28065597, (Europe PMC)	NA	BioGRID
EPHA2	Affinity Capture-Western, Two-hybrid, anti bait coimmunoprecipitation	physical, physical association	10655584, 28065597, (Europe PMC)	0.40	BioGRID, IntAct
EPOR	Affinity Capture-Western, Reconstituted Complex	physical	7534299, 8639815, (Europe PMC)	NA	BioGRID
ERBB2	Affinity Capture-MS, Affinity Capture-Western, Protein-peptide, Two-hybrid, protein array	direct interaction, physical	16273093, 16729043, 28065597, 8959326, 9756944, (Europe PMC)	0.44	BioGRID, IntAct, MINT
ERBB3	Affinity Capture-Western, Two-hybrid	physical	28065597, 9756944, (Europe PMC)	NA	BioGRID
ERBB4	Affinity Capture-MS, Biochemical Activity, Two-hybrid, pull down	physical, physical association	16729043, 28065597, (Europe PMC)	0.40	BioGRID, IntAct, MINT
FAM71E1	Two-hybrid	physical	27229929, (Europe PMC)	NA	BioGRID
FASN	Affinity Capture-Western	physical	23269672, (Europe PMC)	NA	BioGRID
FCGR2A	Affinity Capture-MS	physical	26186194, 28514442, (Europe PMC)	NA	BioGRID
FCGR2B	Affinity Capture-Western, pull down	association, physical	10382761, (Europe PMC)	0.35	BioGRID, IntAct, MINT
FCRL3	Reconstituted Complex	physical	12051764, (Europe PMC)

Top

PTPN11