DEPOD - human DEPhOsphorylation Database

Basic Information
Phosphatases
Pathway
Interacting Proteins
Phosphorylating Kinases

Gene Name	MET (QuickGO)	Interactive visualization of MET structures (A quick tutorial to explore the interctive visulaization) Representative structure: 2G15
Synonyms	MET
Protein Name	MET
Alternative Name(s)	Hepatocyte growth factor receptor;HGF receptor;2.7.10.1;HGF/SF receptor;Proto-oncogene c-Met;Scatter factor receptor;SF receptor;Tyrosine-protein kinase Met;
Protein Family	Belongs to the protein kinase superfamily Tyr proteinkinase family
EntrezGene ID	4233 (Comparitive Toxicogenomics)
UniProt AC (Human)	P08581 (protein sequence)
Enzyme Class	2.7.10.1 (BRENDA )
Molecular Weight	155541 Dalton
Protein Length	1390 amino acids (AA)
Genome Browsers	NCBI \| ENSG00000105976 (Ensembl) \| UCSC
Crosslinking annotations	Query our ID-mapping table
Orthologues	Quest For Orthologues (QFO) \| GeneTree \| eggNOG - KOG1095 \| eggNOG - KOG3610 \| eggNOG - COG0515
Phosphorylation Network	Visualize

Domain organization, Expression, Diseases

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Localization, Function, Catalytic activity and Sequence

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Localization (UniProt annotation)
Membrane; Single-pass type I membraneprotein Isoform 3: Secreted
Function (UniProt annotation)
Receptor tyrosine kinase that transduces signals fromthe extracellular matrix into the cytoplasm by binding tohepatocyte growth factor/HGF ligand Regulates many physiologicalprocesses including proliferation, scattering, morphogenesis andsurvival Ligand binding at the cell surface inducesautophosphorylation of MET on its intracellular domain thatprovides docking sites for downstream signaling moleculesFollowing activation by ligand, interacts with the PI3-kinasesubunit PIK3R1, PLCG1, SRC, GRB2, STAT3 or the adapter GAB1Recruitment of these downstream effectors by MET leads to theactivation of several signaling cascades including the RAS-ERK,PI3 kinase-AKT, or PLCgamma-PKC The RAS-ERK activation isassociated with the morphogenetic effects while PI3K/AKTcoordinates prosurvival effects During embryonic development, METsignaling plays a role in gastrulation, development and migrationof muscles and neuronal precursors, angiogenesis and kidneyformation In adults, participates in wound healing as well asorgan regeneration and tissue remodeling Promotes alsodifferentiation and proliferation of hematopoietic cells Mayregulate cortical bone osteogenesis (By similarity) Acts as a receptor for Listeria internalin inlB,mediating entry of the pathogen into cells
Catalytic Activity (UniProt annotation)
ATP + a [protein]-L-tyrosine = ADP + a[protein]-L-tyrosine phosphate
Protein Sequence
MKAPAVLAPGILVLLFTLVQRSNGECKEALAKSEMNVNMKYQLPNFTAETPIQNVILHEHHIFLGATNYIYVLNEEDLQK VAEYKTGPVLEHPDCFPCQDCSSKANLSGGVWKDNINMALVVDTYYDDQLISCGSVNRGTCQRHVFPHNHTADIQSEVHC IFSPQIEEPSQCPDCVVSALGAKVLSSVKDRFINFFVGNTINSSYFPDHPLHSISVRRLKETKDGFMFLTDQSYIDVLPE FRDSYPIKYVHAFESNNFIYFLTVQRETLDAQTFHTRIIRFCSINSGLHSYMEMPLECILTEKRKKRSTKKEVFNILQAA YVSKPGAQLARQIGASLNDDILFGVFAQSKPDSAEPMDRSAMCAFPIKYVNDFFNKIVNKNNVRCLQHFYGPNHEHCFNR TLLRNSSGCEARRDEYRTEFTTALQRVDLFMGQFSEVLLTSISTFIKGDLTIANLGTSEGRFMQVVVSRSGPSTPHVNFL LDSHPVSPEVIVEHTLNQNGYTLVITGKKITKIPLNGLGCRHFQSCSQCLSAPPFVQCGWCHDKCVRSEECLSGTWTQQI CLPAIYKVFPNSAPLEGGTRLTICGWDFGFRRNNKFDLKKTRVLLGNESCTLTLSESTMNTLKCTVGPAMNKHFNMSIII SNGHGTTQYSTFSYVDPVITSISPKYGPMAGGTLLTLTGNYLNSGNSRHISIGGKTCTLKSVSNSILECYTPAQTISTEF AVKLKIDLANRETSIFSYREDPIVYEIHPTKSFISGGSTITGVGKNLNSVSVPRMVINVHEAGRNFTVACQHRSNSEIIC CTTPSLQQLNLQLPLKTKAFFMLDGILSKYFDLIYVHNPVFKPFEKPVMISMGNENVLEIKGNDIDPEAVKGEVLKVGNK SCENIHLHSEAVLCTVPNDLLKLNSELNIEWKQAISSTVLGKVIVQPDQNFTGLIAGVVSISTALLLLLGFFLWLKKRKQ IKDLGSELVRYDARVHTPHLDRLVSARSVSPTTEMVSNESVDYRATFPEDQFPNSSQNGSCRQVQYPLTDMSPILTSGDS DISSPLLQNTVHIDLSALNPELVQAVQHVVIGPSSLIVHFNEVIGRGHFGCVYHGTLLDNDGKKIHCAVKSLNRITDIGE VSQFLTEGIIMKDFSHPNVLSLLGICLRSEGSPLVVLPYMKHGDLRNFIRNETHNPTVKDLIGFGLQVAKGMKYLASKKF VHRDLAARNCMLDEKFTVKVADFGLARDMYDKEYYSVHNKTGAKLPVKWMALESLQTQKFTTKSDVWSFGVLLWELMTRG APPYPDVNTFDITVYLLQGRRLLQPEYCPDPLYEVMLKCWHPKAEMRPSFSELVSRISAIFSTFIGEHYVHVNATYVNVK CVAPYPSLLSSEDNADDEVDTRPASFWETS

Motif information from Eukaryotic Linear Motif atlas (ELM)

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

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KEGG Pathway
Reactome Pathway

Pathway ID	Pathway Name	Pathway Description (KEGG)
hsa01521	EGFR tyrosine kinase inhibitor resistance	EGFR is a tyrosine kinase that participates in the regulation of cellular homeostasis. EGFR also serves as a stimulus for cancer growth. EGFR gene mutations and protein overexpression, both of which activate down- stream pathways, are associated with cancers, especially lung cancer. Several tyrosine kinase inhibitor (TKI) therapies against EGFR are currently administered and are initially effective in cancer patients who have EGFR mutations or aberrant activation of EGFR. However, the development of TKI resistance is common and results in the recurrence of tumors. Studies over the last decade have identified mechanisms that drive resistance to EGFR TKI treatment. Most outstanding mechanisms are: the secondary EGFR mutation (T790M), activation of alternative pathways (c-Met, HGF, AXL), aberrance of the downstream pathways (K-RAS mutations, loss of PTEN), impairment of the EGFR-TKIs-mediated apoptosis pathway (BCL2-like 11/BIM deletion polymorphism), histologic transformation, etc.
hsa04010	MAPK signaling pathway	The mitogen-activated protein kinase (MAPK) cascade is a highly conserved module that is involved in various cellular functions, including cell proliferation, differentiation and migration. Mammals express at least four distinctly regulated groups of MAPKs, extracellular signal-related kinases (ERK)-1/2, Jun amino-terminal kinases (JNK1/2/3), p38 proteins (p38alpha/beta/gamma/delta) and ERK5, that are activated by specific MAPKKs: MEK1/2 for ERK1/2, MKK3/6 for the p38, MKK4/7 (JNKK1/2) for the JNKs, and MEK5 for ERK5. Each MAPKK, however, can be activated by more than one MAPKKK, increasing the complexity and diversity of MAPK signalling. Presumably each MAPKKK confers responsiveness to distinct stimuli. For example, activation of ERK1/2 by growth factors depends on the MAPKKK c-Raf, but other MAPKKKs may activate ERK1/2 in response to pro-inflammatory stimuli.
hsa04014	Ras signaling pathway	The Ras proteins are GTPases that function as molecular switches for signaling pathways regulating cell proliferation, survival, growth, migration, differentiation or cytoskeletal dynamism. Ras proteins transduce signals from extracellular growth factors by cycling between inactive GDP-bound and active GTP-bound states. The exchange of GTP for GDP on RAS is regulated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). Activated RAS (RAS-GTP) regulates multiple cellular functions through effectors including Raf, phosphatidylinositol 3-kinase (PI3K) and Ral guanine nucleotide-dissociation stimulator (RALGDS).
hsa04015	Rap1 signaling pathway	Rap1 is a small GTPase that controls diverse processes, such as cell adhesion, cell-cell junction formation and cell polarity. Like all G proteins, Rap1 cycles between an inactive GDP-bound and an active GTP-bound conformation. A variety of extracellular signals control this cycle through the regulation of several unique guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs). Rap1 plays a dominant role in the control of cell-cell and cell-matrix interactions by regulating the function of integrins and other adhesion molecules in various cell types. Rap1 also regulates MAP kinase (MAPK) activity in a manner highly dependent on the context of cell types.
hsa04151	PI3K-Akt signaling pathway	The phosphatidylinositol 3' -kinase(PI3K)-Akt signaling pathway is activated by many types of cellular stimuli or toxic insults and regulates fundamental cellular functions such as transcription, translation, proliferation, growth, and survival. The binding of growth factors to their receptor tyrosine kinase (RTK) or G protein-coupled receptors (GPCR) stimulates class Ia and Ib PI3K isoforms, respectively. PI3K catalyzes the production of phosphatidylinositol-3,4,5-triphosphate (PIP3) at the cell membrane. PIP3 in turn serves as a second messenger that helps to activate Akt. Once active, Akt can control key cellular processes by phosphorylating substrates involved in apoptosis, protein synthesis, metabolism, and cell cycle.
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.
hsa04510	Focal adhesion	Cell-matrix adhesions play essential roles in important biological processes including cell motility, cell proliferation, cell differentiation, regulation of gene expression and cell survival. At the cell-extracellular matrix contact points, specialized structures are formed and termed focal adhesions, where bundles of actin filaments are anchored to transmembrane receptors of the integrin family through a multi-molecular complex of junctional plaque proteins. Some of the constituents of focal adhesions participate in the structural link between membrane receptors and the actin cytoskeleton, while others are signalling molecules, including different protein kinases and phosphatases, their substrates, and various adapter proteins. Integrin signaling is dependent upon the non-receptor tyrosine kinase activities of the FAK and src proteins as well as the adaptor protein functions of FAK, src and Shc to initiate downstream signaling events. These signalling events culminate in reorganization of the actin cytoskeleton; a prerequisite for changes in cell shape and motility, and gene expression. Similar morphological alterations and modulation of gene expression are initiated by the binding of growth factors to their respective receptors, emphasizing the considerable crosstalk between adhesion- and growth factor-mediated signalling.
hsa04520	Adherens junction	Cell-cell adherens junctions (AJs), the most common type of intercellular adhesions, are important for maintaining tissue architecture and cell polarity and can limit cell movement and proliferation. At AJs, E-cadherin serves as an essential cell adhesion molecules (CAMs). The cytoplasmic tail binds beta-catenin, which in turn binds alpha-catenin. Alpha-catenin is associated with F-actin bundles directly and indirectly. The integrity of the cadherin-catenin complex is negatively regulated by phosphorylation of beta-catenin by receptor tyrosine kinases (RTKs) and cytoplasmic tyrosine kinases (Fer, Fyn, Yes, and Src), which leads to dissociation of the cadherin-catenin complex. Integrity of this complex is positively regulated by beta -catenin phosphorylation by casein kinase II, and dephosphorylation by protein tyrosine phosphatases. Changes in the phosphorylation state of beta-catenin affect cell-cell adhesion, cell migration and the level of signaling beta-catenin. Wnt signaling acts as a positive regulator of beta-catenin by inhibiting beta-catenin degradation, which stabilizes beta-catenin, and causes its accumulation. Cadherin may acts as a negative regulator of signaling beta-catenin as it binds beta-catenin at the cell surface and thereby sequesters it from the nucleus. Nectins also function as CAMs at AJs, but are more highly concentrated at AJs than E-cadherin. Nectins transduce signals through Cdc42 and Rac, which reorganize the actin cytoskeleton, regulate the formation of AJs, and strengthen cell-cell adhesion.
hsa05100	Bacterial invasion of epithelial cells	Many pathogenic bacteria can invade phagocytic and non-phagocytic cells and colonize them intracellularly, then become disseminated to other cells. Invasive bacteria induce their own uptake by non-phagocytic host cells (e.g. epithelial cells) using two mechanisms referred to as zipper model and trigger model. Listeria, Staphylococcus, Streptococcus, and Yersinia are examples of bacteria that enter using the zipper model. These bacteria express proteins on their surfaces that interact with cellular receptors, initiating signalling cascades that result in close apposition of the cellular membrane around the entering bacteria. Shigella and Salmonella are the examples of bacteria entering cells using the trigger model. These bacteria use type III secretion systems to inject protein effectors that interact with the actin cytoskeleton.
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.
hsa05144	Malaria	Plasmodium protozoa are parasites that account for malaria infection. Sporozoite forms of the parasite are injected by mosquito bites under the skin and are carried to the liver where they develop into the merozoite form.Sporozoite invasion of hepatocytes is mediated by parasite surface protein like CSP. Subsequent infection into red blood cells (RBCs) by merozoites causes malaria disease via aberrant cytokine production and sequestration of parasite-infected red blood cells (pRBCs) to host endothelium. Microvasculature sequestration in the brain brings about cerebral malaria that can results in death or persisting neurological impairment. PfEMP1 has been suggested as the key adhesive molecule of pRBCs.
hsa05200	Pathways in cancer
hsa05202	Transcriptional misregulation in cancer	In tumor cells, genes encoding transcription factors (TFs) are often amplified, deleted, rearranged via chromosomal translocation and inversion, or subjected to point mutations that result in a gain- or loss-of- function. In hematopoietic cancers and solid tumors, the translocations and inversions increase or deregulate transcription of the oncogene. Recurrent chromosome translocations generate novel fusion oncoproteins, which are common in myeloid cancers and soft-tissue sarcomas. The fusion proteins have aberrant transcriptional function compared to their wild-type counterparts. These fusion transcription factors alter expression of target genes, and thereby result in a variety of altered cellular properties that contribute to the tumourigenic process.
hsa05205	Proteoglycans in cancer	Many proteoglycans (PGs) in the tumor microenvironment have been shown to be key macromolecules that contribute to biology of various types of cancer including proliferation, adhesion, angiogenesis and metastasis, affecting tumor progress. The four main types of proteoglycans include hyaluronan (HA), which does not occur as a PG but in free form, heparan sulfate proteoglycans (HSPGs), chondroitin sulfate proteoglycans (CSPGs), dematan sulfate proteoglycans (DSPG) and keratan sulfate proteoglycans (KSPGs) [BR:00535]. Among these proteoglycans such as HA, acting with CD44, promotes tumor cell growth and migration, whereas other proteoglycans such as syndecans (-1~-4), glypican (-1, -3) and perlecan may interact with growth factors, cytokines, morphogens and enzymes through HS chains [BR: 00536], also leading to tumor growth and invasion. In contrast, some of the small leucine-rich proteolgycans, such as decorin and lumican, can function as tumor repressors, and modulate the signaling pathways by the interaction of their core proteins and multiple receptors.
hsa05206	MicroRNAs in cancer	MicroRNA (miRNA) is a cluster of small non-encoding RNA molecules of 21 - 23 nucleotides in length, which controls gene expression post-transcriptionally either via the degradation of target mRNAs or the inhibition of protein translation. Using high-throughput profiling, dysregulation of miRNAs has been widely observed in different stages of cancer. The upregulation (overexpression) of specific miRNAs could lead to the repression of tumor suppressor gene expression, and conversely the downregulation of specific miRNAs could result in an increase of oncogene expression; both these situations induce subsequent malignant effects on cell proliferation, differentiation, and apoptosis that lead to tumor growth and progress. The miRNA signatures of cancer observed in various studies differ significantly. These inconsistencies occur due to the differences in the study populations and methodologies used. This pathway map shows the summarized results from various studies in 9 cancers, each of which is presented in a review article.
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.
hsa05218	Melanoma	Melanoma is a form of skin cancer that has a poor prognosis and which is on the rise in Western populations. Melanoma arises from the malignant transformation of pigment-producing cells, melanocytes. The only known environmental risk factor is exposure to ultraviolet (UV) light and in people with fair skin the risk is greatly increased. Melanoma pathogenesis is also driven by genetic factors. Oncogenic NRAS mutations activate both effector pathways Raf-MEK-ERK and PI3K-Akt. The Raf-MEK-ERK pathway may also be activated via mutations in the BRAF gene. The PI3K-Akt pathway may be activated through loss or mutation of the inhibitory tumor suppressor gene PTEN. These mutations arise early during melanoma pathogenesis and are preserved throughout tumor progression. Melanoma development has been shown to be strongly associated with inactivation of the p16INK4a/cyclin dependent kinases 4 and 6/retinoblastoma protein (p16INK4a/CDK4,6/pRb) and p14ARF/human double minute 2/p53 (p14ARF/HMD2/p53) tumor suppressor pathways. MITF and TP53 are implicated in further melanoma progression.
hsa05225	Hepatocellular carcinoma	Hepatocellular carcinoma (HCC) is a major type of primary liver cancer and one of the rare human neoplasms etiologically linked to viral factors. It has been shown that, after HBV/HCV infection and alcohol or aflatoxin B1 exposure, genetic and epigenetic changes occur. The recurrent mutated genes were found to be highly enriched in multiple key driver signaling processes, including telomere maintenance, TP53, cell cycle regulation, the Wnt/beta-catenin pathway (CTNNB1 and AXIN1), the phosphatidylinositol-3 kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway. Recent studies using whole-exome sequencing have revealed recurrent mutations in new driver genes involved in the chromatin remodelling (ARID1A and ARID2) and the oxidative stress (NFE2L2) pathways.
hsa05226	Gastric cancer	Gastric cancer (GC) is one of the world's most common cancers. According to Lauren's histological classification gastric cancer is divided into two distinct histological groups - the intestinal and diffuse types. Several genetic changes have been identified in intestinal-type GC. The intestinal metaplasia is characterized by mutations in p53 gene, reduced expression of retinoic acid receptor beta (RAR-beta) and hTERT expression. Gastric adenomas furthermore display mutations in the APC gene, reduced p27 expression and cyclin E amplification. In addition, amplification and overexpression of c-ErbB2, reduced TGF-beta receptor type I (TGFBRI) expression and complete loss of p27 expression are commonly observed in more advanced GC. The main molecular changes observed in diffuse-type GCs include loss of E-cadherin function by mutations in CDH1 and amplification of MET and FGFR2F.
hsa05230	Central carbon metabolism in cancer	Malignant transformation of cells requires specific adaptations of cellular metabolism to support growth and survival. In the early twentieth century, Otto Warburg established that there are fundamental differences in the central metabolic pathways operating in malignant tissue. He showed that cancer cells consume a large amount of glucose, maintain high rate of glycolysis and convert a majority of glucose into lactic acid even under normal oxygen concentrations (Warburg's Effects). More recently, it has been recognized that the 'Warburg effect' encompasses a similarly increased utilization of glutamine. From the intermediate molecules provided by enhanced glycolysis and glutaminolysis, cancer cells synthesize most of the macromolecules required for the duplication of their biomass and genome. These cancer-specific alterations represent a major consequence of genetic mutations and the ensuing changes of signalling pathways in cancer cells. Three transcription factors, c-MYC, HIF-1 and p53, are key regulators and coordinate regulation of cancer metabolism in different ways, and many other oncogenes and tumor suppressor genes cluster along the signaling pathways that regulate c-MYC, HIF-1 and p53.

Pathway ID	Pathway Name	Pathway Description (KEGG)
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-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-416550	Sema4D mediated inhibition of cell attachment and migration.	Repulsive Sema4D-Plexin-B1 signaling involves four GTPases, Rnd1, R-Ras, Rho and Rac1. Sema4D-Plexin-B1 binding promotes Rnd1-dependent activation of the plexin-B1 GAP domain and transient suppression of R-Ras activity. R-Ras inactivation promotes PI3K and Akt inactivation followed by GSK-3beta activation and CRMP2 inactivation. Plexin-B1 also transiently associates with and activates p190Rho-GAP, triggering a transient decrease in activated Rho
R-HSA-5673001	RAF/MAP kinase cascade.	The RAS-RAF-MEK-ERK pathway regulates processes such as proliferation, differentiation, survival, senescence and cell motility in response to growth factors, hormones and cytokines, among others. Binding of these stimuli to receptors in the plasma membrane promotes the GEF-mediated activation of RAS at the plasma membrane and initiates the three-tiered kinase cascade of the conventional MAPK cascades. GTP-bound RAS recruits RAF (the MAPK kinase kinase), and promotes its dimerization and activation (reviewed in Cseh et al, 2014; Roskoski, 2010; McKay and Morrison, 2007; Wellbrock et al, 2004). Activated RAF phosphorylates the MAPK kinase proteins MEK1 and MEK2 (also known as MAP2K1 and MAP2K2), which in turn phophorylate the proline-directed kinases ERK1 and 2 (also known as MAPK3 and MAPK1) (reviewed in Roskoski, 2012a, b; Kryiakis and Avruch, 2012). Activated ERK proteins may undergo dimerization and have identified targets in both the nucleus and the cytosol; consistent with this, a proportion of activated ERK protein relocalizes to the nucleus in response to stimuli (reviewed in Roskoski 2012b; Turjanski et al, 2007; Plotnikov et al, 2010; Cargnello et al, 2011). Although initially seen as a linear cascade originating at the plasma membrane and culminating in the nucleus, the RAS/RAF MAPK cascade is now also known to be activated from various intracellular location. Temporal and spatial specificity of the cascade is achieved in part through the interaction of pathway components with numerous scaffolding proteins (reviewed in McKay and Morrison, 2007; Brown and Sacks, 2009). The importance of the RAS/RAF MAPK cascade is highlighted by the fact that components of this pathway are mutated with high frequency in a large number of human cancers. Activating mutations in RAS are found in approximately one third of human cancers, while ~8% of tumors express an activated form of BRAF (Roberts and Der, 2007; Davies et al, 2002; Cantwell-Dorris et al, 2011)
R-HSA-6806942	MET Receptor Activation.	Hepatocyte growth factor (HGF), the ligand for MET receptor tyrosine kinase (RTK), is secreted into the extracellular matrix (ECM) as an inactive single chain precursor (pro-HGF). The biologically active HGF is the heterodimer of alpha and beta chains that are produced via proteolytic cleavage of pro-HGF by the plasma membrane bound serine protease Hepsin (HPN) (Kirchhofer et al. 2005, Owen et al. 2010) or the ECM-associated serine protease Hepatocyte growth factor activator (HGFAC, commonly known as HGFA) (Shia et al. 2005). HGF binds to the extracellular SEMA and PSI domains of MET RTK, inducing a conformational change that enables MET dimerization or oligomerization (Kirchhofer et al. 2004, Stamos et al. 2004, Hays and Watowich 2004, Gherardi et al. 2006). MET dimers trans-autophosphorylate on tyrosine residues in the activation loop, leading to increased kinase activity, and on tyrosine residues at the cytoplasmic tail that serve as docking sites for adapter proteins involved in MET signal transduction (Ferracini et al. 1991, Longati et al. 1994, Rodrigues and Park 1994, Ponzetto et al. 1994).CD44v6 was implicated as a MET co-receptor, but its role has been disputed (Orian-Rousseau et al. 2002, Dortet et al. 2010, Olaku et al. 2011, Hasenauer et al. 2013, Elliot et al. 2014)
R-HSA-6807004	Negative regulation of MET activity.	Signaling by MET receptor is negatively regulated mainly by MET receptor dephosphorylation or MET receptor degradation. Protein tyrosine phosphatase PTPRJ dephosphorylates MET tyrosine residue Y1349, thus removing the docking site for the GAB1 adapter (Palka et al. 2003). Protein tyrosine phosphatases PTPN1 and PTPN2 dephosphorylate MET tyrosines Y1234 and Y1235 in the kinase activation loop, thus attenuating catalytic activity of MET (Sangwan et al. 2008). The E3 ubiquitin ligase CBL promotes ubiquitination of the activated MET receptor and subsequent MET degradation. CBL contains a RING finger domain that engages E2 protein ubiquitin ligases to mediate ubiquitination of MET, which may occur at the cell membrane or in the early endocytic compartment. Ubiquitinated MET is degraded in a late endosomal or lysosomal compartment in a proteasome-dependent manner. The involvement of proteasome in MET degradation seems to be indirect, through an effect on MET endocytic trafficking (Jeffers et al. 1997, Peschard et al. 2001, Hammond et al. 2001, Petrelli et al. 2002). LRIG1 promotes lysosome-dependent degradation of MET in the absence of HGF-mediated activation (Lee et al. 2014, Oh et al. 2014).MET-mediated activation of RAS signaling is inhibited by MET receptor binding to MUC20 (Higuchi et al. 2004) or RANBP10 (Wang et al. 2004)
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-8851805	MET activates RAS signaling.	Activated MET receptor recruits the RAS guanyl nucleotide exchange factor (GEF) SOS1 indirectly, either through the GRB2 adapter (Ponzetto et al. 1994, Fournier et al. 1996, Shen and Novak 1997, Besser et al. 1997), GAB1 (Weidner et al. 1996) or SHC1 and GRB2 (Pelicci et al. 1995), or RANBP9 (Wang et al. 2002, Wang et al. 2004). Association of SOS1 with the activated MET receptor complex leads to exchange of GDP to GTP on RAS and activation of RAS signaling (Pelicci et al. 1995, Besser et al. 1997, Shen and Novak 1997, Wang et al. 2004).PTPN11 (SHP2) may contribute to activation of RAS signaling downstream of MET (Schaeper et al. 2000, Furcht et al. 2014).Sustained activation of MAPK1 (ERK2) and MAPK3 (ERK1) downstream of MET-activated RAS may require MET endocytosis and signaling from endosomes (Peschard et al. 2001, Hammond et al. 2001, Petrelli et al. 2002, Kermorgant and Parker 2008).Binding of MET to MUC20 or RANBP10 interferes with RAS activation (Higuchi et al. 2004, Wang et al. 2004)
R-HSA-8851907	MET activates PI3K/AKT signaling.	MET binds and phosphorylates the adapter protein GAB1, thus creating a docking site for the regulatory subunit PIK3R1 of the PI3K complex. Recruitment of PI3K to MET-bound phosphorylated GAB1 results in PI3K activation, production of PIP3, and stimulation of downstream AKT signaling (Rodrigues et al. 2000, Schaeper et al. 2000)
R-HSA-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-8874081	MET activates PTK2 signaling.	MET receptor activates the focal adhesion kinase PTK2 (FAK1) in a process that depends on the simultaneous interaction of PTK2 with integrins and with MET. SRC is needed for PTK2 to become fully active. Activation of PTK2 is needed for HGF-induced cell motility (Beviglia et al. 1999, Parr et al. 2001, Chen and Chen 2006, Lietha et al. 2007, Chen et al. 2011, Brami-Cherrier et al. 2014)
R-HSA-8875360	InlB-mediated entry of Listeria monocytogenes into host cell.	InlB, a cell wall protein of Listeria monocytogenes, binds MET receptor, acting as an HGF agonist (Shen et al. 2000, Veiga and Cossart 2005). Listeria monocytogenes InlB proteins dimerize through their leucine-rich repeat regions (LRRs), promoting dimerization of MET receptors that they are bound to (Ferraris et al. 2010). InlB-induced MET receptor dimerization is followed by MET trans-autophosphorylation and activation of downstream RAS/RAF/MAPK signaling and PI3K/AKT signaling (Niemann et al. 2007, Ferraris et al. 2010). InlB-bound phosphorylated MET receptor recruits the E3 ubiquitin ligase CBL through GRB2. CBL-mediated monoubiquitination of InlB-bound MET promotes endocytosis and entry of Listeria monocytogenes to host cells (Veiga and Cossart 2005). CIN85 is necessary for endocytosis-mediated entry of Listeria monocytogenes triggered by CBL-mediated monoubiquitination of MET (Veiga and Cossart 2005). Proteins involved in clathrin-mediated endocytosis EPS15 and HGS (Hrs) are both necessary for CBL and MET-mediated entry of Listeria monocytogenes into host cells (Veiga and Cossart 2005).A potential coreceptor role of CD44 in InlB-mediated MET activation is contradictory (Jung et al. 2009, Dortet et al. 2010)
R-HSA-8875513	MET interacts with TNS proteins.	Interaction of MET with tensin protein TNS4 at focal adhesion sites promotes cell motility through and unknown mechanism. MET also interacts with TNS3, whose expression seems to be inversely correlated with TNS4 (Muharram et al. 2014)
R-HSA-8875555	MET activates RAP1 and RAC1.	The adapter protein GAB1 is involved in recruitment, through CRK and related CRKL proteins, of guanyl nucleotide exchange factors (GEFs) to the activated MET receptor. MET-associated GEFs, such as RAPGEF1 (C3G) and DOCK7, activate RAP1 and RAC1, respectively, leading to morphological changes that contribute to cell motility (Schaeper et al. 2000, Sakkab et al. 2000, Lamorte et al. 2002, Watanabe et al. 2006, Murray et al. 2014)
R-HSA-8875656	MET receptor recycling.	Activated MET receptor is subject to recycling from the plasma membrane through the endosomal compartment and back to the plasma membrane (Peschard et al. 2001, Hammond et al. 2001, Petrelli et al. 2002). In the recycling process, activated MET receptor is endocytosed, and the GGA3 protein directs it, via a largely unknown mechanism, through the RAB4 positive endosomal compartments back to the plasma membrane (Parachoniak et al. 2011). Endosomal signaling by MET during the recycling process appears to play an important role in sustained activation of ERK1/ERK2 (MAPK3/MAPK1) and STAT3 downstream of MET (Kermorgant and Parker 2008)
R-HSA-8875791	MET activates STAT3.	The STAT3 transcription factor binds to activated MET through phosphorylated tyrosine residue Y1356 of MET. STAT3 may also bind to activated MET indirectly through GAB1, but this interaction has not been studied in detail. Activated MET induces phosphorylation of STAT3 at Y705, triggering STAT3 dimerization and nuclear translocation (Schaper et al. 1997, Boccaccio et al. 1998, Zhang et al. 2002, Cramer et al. 2005). Endocytosis of MET and interaction with STAT3 at endosomes may be required for sustained STAT3 phosphorylation in response to HGF stimulation (Kermorgant and Parker 2008). Activated SRC may also contribute to phosphorylation of STAT3 at Y705. STAT3 may promote HGF transcription in a SRC-dependent way, but this autocrine HGF loop may be limited to breast cancer cells (Wojcik et al. 2006, Sam et al. 2007). MET-mediated activation of STAT3 is implicated in anchorage independent cell growth and invasiveness downstream of HGF (Zhang et al. 2002, Cramer et al. 2005). MET can also interact with STAT1A, STAT1B and STAT5, but the biological importance of these interactions is not known (Runge et al. 1999)

BioGRID
IntAct
MINT
ALL

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Interacting partner	Detection method	Interaction type	PubMed IDs	Interaction Score	Source
CBL	Affinity Capture-Western, Biochemical Activity, Co-crystal Structure, Co-localization, Far Western, Reconstituted Complex, anti bait coimmunoprecipitation, coimmunoprecipitation, experimental interaction detection, isothermal titration calorimetry, mass spectrometry studies of complexes, proximity ligation assay, surface plasmon resonance, x-ray crystallography	direct interaction, physical, physical association, ubiquitination reaction	11894096, 15123609, 16397241, 18273061, 19433454, 19450681, 21163258, 21222362, 25241761, (Europe PMC)	0.86	BioGRID, IntAct, MINT
CBLC	Affinity Capture-Western	physical	22888118, (Europe PMC)	NA	BioGRID
CDH1	Affinity Capture-Western	physical	11254878, (Europe PMC)	NA	BioGRID
CEACAM21	Affinity Capture-MS	physical	26186194, 28514442, (Europe PMC)	NA	BioGRID
CHEK1	Negative Genetic	genetic	28319113, (Europe PMC)	NA	BioGRID
CRK	Affinity Capture-Western, fluorescence polarization spectroscopy	direct interaction, physical	24728074, 24828152, (Europe PMC)	0.44	BioGRID, IntAct
CTNNB1	Affinity Capture-Western	physical	11254878, (Europe PMC)	NA	BioGRID
DCN	Affinity Capture-Western, Reconstituted Complex	physical	19433454, (Europe PMC)	NA	BioGRID
EGFR	Affinity Capture-MS, Affinity Capture-Western, anti bait coimmunoprecipitation, protein kinase assay, tandem affinity purification	association, phosphorylation reaction, physical, physical association	20624308, 21918175, 23866081, 24189400, 24362532, 26551075, (Europe PMC)	0.80	BioGRID, IntAct
ERBB3	Affinity Capture-Western, anti bait coimmunoprecipitation	association, physical	21918175, 25326665, (Europe PMC)	0.35	BioGRID, IntAct
FBXO6	Affinity Capture-MS	physical	22268729, (Europe PMC)	NA	BioGRID
GAB1	Affinity Capture-Western, anti tag coimmunoprecipitation	physical, physical association	10871282, 10913131, 9242692, (Europe PMC)	0.40	BioGRID, IntAct, MINT
GAB2	Affinity Capture-Western	physical	10871282, (Europe PMC)	NA	BioGRID
GGA3	Affinity Capture-Western, Co-localization	physical	21664574, (Europe PMC)	NA	BioGRID
GLMN	Affinity Capture-Western, Reconstituted Complex, Two-hybrid	physical	11571281, (Europe PMC)	NA	BioGRID
GNG12	Co-fractionation	physical	22939629, (Europe PMC)	NA	BioGRID
GRB2	Affinity Capture-Western, Reconstituted Complex	physical	19433454, 21222362, 8662889, 9660480, (Europe PMC)	NA	BioGRID
HGF	Affinity Capture-Western, Biochemical Activity, Reconstituted Complex, amplified luminescent proximity homogeneous assay, cross-linking study, enzyme linked immunosorbent assay, fluorescent resonance energy transfer, saturation binding, x ray scattering, x-ray crystallography	direct interaction, physical, physical association	15167892, 16537482, 1655405, 17804794, 17981115, 1846706, 19433454, 20624990, 22897854, 8380735, (Europe PMC)	0.44, 0.68, 0.85	BioGRID, IntAct
HGS	Affinity Capture-Western	physical	24828152, (Europe PMC)	NA	BioGRID
HSP90AA1	Affinity Capture-Western	physical	21325980, 26517842, (Europe PMC)	NA	BioGRID
HSP90AB1	Affinity Capture-Western	physical	26517842, (Europe PMC)	NA	BioGRID
HSPA4	Affinity Capture-Western	physical	21325980, (Europe PMC)	NA	BioGRID
INPPL1	Affinity Capture-Western, fluorescence polarization spectroscopy	direct interaction, physical	19713535, 24728074, (Europe PMC)	0.44	BioGRID, IntAct
LGALS9	Affinity Capture-MS	physical	26186194, 28514442, (Europe PMC)	NA	BioGRID
LRIG1	Affinity Capture-Western, Co-localization	physical	17178829, 24828152, (Europe PMC)	NA	BioGRID
MET	Biochemical Activity, amplified luminescent proximity homogeneous assay, cross-linking study	direct interaction, physical, physical association	16537482, 20624990, 23794705, 26285778, (Europe PMC)	0.61	BioGRID, IntAct
PCBP1	Affinity Capture-MS	physical	26186194, 28514442, (Europe PMC)	NA	BioGRID
PTEN	Positive Genetic	genetic	28319113, (Europe PMC)	NA	BioGRID
RANBP10	Affinity Capture-Western, Reconstituted Complex	physical	14684163, (Europe PMC)	NA	BioGRID
RANBP9	Affinity Capture-Western, Reconstituted Complex, Two-hybrid, coimmunoprecipitation, pull down, two hybrid	direct interaction, physical, physical association	12147692, (Europe PMC)	0.59	BioGRID, IntAct, MINT
SCGB1D1	Affinity Capture-MS	physical	28514442, (Europe PMC)	NA	BioGRID
SH3KBP1	Affinity Capture-Western	physical	11894096, (Europe PMC)	NA	BioGRID
SHC1	Affinity Capture-Western, fluorescence polarization spectroscopy	direct interaction, physical	24728074, 9660480, (Europe PMC)	0.44	BioGRID, IntAct
SOCS1	Affinity Capture-Western, Reconstituted Complex, fluorescence polarization spectroscopy	direct interaction, physical	24728074, 25728680, (Europe PMC)	0.44	BioGRID, IntAct
SOS1	Affinity Capture-Western	physical	9660480, (Europe PMC)	NA	BioGRID
SPSB1	Affinity Capture-Western	physical	15713673, (Europe PMC)	NA	BioGRID
SPSB2	Affinity Capture-Western	physical	15713673, (Europe PMC)	NA	BioGRID
SPSB3	Affinity Capture-Western	physical	15713673, (Europe PMC)	NA	BioGRID
SPSB4	Affinity Capture-Western	physical	15713673, (Europe PMC)	NA	BioGRID
SRC	Affinity Capture-Western, anti bait coimmunoprecipitation, fluorescence polarization spectroscopy	association, direct interaction, physical, physical association	20624308, 24034250, 24728074, 9837958, (Europe PMC)	0.70	BioGRID, IntAct
STAT3	Affinity Capture-Western	physical	9440692, (Europe PMC)	NA	BioGRID
STUB1	Affinity Capture-Western	physical	21325980, (Europe PMC)	NA	BioGRID

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Interacting partner	Detection method	Interaction type	PubMed IDs	Interaction Score	Source
BCAR3	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
BLK	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
BTK	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
CASP3	Co-localization, proximity ligation assay	physical, physical association	25241761, (Europe PMC)	0.40	BioGRID, IntAct
CBL	Affinity Capture-Western, Biochemical Activity, Co-crystal Structure, Co-localization, Far Western, Reconstituted Complex, anti bait coimmunoprecipitation, coimmunoprecipitation, experimental interaction detection, isothermal titration calorimetry, mass spectrometry studies of complexes, proximity ligation assay, surface plasmon resonance, x-ray crystallography	direct interaction, physical, physical association, ubiquitination reaction	11894096, 15123609, 16397241, 18273061, 19433454, 19450681, 21163258, 21222362, 25241761, (Europe PMC)	0.86	BioGRID, IntAct, MINT
CD44	cross-linking study	physical association	22897854, (Europe PMC)	0.40	IntAct
CRK	Affinity Capture-Western, fluorescence polarization spectroscopy	direct interaction, physical	24728074, 24828152, (Europe PMC)	0.44	BioGRID, IntAct
DNAJA3	anti bait coimmunoprecipitation, confocal microscopy, pull down	colocalization, physical association	21242965, (Europe PMC)	0.46, 0.52	IntAct
EGFR	Affinity Capture-MS, Affinity Capture-Western, anti bait coimmunoprecipitation, protein kinase assay, tandem affinity purification	association, phosphorylation reaction, physical, physical association	20624308, 21918175, 23866081, 24189400, 24362532, 26551075, (Europe PMC)	0.80	BioGRID, IntAct
ERBB3	Affinity Capture-Western, anti bait coimmunoprecipitation	association, physical	21918175, 25326665, (Europe PMC)	0.35	BioGRID, IntAct
FES	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
FGR	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
GAB1	Affinity Capture-Western, anti tag coimmunoprecipitation	physical, physical association	10871282, 10913131, 9242692, (Europe PMC)	0.40	BioGRID, IntAct, MINT
GRB14	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
GRB7	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
HCK	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
HGF	Affinity Capture-Western, Biochemical Activity, Reconstituted Complex, amplified luminescent proximity homogeneous assay, cross-linking study, enzyme linked immunosorbent assay, fluorescent resonance energy transfer, saturation binding, x ray scattering, x-ray crystallography	direct interaction, physical, physical association	15167892, 16537482, 1655405, 17804794, 17981115, 1846706, 19433454, 20624990, 22897854, 8380735, (Europe PMC)	0.44, 0.68, 0.85	BioGRID, IntAct
HSH2D	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
INPPL1	Affinity Capture-Western, fluorescence polarization spectroscopy	direct interaction, physical	19713535, 24728074, (Europe PMC)	0.44	BioGRID, IntAct
ITK	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
KDR	anti bait coimmunoprecipitation	physical association	22789536, (Europe PMC)	0.40	IntAct
LAMP1	pull down	association	29568061, (Europe PMC)	0.35	IntAct
LAPTM4B	anti tag coimmunoprecipitation, fluorescence microscopy	colocalization, physical association	25594178, (Europe PMC)	0.46	IntAct
LCK	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
LYN	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
MATK	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
MET	Biochemical Activity, amplified luminescent proximity homogeneous assay, cross-linking study	direct interaction, physical, physical association	16537482, 20624990, 23794705, 26285778, (Europe PMC)	0.61	BioGRID, IntAct
MUC1	anti bait coimmunoprecipitation	physical association	22962849, (Europe PMC)	0.40	IntAct
NCK1	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
NCK2	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
PASK	peptide array	phosphorylation reaction	21418524, (Europe PMC)	0.44	IntAct, MINT
PIK3R1	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
PIK3R2	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
PIK3R3	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
PKM	protein kinase assay	phosphorylation reaction	24606918, (Europe PMC)	0.44	IntAct
PLCG1	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
PLCG2	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
PLXNB1	anti bait coimmunoprecipitation, anti tag coimmunoprecipitation	phosphorylation reaction, physical association	12198496, 15184888, 22404908, (Europe PMC)	0.78	IntAct, MINT
PLXNB2	anti bait coimmunoprecipitation, anti tag coimmunoprecipitation	physical association	15184888, (Europe PMC)	0.52	IntAct
PLXNB3	anti bait coimmunoprecipitation, anti tag coimmunoprecipitation	physical association	15184888, (Europe PMC)	0.52	IntAct
PTK6	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
PTPN1	anti bait coimmunoprecipitation, cross-linking study, phosphatase assay	dephosphorylation reaction, physical association	16537444, 18579758, 22789536, (Europe PMC)	0.71	IntAct, MINT
PTPN11	anti bait coimmunoprecipitation, fluorescence polarization spectroscopy	direct interaction, physical association	18579758, 24728074, (Europe PMC)	0.61	IntAct, MINT
PTPN12	phosphatase assay	dephosphorylation reaction	19167335, (Europe PMC)	0.44	IntAct
PTPN3	phosphatase assay	dephosphorylation reaction	19167335, (Europe PMC)	0.44	IntAct
PTPRB	phosphatase assay	dephosphorylation reaction	16101282, (Europe PMC)	0.44	IntAct, MINT
PTPRC	phosphatase assay	dephosphorylation reaction	19167335, (Europe PMC)	0.44	IntAct
PTPRG	phosphatase assay	dephosphorylation reaction	19167335, (Europe PMC)	0.44	IntAct
PTPRJ	affinity chromatography technology, biochemical, coimmunoprecipitation, phosphatase assay, pull down	dephosphorylation reaction, physical association	12475979, 19167335, (Europe PMC)	0.73	IntAct, MINT
PTPRK	phosphatase assay	dephosphorylation reaction	19167335, (Europe PMC)	0.44	IntAct
PTPRO	phosphatase assay, pull down	association, dephosphorylation reaction	19167335, 28330616, (Europe PMC)	0.59	IntAct
RANBP9	Affinity Capture-Western, Reconstituted Complex, Two-hybrid, coimmunoprecipitation, pull down, two hybrid	direct interaction, physical, physical association	12147692, (Europe PMC)	0.59	BioGRID, IntAct, MINT
RASA1	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
SCRIB	phage display	physical association	24550280, (Europe PMC)	0.40	IntAct, MINT
SH2B1	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
SH2B2	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
SH2B3	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
SH2D1A	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
SH2D1B	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
SH2D2A	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
SH2D3C	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
SH3BP2	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
SHB	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
SHC1	Affinity Capture-Western, fluorescence polarization spectroscopy	direct interaction, physical	24728074, 9660480, (Europe PMC)	0.44	BioGRID, IntAct
SHC2	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
SHC3	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
SHC4	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
SHD	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
SLA2	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
SOCS1	Affinity Capture-Western, Reconstituted Complex, fluorescence polarization spectroscopy	direct interaction, physical	24728074, 25728680, (Europe PMC)	0.44	BioGRID, IntAct
SOCS2	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
SOCS3	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
SOCS5	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
SOCS6	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
SRC	Affinity Capture-Western, anti bait coimmunoprecipitation, fluorescence polarization spectroscopy	association, direct interaction, physical, physical association	20624308, 24034250, 24728074, 9837958, (Europe PMC)	0.70	BioGRID, IntAct
STAP1	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
SYK	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
TEC	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
TNS1	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
TNS2	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
TNS3	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
TNS4	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
TXK	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
VAV2	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
VAV3	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
YES1	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
YWHAZ	anti bait coimmunoprecipitation	physical association	17353931, (Europe PMC)	0.40	IntAct
ZAP70	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct

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Interacting partner	Detection method	Interaction type	PubMed IDs	Interaction Score	Source
BCAR3	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
BLK	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
BTK	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
CASP3	Co-localization, proximity ligation assay	physical, physical association	25241761, (Europe PMC)	0.40	BioGRID, IntAct
CBL	Affinity Capture-Western, Biochemical Activity, Co-crystal Structure, Co-localization, Far Western, Reconstituted Complex, anti bait coimmunoprecipitation, coimmunoprecipitation, experimental interaction detection, isothermal titration calorimetry, mass spectrometry studies of complexes, proximity ligation assay, surface plasmon resonance, x-ray crystallography	direct interaction, physical, physical association, ubiquitination reaction	11894096, 15123609, 16397241, 18273061, 19433454, 19450681, 21163258, 21222362, 25241761, (Europe PMC)	0.86	BioGRID, IntAct, MINT
CBLC	Affinity Capture-Western	physical	22888118, (Europe PMC)	NA	BioGRID
CD44	cross-linking study	physical association	22897854, (Europe PMC)	0.40	IntAct
CDH1	Affinity Capture-Western	physical	11254878, (Europe PMC)	NA	BioGRID
CEACAM21	Affinity Capture-MS	physical	26186194, 28514442, (Europe PMC)	NA	BioGRID
CHEK1	Negative Genetic	genetic	28319113, (Europe PMC)	NA	BioGRID
CRK	Affinity Capture-Western, fluorescence polarization spectroscopy	direct interaction, physical	24728074, 24828152, (Europe PMC)	0.44	BioGRID, IntAct
CTNNB1	Affinity Capture-Western	physical	11254878, (Europe PMC)	NA	BioGRID
DCN	Affinity Capture-Western, Reconstituted Complex	physical	19433454, (Europe PMC)	NA	BioGRID
DNAJA3	anti bait coimmunoprecipitation, confocal microscopy, pull down	colocalization, physical association	21242965, (Europe PMC)	0.46, 0.52	IntAct
EGFR	Affinity Capture-MS, Affinity Capture-Western, anti bait coimmunoprecipitation, protein kinase assay, tandem affinity purification	association, phosphorylation reaction, physical, physical association	20624308, 21918175, 23866081, 24189400, 24362532, 26551075, (Europe PMC)	0.80	BioGRID, IntAct
ERBB3	Affinity Capture-Western, anti bait coimmunoprecipitation	association, physical	21918175, 25326665, (Europe PMC)	0.35	BioGRID, IntAct
FBXO6	Affinity Capture-MS	physical	22268729, (Europe PMC)	NA	BioGRID
FES	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
FGR	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
GAB1	Affinity Capture-Western, anti tag coimmunoprecipitation	physical, physical association	10871282, 10913131, 9242692, (Europe PMC)	0.40	BioGRID, IntAct, MINT
GAB2	Affinity Capture-Western	physical	10871282, (Europe PMC)	NA	BioGRID
GGA3	Affinity Capture-Western, Co-localization	physical	21664574, (Europe PMC)	NA	BioGRID
GLMN	Affinity Capture-Western, Reconstituted Complex, Two-hybrid	physical	11571281, (Europe PMC)	NA	BioGRID
GNG12	Co-fractionation	physical	22939629, (Europe PMC)	NA	BioGRID
GRB14	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
GRB2	Affinity Capture-Western, Reconstituted Complex	physical	19433454, 21222362, 8662889, 9660480, (Europe PMC)	NA	BioGRID
GRB7	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
HCK	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
HGF	Affinity Capture-Western, Biochemical Activity, Reconstituted Complex, amplified luminescent proximity homogeneous assay, cross-linking study, enzyme linked immunosorbent assay, fluorescent resonance energy transfer, saturation binding, x ray scattering, x-ray crystallography	direct interaction, physical, physical association	15167892, 16537482, 1655405, 17804794, 17981115, 1846706, 19433454, 20624990, 22897854, 8380735, (Europe PMC)	0.44, 0.68, 0.85	BioGRID, IntAct
HGS	Affinity Capture-Western	physical	24828152, (Europe PMC)	NA	BioGRID
HSH2D	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
HSP90AA1	Affinity Capture-Western	physical	21325980, 26517842, (Europe PMC)	NA	BioGRID
HSP90AB1	Affinity Capture-Western	physical	26517842, (Europe PMC)	NA	BioGRID
HSPA4	Affinity Capture-Western	physical	21325980, (Europe PMC)	NA	BioGRID
INPPL1	Affinity Capture-Western, fluorescence polarization spectroscopy	direct interaction, physical	19713535, 24728074, (Europe PMC)	0.44	BioGRID, IntAct
ITK	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
KDR	anti bait coimmunoprecipitation	physical association	22789536, (Europe PMC)	0.40	IntAct
LAMP1	pull down	association	29568061, (Europe PMC)	0.35	IntAct
LAPTM4B	anti tag coimmunoprecipitation, fluorescence microscopy	colocalization, physical association	25594178, (Europe PMC)	0.46	IntAct
LCK	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
LGALS9	Affinity Capture-MS	physical	26186194, 28514442, (Europe PMC)	NA	BioGRID
LRIG1	Affinity Capture-Western, Co-localization	physical	17178829, 24828152, (Europe PMC)	NA	BioGRID
LYN	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
MATK	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
MET	Biochemical Activity, amplified luminescent proximity homogeneous assay, cross-linking study	direct interaction, physical, physical association	16537482, 20624990, 23794705, 26285778, (Europe PMC)	0.61	BioGRID, IntAct
MUC1	anti bait coimmunoprecipitation	physical association	22962849, (Europe PMC)	0.40	IntAct
NCK1	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
NCK2	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
PASK	peptide array	phosphorylation reaction	21418524, (Europe PMC)	0.44	IntAct, MINT
PCBP1	Affinity Capture-MS	physical	26186194, 28514442, (Europe PMC)	NA	BioGRID
PIK3R1	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
PIK3R2	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
PIK3R3	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
PKM	protein kinase assay	phosphorylation reaction	24606918, (Europe PMC)	0.44	IntAct
PLCG1	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
PLCG2	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
PLXNB1	anti bait coimmunoprecipitation, anti tag coimmunoprecipitation	phosphorylation reaction, physical association	12198496, 15184888, 22404908, (Europe PMC)	0.78	IntAct, MINT
PLXNB2	anti bait coimmunoprecipitation, anti tag coimmunoprecipitation	physical association	15184888, (Europe PMC)	0.52	IntAct
PLXNB3	anti bait coimmunoprecipitation, anti tag coimmunoprecipitation	physical association	15184888, (Europe PMC)	0.52	IntAct
PTEN	Positive Genetic	genetic	28319113, (Europe PMC)	NA	BioGRID
PTK6	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
PTPN1	anti bait coimmunoprecipitation, cross-linking study, phosphatase assay	dephosphorylation reaction, physical association	16537444, 18579758, 22789536, (Europe PMC)	0.71	IntAct, MINT
PTPN11	anti bait coimmunoprecipitation, fluorescence polarization spectroscopy	direct interaction, physical association	18579758, 24728074, (Europe PMC)	0.61	IntAct, MINT
PTPN12	phosphatase assay	dephosphorylation reaction	19167335, (Europe PMC)	0.44	IntAct
PTPN3	phosphatase assay	dephosphorylation reaction	19167335, (Europe PMC)	0.44	IntAct
PTPRB	phosphatase assay	dephosphorylation reaction	16101282, (Europe PMC)	0.44	IntAct, MINT
PTPRC	phosphatase assay	dephosphorylation reaction	19167335, (Europe PMC)	0.44	IntAct
PTPRG	phosphatase assay	dephosphorylation reaction	19167335, (Europe PMC)	0.44	IntAct
PTPRJ	affinity chromatography technology, biochemical, coimmunoprecipitation, phosphatase assay, pull down	dephosphorylation reaction, physical association	12475979, 19167335, (Europe PMC)	0.73	IntAct, MINT
PTPRK	phosphatase assay	dephosphorylation reaction	19167335, (Europe PMC)	0.44	IntAct
PTPRO	phosphatase assay, pull down	association, dephosphorylation reaction	19167335, 28330616, (Europe PMC)	0.59	IntAct
RANBP10	Affinity Capture-Western, Reconstituted Complex	physical	14684163, (Europe PMC)	NA	BioGRID
RANBP9	Affinity Capture-Western, Reconstituted Complex, Two-hybrid, coimmunoprecipitation, pull down, two hybrid	direct interaction, physical, physical association	12147692, (Europe PMC)	0.59	BioGRID, IntAct, MINT
RASA1	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
SCGB1D1	Affinity Capture-MS	physical	28514442, (Europe PMC)	NA	BioGRID
SCRIB	phage display	physical association	24550280, (Europe PMC)	0.40	IntAct, MINT
SH2B1	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
SH2B2	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
SH2B3	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
SH2D1A	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
SH2D1B	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
SH2D2A	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
SH2D3C	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
SH3BP2	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
SH3KBP1	Affinity Capture-Western	physical	11894096, (Europe PMC)	NA	BioGRID
SHB	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
SHC1	Affinity Capture-Western, fluorescence polarization spectroscopy	direct interaction, physical	24728074, 9660480, (Europe PMC)	0.44	BioGRID, IntAct
SHC2	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
SHC3	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
SHC4	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
SHD	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
SLA2	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
SOCS1	Affinity Capture-Western, Reconstituted Complex, fluorescence polarization spectroscopy	direct interaction, physical	24728074, 25728680, (Europe PMC)	0.44	BioGRID, IntAct
SOCS2	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
SOCS3	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
SOCS5	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
SOCS6	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
SOS1	Affinity Capture-Western	physical	9660480, (Europe PMC)	NA	BioGRID
SPSB1	Affinity Capture-Western	physical	15713673, (Europe PMC)	NA	BioGRID
SPSB2	Affinity Capture-Western	physical	15713673, (Europe PMC)	NA	BioGRID
SPSB3	Affinity Capture-Western	physical	15713673, (Europe PMC)	NA	BioGRID
SPSB4	Affinity Capture-Western	physical	15713673, (Europe PMC)	NA	BioGRID
SRC	Affinity Capture-Western, anti bait coimmunoprecipitation, fluorescence polarization spectroscopy	association, direct interaction, physical, physical association	20624308, 24034250, 24728074, 9837958, (Europe PMC)	0.70	BioGRID, IntAct
STAP1	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
STAT3	Affinity Capture-Western	physical	9440692, (Europe PMC)	NA	BioGRID
STUB1	Affinity Capture-Western	physical	21325980, (Europe PMC)	NA	BioGRID
SYK	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
TEC	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
TNS1	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
TNS2	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
TNS3	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
TNS4	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
TXK	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
VAV2	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
VAV3	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
YES1	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
YWHAZ	anti bait coimmunoprecipitation	physical association	17353931, (Europe PMC)	0.40	IntAct
ZAP70	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct

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MET