DEPOD - human DEPhOsphorylation Database

Basic Information
Phosphatases
Pathway
Interacting Proteins
Phosphorylating Kinases

Gene Name	GAB1 (QuickGO)	Interactive visualization of GAB1 structures (A quick tutorial to explore the interctive visulaization) Representative structure: 4QSY
Synonyms	GAB1
Protein Name	GAB1
Alternative Name(s)	GRB2-associated-binding protein 1;GRB2-associated binder 1;Growth factor receptor bound protein 2-associated protein 1;
Protein Family	Belongs to the GAB family
EntrezGene ID	2549 (Comparitive Toxicogenomics)
UniProt AC (Human)	Q13480 (protein sequence)
Enzyme Class	N/A
Molecular Weight	76616 Dalton
Protein Length	694 amino acids (AA)
Genome Browsers	NCBI \| ENSG00000109458 (Ensembl) \| UCSC
Crosslinking annotations	Query our ID-mapping table
Orthologues	Quest For Orthologues (QFO) \| GeneTree \| eggNOG - ENOG410IEIX \| eggNOG - ENOG4111RDE
Phosphorylation Network	Visualize

Domain organization, Expression, Diseases

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Localization, Function, Catalytic activity and Sequence

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Motif information from Eukaryotic Linear Motif atlas (ELM)

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

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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.
hsa04012	ErbB signaling pathway	The ErbB family of receptor tyrosine kinases (RTKs) couples binding of extracellular growth factor ligands to intracellular signaling pathways regulating diverse biologic responses, including proliferation, differentiation, cell motility, and survival. Ligand binding to the four closely related members of this RTK family -epidermal growth factor receptor (EGFR, also known as ErbB-1 or HER1), ErbB-2 (HER2), ErbB-3 (HER3), and ErbB-4 (HER4)-induces the formation of receptor homo- and heterodimers and the activation of the intrinsic kinase domain, resulting in phosphorylation on specific tyrosine residues (pY) within the cytoplasmic tail. Signaling effectors containing binding pockets for pY-containing peptides are recruited to activated receptors and induce the various signaling pathways. The Shc- and/or Grb2-activated mitogen-activated protein kinase (MAPK) pathway is a common target downstream of all ErbB receptors. Similarly, the phosphatidylinositol-3-kinase (PI-3K) pathway is directly or indirectly activated by most ErbBs. Several cytoplasmic docking proteins appear to be recruited by specific ErbB receptors and less exploited by others. These include the adaptors Crk, Nck, the phospholipase C gamma (PLCgamma), the intracellular tyrosine kinase Src, or the Cbl E3 ubiquitin protein ligase.
hsa04014	Ras signaling pathway	The Ras proteins are GTPases that function as molecular switches for signaling pathways regulating cell proliferation, survival, growth, migration, differentiation or cytoskeletal dynamism. Ras proteins transduce signals from extracellular growth factors by cycling between inactive GDP-bound and active GTP-bound states. The exchange of GTP for GDP on RAS is regulated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). Activated RAS (RAS-GTP) regulates multiple cellular functions through effectors including Raf, phosphatidylinositol 3-kinase (PI3K) and Ral guanine nucleotide-dissociation stimulator (RALGDS).
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.
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.
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.
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.
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.

Pathway ID	Pathway Name	Pathway Description (KEGG)
R-HSA-109704	PI3K Cascade.	The PI3K (Phosphatidlyinositol-3-kinase) - AKT signaling pathway stimulates cell growth and survival
R-HSA-1236382	Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants.	Signaling by EGFR is frequently activated in cancer through activating mutations in the coding sequence of the EGFR gene, resulting in expression of a constitutively active mutant protein. Epidermal growth factor receptor kinase domain mutants are present in ~16% of non-small-cell lung cancers (NSCLCs), but are also found in other cancer types, such as breast cancer, colorectal cancer, ovarian cancer and thyroid cancer. EGFR kinase domain mutants harbor activating mutations in exons 18-21 which code for the kinase domain (amino acids 712-979) . Small deletions, insertions or substitutions of amino acids within the kinase domain lock EGFR in its active conformation in which the enzyme can dimerize and undergo autophosphorylation spontaneously, without ligand binding (although ligand binding ability is preserved), and activate downstream signaling pathways that promote cell survival (Greulich et al. 2005, Zhang et al. 2006, Yun et al. 2007, Red Brewer et al. 2009). Point mutations in the extracellular domain of EGFR are frequently found in glioblastoma. Similar to kinase domain mutations, point mutations in the extracellular domain result in constitutively active EGFR proteins that signal in the absence of ligands, but ligand binding ability and responsiveness are preserved (Lee et al. 2006). EGFR kinase domain mutants need to maintain association with the chaperone heat shock protein 90 (HSP90) for proper functioning (Shimamura et al. 2005, Lavictoire et al. 2003). CDC37 is a co-chaperone of HSP90 that acts as a scaffold and regulator of interaction between HSP90 and its protein kinase clients. CDC37 is frequently over-expressed in cancers involving mutant kinases and acts as an oncogene (Roe et al. 2004, reviewed by Gray Jr. et al. 2008). Over-expression of the wild-type EGFR or EGFR cancer mutants results in aberrant activation of downstream signaling cascades, namely RAS/RAF/MAP kinase signaling and PI3K/AKT signaling, and possibly signaling by PLCG1, which leads to increased cell proliferation and survival, providing selective advantage to cancer cells that harbor activating mutations in the EGFR gene (Sordella et al. 2004, Huang et al. 2007). While growth factor activated wild-type EGFR is promptly down-regulated by internalization and degradation, cancer mutants of EGFR demonstrate prolonged activation (Lynch et al. 2004). Association of HSP90 with EGFR kinase domain mutants negatively affects CBL-mediated ubiquitination, possibly through decreasing the affinity of EGFR kinase domain mutants for phosphorylated CBL, so that CBL dissociates from the complex upon phosphorylation and cannot perform ubiquitination (Yang et al. 2006, Padron et al. 2007). Various molecular therapeutics are being developed to target aberrantly activated EGFR in cancer. Non-covalent (reversible) small tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, selectively bind kinase domain of EGFR, competitively inhibiting ATP binding and subsequent autophosphorylation of EGFR dimers. EGFR kinase domain mutants sensitive to non-covalent TKIs exhibit greater affinity for TKIs than ATP compared with the wild-type EGFR protein, and are therefore preferential targets of non-covalent TKI therapeutics (Yun et al. 2007). EGFR proteins that harbor point mutations in the extracellular domain also show sensitivity to non-covalent tyrosine kinase inhibitors (Lee et al. 2006). EGFR kinase domain mutants harboring small insertions in exon 20 or a secondary T790M mutation are resistant to reversible TKIs (Balak et al. 2006) due to increased affinity for ATP (Yun et al. 2008), and are targets of covalent (irreversible) TKIs that form a covalent bond with EGFR cysteine residue C397. However, effective concentrations of covalent TKIs also inhibit wild-type EGFR, causing severe side effects (Zhou et al. 2009). Hence, covalent TKIs have not shown much promise in clinical trials (Reviewed by Pao and Chmielecki in 2010)
R-HSA-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-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-1963642	PI3K events in ERBB2 signaling.	ERBB2:ERBB3 and ERBB2:ERBB4cyt1 heterodimers activate PI3K signaling by direct binding of PI3K regulatory subunit p85 (Yang et al. 2007, Cohen et al. 1996, Kaushansky et al. 2008) to phosphorylated tyrosine residues in the C-tail of ERBB3 (Y1054, Y1197, Y1222, Y1224, Y1276 and Y1289) and ERBB4 CYT1 isoforms (Y1056 in JM-A CYT1 isoform and Y1046 in JM-B CYT1 isoform). Regulatory subunit p85 subsequently recruits catalytic subunit p110 of PI3K, resulting in the formation of active PI3K, conversion of PIP2 to PIP3, and PIP3-mediated activation of AKT signaling (Junttila et al. 2009, Kainulainen et al. 2000). Heterodimers of ERBB2 and EGFR recruit PI3K indirectly, through GRB2:GAB1 complex (Jackson et al. 2004), which again leads to PIP3-mediated activation of AKT signaling
R-HSA-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-5637810	Constitutive Signaling by EGFRvIII.	In glioblastoma, the most prevalent EGFR mutation, present in ~25% of tumors, is the deletion of the ligand binding domain of EGFR, accompanied with amplification of the mutated allele, which results in over-expression of the mutant protein known as EGFRvIII. EGFRvIII mutant is not able to bind a ligand, but dimerizes and autophosphorylates spontaneously and is therefore constitutively active (Fernandes et al. 2001). Point mutations in the extracellular domain of EGFR are also frequently found in glioblastoma, but ligand binding ability and responsiveness are preserved (Lee et al. 2006). Similar to EGFR kinase domain mutants, EGFRvIII mutant needs to maintain association with the chaperone heat shock protein 90 (HSP90) for proper functioning (Shimamura et al. 2005, Lavictoire et al. 2003). CDC37 is a co-chaperone of HSP90 that acts as a scaffold and regulator of interaction between HSP90 and its protein kinase clients. CDC37 is frequently over-expressed in cancers involving mutant kinases and acts as an oncogene (Roe et al. 2004, reviewed by Gray Jr. et al. 2008). Expression of EGFRvIII mutant results in aberrant activation of downstream signaling cascades, namely RAS/RAF/MAP kinase signaling and PI3K/AKT signaling, and possibly signaling by PLCG1, which leads to increased cell proliferation and survival, providing selective advantage to cancer cells that harbor EGFRvIII (Huang et al. 2007). EGFRvIII mutant does not autophosorylate on the tyrosine residue Y1045, a docking site for CBL, and is therefore unable to recruit CBL ubiquitin ligase, which enables it to escape degradation (Han et al
R-HSA-5654689	PI-3K cascade:FGFR1.	The ability of growth factors to protect from apoptosis is primarily due to the activation of the AKT survival pathway. P-I-3-kinase dependent activation of PDK leads to the activation of AKT which in turn affects the activity or expression of pro-apoptotic factors, which contribute to protection from apoptosis. AKT activation also blocks the activity of GSK-3b which could lead to additional antiapoptotic signals
R-HSA-5654695	PI-3K cascade:FGFR2.	The ability of growth factors to protect from apoptosis is primarily due to the activation of the AKT survival pathway. P-I-3-kinase dependent activation of PDK leads to the activation of AKT which in turn affects the activity or expression of pro-apoptotic factors, which contribute to protection from apoptosis. AKT activation also blocks the activity of GSK-3b which could lead to additional antiapoptotic signals
R-HSA-5654710	PI-3K cascade:FGFR3.	The ability of growth factors to protect from apoptosis is primarily due to the activation of the AKT survival pathway. P-I-3-kinase dependent activation of PDK leads to the activation of AKT which in turn affects the activity or expression of pro-apoptotic factors, which contribute to protection from apoptosis. AKT activation also blocks the activity of GSK-3b which could lead to additional antiapoptotic signals
R-HSA-5654720	PI-3K cascade:FGFR4.	The ability of growth factors to protect from apoptosis is primarily due to the activation of the AKT survival pathway. P-I-3-kinase dependent activation of PDK leads to the activation of AKT which in turn affects the activity or expression of pro-apoptotic factors, which contribute to protection from apoptosis. AKT activation also blocks the activity of GSK-3b which could lead to additional antiapoptotic signals
R-HSA-5655253	Signaling by FGFR2 in disease.	The FGFR2 gene has been shown to be subject to activating mutations and gene amplification leading to a variety of proliferative and developmental disorders depending on whether these events occur in the germline or arise somatically. Activating FGFR2 mutations in the germline give rise to a range of craniosynostotic conditions including Pfeiffer, Apert, Jackson-Weiss, Crouzon and Beare-Stevensen Cutis Gyrata syndromes. These autosomal dominant skeletal disorders are characterized by premature fusion of several sutures in the skull, and in some cases also involve syndactyly (abnormal bone fusions in the hands and feet) (reviewed in Webster and Donoghue, 1997; Burke, 1998; Cunningham, 2007). Activating FGFR2 mutations arising somatically have been linked to the development of gastric and endometrial cancers (reviewed in Greulich and Pollock, 2011; Wesche, 2011). Many of these mutations are similar or identical to those that contribute to the autosomal disorders described above. Notably, loss-of-function mutations in FGFR2 have also been recently described in melanoma (Gartside, 2009). FGFR2 may also contribute to tumorigenesis through overexpression, as FGFR2 has been identified as a target of gene amplification in gastric and breast cancers (Kunii, 2008; Takeda, 2007)
R-HSA-5655291	Signaling by FGFR4 in disease.	FGFR4 is perhaps the least well studied of the FGF receptors, and unlike the case for the other FGFR genes, mutations in FGFR4 are not known to be associated with any developmental disorders. Recently, however, somatically arising mutations in the FGFR4 coding sequence have begun to be identified in some cancers. 8% of rhabdomyosarcomas have activating mutations in the kinase domain of FGFR4. Two of these mutations - N535K (paralogous to the FGFR2 N550K allele found in endometrial cancers) and V550E - have been shown to support the oncogenic transformation of NIH 3T3 cells (Taylor, 2009). An FGFR4 Y367C mutation has also been identified in breast cancers (Ruhe, 2007; Roidl, 2010); mutations of paralogous residues in FGFR2 and FGFR3 are associated with both skeletal dysplasias and the development of diverse cancers (Pollock, 2007; Ruhe, 2007; Rousseau, 1996; Chesi, 1997, 2001).Finally, a SNP at position 388 of FGFR4 is associated with aggressive disease development. Expression of the G388R allele in breast, colorectal and prostate cancers is correlated with rapid progression times and increased rates of recurrence and metastasis (Bange, 2002; Spinola, 2005; Wang, 2004)
R-HSA-5655302	Signaling by FGFR1 in disease.	The FGFR1 gene has been shown to be subject to activating mutations, chromosomal rearrangements and gene amplification leading to a variety of proliferative and developmental disorders depending on whether these events occur in the germline or arise somatically (reviewed in Webster and Donoghue, 1997; Burke, 1998; Cunningham, 2007; Wesche, 2011; Greulich and Pollock, 2011). Activating mutation P252R in FGFR1 is associated with the development of Pfeiffer syndrome, characterized by craniosynostosis (premature fusion of several sutures in the skull) and broadened thumbs and toes (Muenke, 1994; reviewed in Cunningham, 2007). This residue falls in a highly conserved Pro-Ser dipeptide between the second and third Ig domains of the extracellular region of the receptor. The mutation is thought to increase the number of hydrogen bonds formed with the ligand and to thereby increase ligand-binding affinity (Ibrahimi, 2004a). Unlike other FGF receptors, few activating point mutations in the FGFR1 coding sequence have been identified in cancer. Point mutations in the Ig II-III linker analagous to the P252R Pfeiffer syndrome mutation have been identified in lung cancer and melanoma (Ruhe, 2007; Davies, 2005), and two kinase-domain mutations in FGFR1 have been identified in glioblastoma (Rand, 2005, Network TCGA, 2008).In contrast, FGFR1 is a target of chromosomal rearrangements in a number of cancers. FGFR1 has been shown to be recurrently translocated in the 8p11 myeloproliferative syndrome (EMS), a pre-leukemic condition also known as stem cell leukemia/lymphoma (SCLL) that rapidly progresses to leukemia. This translocation fuses the kinase domain of FGFR1 with the dimerization domain of one of 10 identified fusion partners, resulting in the constitutive dimerization and activation of the kinase (reviewed in Jackson, 2010). Amplification of the FGFR1 gene has been implicated as a oncogenic factor in a range of cancers, including breast, ovarian, bladder, lung, oral squamous carcinomas, and rhabdomyosarcoma (reviewed in Turner and Grose, 2010; Wesche, 2011; Greulich and Pollock, 2011), although there are other candidate genes in the amplified region and the definitive role of FGFR1 has not been fully established.More recently, FGFR1 fusion proteins have been identified in a number of cancers; these are thought to undergo constitutive ligand-independent dimerization and activation based on dimerization motifs found in the fusion partners (reviewed in Parker, 2014)
R-HSA-6811558	PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling.	Phosphatidylinositol-5-phosphate (PI5P) may modulate PI3K/AKT signaling in several ways. PI5P is used as a substrate for production of phosphatidylinositol-4,5-bisphosphate, PI(4,5)P2 (Rameh et al. 1997, Clarke et al. 2008, Clarke et al. 2010, Clarke and Irvine 2013, Clarke et al. 2015), which serves as a substrate for activated PI3K, resulting in the production of PIP3 (Mandelker et al. 2009, Burke et al. 2011). The majority of PI(4,5)P2 in the cell, however, is produced from the phosphatidylinositol-4-phosphate (PI4P) substrate (Zhang et al. 1997, Di Paolo et al. 2002, Oude Weernink et al. 2004, Halstead et al. 2006, Oude Weernink et al. 2007). PIP3 is necessary for the activating phosphorylation of AKT. AKT1 can be deactivated by the protein phosphatase 2A (PP2A) complex that contains a regulatory subunit B56-beta (PPP2R5B) or B56-gamma (PPP2R5C). PI5P inhibits AKT1 dephosphorylation by PP2A through an unknown mechanism (Ramel et al. 2009). Increased PI5P levels correlate with inhibitory phosphorylation(s) of the PP2A complex. MAPK1 (ERK2) and MAPK3 (ERK1) are involved in inhibitory phosphorylation of PP2A, in a process that involves IER3 (IEX-1) (Letourneux et al. 2006, Rocher et al. 2007). It is uncertain, however, whether PI5P is in any way involved in ERK-mediated phosphorylation of PP2A or if it regulates another PP2A kinase
R-HSA-8851907	MET activates PI3K/AKT signaling.	MET binds and phosphorylates the adapter protein GAB1, thus creating a docking site for the regulatory subunit PIK3R1 of the PI3K complex. Recruitment of PI3K to MET-bound phosphorylated GAB1 results in PI3K activation, production of PIP3, and stimulation of downstream AKT signaling (Rodrigues et al. 2000, Schaeper et al. 2000)
R-HSA-8853334	Signaling by FGFR3 fusions in cancer.	In recent years, recurrent fusions of FGFR3 have been identified in a number of cancers, including glioblastoma and cancers of the lung and bladder, among others (Singh et al, 2012; Parker et al, 2013; Williams et al, 2013; Wu et al, 2013; Capelletti et al, 2014; Yuan et al, 2014; Wang et al, 2014; Carneiro et al, 2015; reviewed in Parker et al, 2014). The most common fusion partner of FGFR3 is TACC3 (transforming acidic coiled coil protein 3), a protein involved in mitotic spindle assembly and chromosome segregation (Lin et al, 2010; Burgess et al, 2015). FGFR3 fusions are constitutively active and may form oligomers in a ligand-independent manner based on dimerization domains provided by the fusion partner (Singh et al, 2012; Williams et al, 2013; Parker et al, 2013; reviewed in Parker et al, 2014). Transformation and proliferation appear to be promoted through activation of the ERK and AKT signaling pathways. In contrast, PLC gamma signaling is not stimulated downstream of FGFR3 fusions, as the PLC gamma docking site is not present in the fusion. FGFR3 fusions are sensitive to protein kinase inhibitors, suggesting their potential as therapeutic targets (Singh et al, 2012; Williams et al, 2013; Wu et al, 2013; reviewed in Parker et al, 2014)
R-HSA-8853338	Signaling by FGFR3 point mutants in cancer.	The FGFR3 gene has been shown to be subject to activating mutations and gene amplification leading to a variety of proliferative and developmental disorders depending on whether these events occur in the germline or arise somatically. Activating mutations in FGFR3 are associated with the development of a range of skeletal dysplasias that result in dwarfism (reviewed in Webster and Donoghue, 1997; Burke et al, 1998; Harada et al, 2009). The most common form of human dwarfism is achondroplasia (ACH), which is caused by mutations G380R and G375C in the transmembrane domain of FGFR3 that are thought to promote ligand-independent dimerization (Rousseau et al, 1994; Shiang et al, 1994; Bellus et al, 1995a) Hypochondroplasia (HCH) is a milder form dwarfism that is the result of mutations in the tyrosine kinase domain of FGFR3 (Bellus et al, 1995b). Two neonatal lethal conditions, thanatophoric dysplasia type I and II (TDI and TDII) are also the result of mutations in FGFR3; TDI arises from a range of mutations that either result in the formation of unpaired cysteine residues in the extracellular region that promote aberrant ligand-independent dimerization or by mutations that introduce stop codons (Rousseau et al, 1995; Rousseau et al, 1996, D'Avis et al,1998). A single mutation, K650E in the second tyrosine kinase domain of FGFR3 is responsible for all identified cases of TDII (Tavormina et al, 1995a, b). Other missense mutations at the same K650 residue give rise to Severe Achondroplasia with Developmental Disorders and Acanthosis Nigricans (SADDAN) syndrome (Tavormina et al, 1999; Bellus et al, 1999). The severity of the phenotype arising from many of the activating FGFR3 mutations has recently been shown to correlate with the extent to which the mutations activate the receptor (Naski et al, 1996; Bellus et al, 2000) In addition to mutations that cause dwarfism syndromes, a Pro250Arg mutation in the conserved dipeptide between the IgII and IgIII domains has been identified in an atypical craniosynostosis condition (Bellus et al, 1996; Reardon et al, 1997). This mutation, which is paralogous to mutations seen in FGFR1 and 2 in Pfeiffer and Apert Syndrome, respectively, results in an increase in ligand-binding affinity for the receptor (Ibrahimi et al, 2004b).Of all the FGF receptors, FGFR3 has perhaps the best established link to the development in cancer. 50% of bladder cancers have somatic mutations in the coding sequence of FGFR3; of these, more than half occur in the extracellular region at a single position (S249C) (Cappellen et al, 1999; Naski et al, 1996; di Martino et al, 2009, Sibley et al, 2001). Activating mutations are also seen in the juxta- and trans-membrane domains, as well as in the kinase domain (reviewed in Weshe et al, 2011). As is the case for the other receptors, many of the activating mutations that are seen in FGFR3-related cancers mimic the germline FGFR3 mutations that give rise to autosomal skeletal disorders and include both ligand-dependent and independent mechanisms (reviewed in Webster and Donoghue, 1997; Burke et al, 1998). In addition to activating mutations, the FGFR3 gene is subject to a translocation event in 15% of multiple myelomas (Avet-Loiseau et al, 1998; Chesi et al, 1997). This chromosomal rearrangement puts the FGFR3 gene under the control of the highly active IGH promoter and promotes overexpression and constitutive activation of FGFR3. In a small proportion of multiple myelomas, the translocation event is accompanied by activating mutations in the FGFR3 coding sequence (Chesi et al, 1997).More recently, a number of fusion proteins of FGFR3 have been identified in various cancers (Singh et al, 2012; Williams et al, 2013; Parker et al, 2013; Wu et al, 2013; Wang et al, 2014; Yuan et al, 2014; reviewed in Parker et al, 2014). The most common fusion protein is TACC3, a coiled coil protein involved in mitotic spindle assembly. FGFR3 fusion proteins are constitutively active and appear to contribute to proliferation and tumorigenesis through activation of the ERK and AKT signaling pathways (reviewed in Parker et al, 2014)
R-HSA-8853659	RET signaling.	The RET proto-oncogene encodes a receptor tyrosine kinase expressed primarily in urogenital precursor cells, spermatogonocytes, dopaminergic neurons, motor neurons and neural crest progenitors and derived cells. It is essential for kidney genesis, spermatogonial self-renewal and survivial, specification, migration, axonal growth and axon guidance of developing enteric neurons, motor neurons, parasympathetic neurons and somatosensory neurons (Schuchardt et al. 1994, Enomoto et al. 2001, Naughton et al. 2006, Kramer et al. 2006, Luo et al. 2006, 2009). RET was identified as the causative gene for human papillary thyroid carcinoma (Grieco et al. 1990), multiple endocrine neoplasia (MEN) type 2A (Mulligan et al. 1993), type 2B (Hofstra et al. 1994, Carlson et al. 1994), and Hirschsprung's disease (Romeo et al. 1994, Edery et al. 1994). RET contains a cadherin-related motif and a cysteine-rich domain in the extracellular domain (Takahashi et al. 1988). It is the receptor for members of the glial cell-derived neurotrophic factor (GDNF) family of ligands, GDNF (Lin et al. 1993), neurturin (NRTN) (Kotzbauer et al. 1996), artemin (ARTN) (Baloh et al. 1998), and persephin (PSPN) (Milbrandt et al. 1998), which form a family of neurotrophic factors. To stimulate RET, these ligands need a glycosylphosphatidylinositol (GPI)-anchored co-receptor, collectively termed GDNF family receptor-alpha (GFRA) (Treanor et al. 1996, Jing et al. 1996). The four members of this family have different, overlapping ligand preferences. GFRA1, GFRA2, GFRA3, and GFRA4 preferentially bind GDNF, NRTN, ARTN and PSPN, respectively (Jing et al. 1996, 1997, Creedon et al. 1997, Baloh et al. 1997, 1998, Masure et al. 2000). The GFRA co-receptor can come from the same cell as RET, or from a different cell. When the co-receptor is produced by the same cell as RET, it is termed cis signaling. When the co-receptor is produced by another cell, it is termed trans signaling. Cis and trans activation has been proposed to diversify RET signaling, either by recruiting different downstream effectors or by changing the kinetics or efficacy of kinase activation (Tansey et al. 2000, Paratcha et al. 2001). Whether cis and trans signaling has significant differences in vivo is unresolved (Fleming et al. 2015). Different GDNF family members could activate similar downstream signaling pathways since all GFRAs bind to and activate the same tyrosine kinase and induce coordinated phosphorylation of the same four RET tyrosines (Tyr905, Tyr1015, Tyr1062, and Tyr1096) with similar kinetics (Coulpier et al. 2002). However the exact RET signaling pathways in different types of cells and neurons remain to be determined
R-HSA-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-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-9028335	Activated NTRK2 signals through PI3K.	Neurotrophin receptor NTRK2 (TRKB), activated by BDNF or NTF4, activates PI3K, resulting in formation of the PIP3 secondary messenger. PIP3 activates AKT signaling, and AKT signaling activates mTOR signaling (Yuen and Mobley 1999, Cao et al. 2013)

BioGRID
IntAct
MINT
ALL

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Interacting partner	Detection method	Interaction type	PubMed IDs	Interaction Score	Source
ARL4C	Affinity Capture-MS	physical	28514442, (Europe PMC)	NA	BioGRID
BAG3	Affinity Capture-Luminescence	physical	23824909, (Europe PMC)	NA	BioGRID
C1QBP	Affinity Capture-Western	physical	10747014, (Europe PMC)	NA	BioGRID
CASP1	Affinity Capture-MS	physical	26186194, 28514442, (Europe PMC)	NA	BioGRID
CDH1	Proximity Label-MS	physical	25468996, (Europe PMC)	NA	BioGRID
CRK	Affinity Capture-MS, fluorescence polarization spectroscopy	direct interaction, physical	19380743, 24728074, (Europe PMC)	0.44	BioGRID, IntAct
CRKL	Affinity Capture-Western, Co-localization, fluorescence polarization spectroscopy, proximity ligation assay	direct interaction, physical, physical association	10753869, 23397142, 24728074, 25241761, (Europe PMC)	0.71	BioGRID, IntAct
DYNLT1	Proximity Label-MS	physical	26638075, (Europe PMC)	NA	BioGRID
EGFR	Affinity Capture-MS, Affinity Capture-Western, Biochemical Activity, PCA, Two-hybrid, anti bait coimmunoprecipitation, ubiquitin reconstruction	association, physical, physical association	11432805, 18271526, 21278788, 23066441, 24658140, 25402006, 9890893, (Europe PMC)	0.55	BioGRID, IntAct
ERBB2	Biochemical Activity	physical	23612964, (Europe PMC)	NA	BioGRID
FRS2	Affinity Capture-Western	physical	25159185, (Europe PMC)	NA	BioGRID
GAB2	Two-hybrid	physical	14982882, (Europe PMC)	NA	BioGRID
GRAP2	Affinity Capture-MS, Protein-peptide, Two-hybrid, fluorescence polarization spectroscopy, pull down	direct interaction, physical, physical association	10913131, 12176364, 24728074, 26186194, 28514442, 9878555, (Europe PMC)	0.61	BioGRID, IntAct, MINT
GRB2	Affinity Capture-MS, Affinity Capture-Western, Far Western, Reconstituted Complex, Two-hybrid, anti tag coimmunoprecipitation, far western blotting, isothermal titration calorimetry, pull down, tandem affinity purification, two hybrid pooling approach	association, direct interaction, physical, physical association	10913131, 11314042, 11960376, 19380743, 20473329, 20936779, 21706016, 22536782, 28514442, 8596638, 9242692, 9804835, 9890893, (Europe PMC)	0.35, 0.82	BioGRID, IntAct, MINT
GTF2A1L	Two-hybrid	physical	25416956, (Europe PMC)	NA	BioGRID
LGALS7	Affinity Capture-MS	physical	28514442, (Europe PMC)	NA	BioGRID
MAP3K3	Affinity Capture-Western, Reconstituted Complex	physical	12065326, (Europe PMC)	NA	BioGRID
MARK2	Affinity Capture-Western, Reconstituted Complex	physical	22883624, (Europe PMC)	NA	BioGRID
MET	Affinity Capture-Western, anti tag coimmunoprecipitation	physical, physical association	10871282, 10913131, 9242692, (Europe PMC)	0.40	BioGRID, IntAct, MINT
MST1R	Affinity Capture-Western, Two-hybrid	physical	14982882, (Europe PMC)	NA	BioGRID
NTRK1	Affinity Capture-MS	physical	25921289, (Europe PMC)	NA	BioGRID
PARD3	Affinity Capture-Western	physical	22883624, (Europe PMC)	NA	BioGRID
PIK3R1	Affinity Capture-Western, Far Western, Reconstituted Complex, Two-hybrid, coimmunoprecipitation, fluorescence polarization spectroscopy, pull down, two hybrid	association, direct interaction, physical, physical association	10978177, 16638574, 23612964, 24728074, 8596638, 9658397, 9804835, 9891995, (Europe PMC)	0.80	BioGRID, IntAct, MINT
PLCG1	Affinity Capture-Western, Far Western, fluorescence polarization spectroscopy	direct interaction, physical	11507676, 24728074, 8596638, (Europe PMC)	0.44	BioGRID, IntAct
PRKCI	Affinity Capture-Western	physical	22883624, (Europe PMC)	NA	BioGRID
PTPN11	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
PTPRA	Proximity Label-MS	physical	27880917, (Europe PMC)	NA	BioGRID
ROCK1	Co-crystal Structure	physical	12748184, (Europe PMC)	NA	BioGRID
SHC1	Affinity Capture-Western, Far Western, fluorescence polarization spectroscopy	direct interaction, physical	14982882, 24728074, 9804835, (Europe PMC)	0.44	BioGRID, IntAct
SYP	Reconstituted Complex	physical	9890893, (Europe PMC)	NA	BioGRID
TRIM15	PCA	physical	25450970, (Europe PMC)	NA	BioGRID
TUFM	Affinity Capture-MS	physical	28514442, (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
BLNK	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
BTK	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
CRK	Affinity Capture-MS, fluorescence polarization spectroscopy	direct interaction, physical	19380743, 24728074, (Europe PMC)	0.44	BioGRID, IntAct
CRKL	Affinity Capture-Western, Co-localization, fluorescence polarization spectroscopy, proximity ligation assay	direct interaction, physical, physical association	10753869, 23397142, 24728074, 25241761, (Europe PMC)	0.71	BioGRID, IntAct
EGFR	Affinity Capture-MS, Affinity Capture-Western, Biochemical Activity, PCA, Two-hybrid, anti bait coimmunoprecipitation, ubiquitin reconstruction	association, physical, physical association	11432805, 18271526, 21278788, 23066441, 24658140, 25402006, 9890893, (Europe PMC)	0.55	BioGRID, IntAct
EZR	proximity-dependent biotin identification	association	29568061, (Europe PMC)	0.35	IntAct
FES	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
GRAP2	Affinity Capture-MS, Protein-peptide, Two-hybrid, fluorescence polarization spectroscopy, pull down	direct interaction, physical, physical association	10913131, 12176364, 24728074, 26186194, 28514442, 9878555, (Europe PMC)	0.61	BioGRID, IntAct, MINT
GRB2	Affinity Capture-MS, Affinity Capture-Western, Far Western, Reconstituted Complex, Two-hybrid, anti tag coimmunoprecipitation, far western blotting, isothermal titration calorimetry, pull down, tandem affinity purification, two hybrid pooling approach	association, direct interaction, physical, physical association	10913131, 11314042, 11960376, 19380743, 20473329, 20936779, 21706016, 22536782, 28514442, 8596638, 9242692, 9804835, 9890893, (Europe PMC)	0.35, 0.82	BioGRID, IntAct, MINT
HCK	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
HSH2D	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
INPPL1	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
ITK	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	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
MET	Affinity Capture-Western, anti tag coimmunoprecipitation	physical, physical association	10871282, 10913131, 9242692, (Europe PMC)	0.40	BioGRID, IntAct, MINT
NCK1	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
NCK2	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
PIK3R1	Affinity Capture-Western, Far Western, Reconstituted Complex, Two-hybrid, coimmunoprecipitation, fluorescence polarization spectroscopy, pull down, two hybrid	association, direct interaction, physical, physical association	10978177, 16638574, 23612964, 24728074, 8596638, 9658397, 9804835, 9891995, (Europe PMC)	0.80	BioGRID, IntAct, MINT
PIK3R2	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
PIK3R3	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
PLCG1	Affinity Capture-Western, Far Western, fluorescence polarization spectroscopy	direct interaction, physical	11507676, 24728074, 8596638, (Europe PMC)	0.44	BioGRID, IntAct
PLCG2	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
PTK6	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
PTPN11	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
PTPN12	phosphatase assay	dephosphorylation reaction	19167335, (Europe PMC)	0.44	IntAct
PTPN9	phosphatase assay	dephosphorylation reaction	19167335, (Europe PMC)	0.44	IntAct
PTPRB	phosphatase assay	dephosphorylation reaction	19167335, (Europe PMC)	0.44	IntAct
PTPRC	phosphatase assay	dephosphorylation reaction	19167335, (Europe PMC)	0.44	IntAct
PTPRG	phosphatase assay	dephosphorylation reaction	19167335, (Europe PMC)	0.44	IntAct
PTPRJ	phosphatase assay, pull down	dephosphorylation reaction, physical association	12475979, 19167335, (Europe PMC)	0.61	IntAct, MINT
PTPRO	phosphatase assay	dephosphorylation reaction	19167335, (Europe PMC)	0.44	IntAct
PXN	anti bait coimmunoprecipitation, anti tag coimmunoprecipitation	association, physical association	14665621, (Europe PMC)	0.50	IntAct, MINT
RASA1	coimmunoprecipitation, fluorescence polarization spectroscopy	association, direct interaction	15574420, 24728074, (Europe PMC)	0.59	IntAct, MINT
RET	anti bait coimmunoprecipitation	association	19914172, (Europe PMC)	0.35	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
SH2D3A	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
SHC1	Affinity Capture-Western, Far Western, fluorescence polarization spectroscopy	direct interaction, physical	14982882, 24728074, 9804835, (Europe PMC)	0.44	BioGRID, IntAct
SHC3	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
SLA	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
SLA2	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
SOCS3	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
SOCS6	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
SOS1	proximity ligation assay	physical association	23397142, (Europe PMC)	0.40	IntAct
SRC	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
STAP1	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
STON1	two hybrid array, two hybrid prey pooling approach, validated two hybrid	physical association	25416956, (Europe PMC)	0.56	IntAct
SUPT6H	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
SYK	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
TCTE1	proximity-dependent biotin identification	association	26638075, (Europe PMC)	0.35	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
TNS3	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
TNS4	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
VAV1	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

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Interacting partner	Detection method	Interaction type	PubMed IDs	Interaction Score	Source
GRAP2	Affinity Capture-MS, Protein-peptide, Two-hybrid, fluorescence polarization spectroscopy, pull down	direct interaction, physical, physical association	10913131, 12176364, 24728074, 26186194, 28514442, 9878555, (Europe PMC)	0.61	BioGRID, IntAct, MINT
GRB2	Affinity Capture-MS, Affinity Capture-Western, Far Western, Reconstituted Complex, Two-hybrid, anti tag coimmunoprecipitation, far western blotting, isothermal titration calorimetry, pull down, tandem affinity purification, two hybrid pooling approach	association, direct interaction, physical, physical association	10913131, 11314042, 11960376, 19380743, 20473329, 20936779, 21706016, 22536782, 28514442, 8596638, 9242692, 9804835, 9890893, (Europe PMC)	0.35, 0.82	BioGRID, IntAct, MINT
MET	Affinity Capture-Western, anti tag coimmunoprecipitation	physical, physical association	10871282, 10913131, 9242692, (Europe PMC)	0.40	BioGRID, IntAct, MINT
PIK3R1	Affinity Capture-Western, Far Western, Reconstituted Complex, Two-hybrid, coimmunoprecipitation, fluorescence polarization spectroscopy, pull down, two hybrid	association, direct interaction, physical, physical association	10978177, 16638574, 23612964, 24728074, 8596638, 9658397, 9804835, 9891995, (Europe PMC)	0.80	BioGRID, IntAct, MINT
PTPN11	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
PTPRJ	phosphatase assay, pull down	dephosphorylation reaction, physical association	12475979, 19167335, (Europe PMC)	0.61	IntAct, MINT
PXN	anti bait coimmunoprecipitation, anti tag coimmunoprecipitation	association, physical association	14665621, (Europe PMC)	0.50	IntAct, MINT
RASA1	coimmunoprecipitation, fluorescence polarization spectroscopy	association, direct interaction	15574420, 24728074, (Europe PMC)	0.59	IntAct, MINT

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Interacting partner	Detection method	Interaction type	PubMed IDs	Interaction Score	Source
ARL4C	Affinity Capture-MS	physical	28514442, (Europe PMC)	NA	BioGRID
BAG3	Affinity Capture-Luminescence	physical	23824909, (Europe PMC)	NA	BioGRID
BCAR3	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
BLK	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
BLNK	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
BTK	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
C1QBP	Affinity Capture-Western	physical	10747014, (Europe PMC)	NA	BioGRID
CASP1	Affinity Capture-MS	physical	26186194, 28514442, (Europe PMC)	NA	BioGRID
CDH1	Proximity Label-MS	physical	25468996, (Europe PMC)	NA	BioGRID
CRK	Affinity Capture-MS, fluorescence polarization spectroscopy	direct interaction, physical	19380743, 24728074, (Europe PMC)	0.44	BioGRID, IntAct
CRKL	Affinity Capture-Western, Co-localization, fluorescence polarization spectroscopy, proximity ligation assay	direct interaction, physical, physical association	10753869, 23397142, 24728074, 25241761, (Europe PMC)	0.71	BioGRID, IntAct
DYNLT1	Proximity Label-MS	physical	26638075, (Europe PMC)	NA	BioGRID
EGFR	Affinity Capture-MS, Affinity Capture-Western, Biochemical Activity, PCA, Two-hybrid, anti bait coimmunoprecipitation, ubiquitin reconstruction	association, physical, physical association	11432805, 18271526, 21278788, 23066441, 24658140, 25402006, 9890893, (Europe PMC)	0.55	BioGRID, IntAct
ERBB2	Biochemical Activity	physical	23612964, (Europe PMC)	NA	BioGRID
EZR	proximity-dependent biotin identification	association	29568061, (Europe PMC)	0.35	IntAct
FES	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
FRS2	Affinity Capture-Western	physical	25159185, (Europe PMC)	NA	BioGRID
GAB2	Two-hybrid	physical	14982882, (Europe PMC)	NA	BioGRID
GRAP2	Affinity Capture-MS, Protein-peptide, Two-hybrid, fluorescence polarization spectroscopy, pull down	direct interaction, physical, physical association	10913131, 12176364, 24728074, 26186194, 28514442, 9878555, (Europe PMC)	0.61	BioGRID, IntAct, MINT
GRB2	Affinity Capture-MS, Affinity Capture-Western, Far Western, Reconstituted Complex, Two-hybrid, anti tag coimmunoprecipitation, far western blotting, isothermal titration calorimetry, pull down, tandem affinity purification, two hybrid pooling approach	association, direct interaction, physical, physical association	10913131, 11314042, 11960376, 19380743, 20473329, 20936779, 21706016, 22536782, 28514442, 8596638, 9242692, 9804835, 9890893, (Europe PMC)	0.35, 0.82	BioGRID, IntAct, MINT
GTF2A1L	Two-hybrid	physical	25416956, (Europe PMC)	NA	BioGRID
HCK	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
HSH2D	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
INPPL1	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
ITK	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
LCK	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
LGALS7	Affinity Capture-MS	physical	28514442, (Europe PMC)	NA	BioGRID
LYN	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
MAP3K3	Affinity Capture-Western, Reconstituted Complex	physical	12065326, (Europe PMC)	NA	BioGRID
MARK2	Affinity Capture-Western, Reconstituted Complex	physical	22883624, (Europe PMC)	NA	BioGRID
MET	Affinity Capture-Western, anti tag coimmunoprecipitation	physical, physical association	10871282, 10913131, 9242692, (Europe PMC)	0.40	BioGRID, IntAct, MINT
MST1R	Affinity Capture-Western, Two-hybrid	physical	14982882, (Europe PMC)	NA	BioGRID
NCK1	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
NCK2	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
NTRK1	Affinity Capture-MS	physical	25921289, (Europe PMC)	NA	BioGRID
PARD3	Affinity Capture-Western	physical	22883624, (Europe PMC)	NA	BioGRID
PIK3R1	Affinity Capture-Western, Far Western, Reconstituted Complex, Two-hybrid, coimmunoprecipitation, fluorescence polarization spectroscopy, pull down, two hybrid	association, direct interaction, physical, physical association	10978177, 16638574, 23612964, 24728074, 8596638, 9658397, 9804835, 9891995, (Europe PMC)	0.80	BioGRID, IntAct, MINT
PIK3R2	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
PIK3R3	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
PLCG1	Affinity Capture-Western, Far Western, fluorescence polarization spectroscopy	direct interaction, physical	11507676, 24728074, 8596638, (Europe PMC)	0.44	BioGRID, IntAct
PLCG2	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
PRKCI	Affinity Capture-Western	physical	22883624, (Europe PMC)	NA	BioGRID
PTK6	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
PTPN11	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
PTPN12	phosphatase assay	dephosphorylation reaction	19167335, (Europe PMC)	0.44	IntAct
PTPN9	phosphatase assay	dephosphorylation reaction	19167335, (Europe PMC)	0.44	IntAct
PTPRA	Proximity Label-MS	physical	27880917, (Europe PMC)	NA	BioGRID
PTPRB	phosphatase assay	dephosphorylation reaction	19167335, (Europe PMC)	0.44	IntAct
PTPRC	phosphatase assay	dephosphorylation reaction	19167335, (Europe PMC)	0.44	IntAct
PTPRG	phosphatase assay	dephosphorylation reaction	19167335, (Europe PMC)	0.44	IntAct
PTPRJ	phosphatase assay, pull down	dephosphorylation reaction, physical association	12475979, 19167335, (Europe PMC)	0.61	IntAct, MINT
PTPRO	phosphatase assay	dephosphorylation reaction	19167335, (Europe PMC)	0.44	IntAct
PXN	anti bait coimmunoprecipitation, anti tag coimmunoprecipitation	association, physical association	14665621, (Europe PMC)	0.50	IntAct, MINT
RASA1	coimmunoprecipitation, fluorescence polarization spectroscopy	association, direct interaction	15574420, 24728074, (Europe PMC)	0.59	IntAct, MINT
RET	anti bait coimmunoprecipitation	association	19914172, (Europe PMC)	0.35	IntAct
ROCK1	Co-crystal Structure	physical	12748184, (Europe PMC)	NA	BioGRID
SH2D1B	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
SH2D2A	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
SH2D3A	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
SHC1	Affinity Capture-Western, Far Western, fluorescence polarization spectroscopy	direct interaction, physical	14982882, 24728074, 9804835, (Europe PMC)	0.44	BioGRID, IntAct
SHC3	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
SLA	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
SLA2	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
SOCS3	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
SOCS6	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
SOS1	proximity ligation assay	physical association	23397142, (Europe PMC)	0.40	IntAct
SRC	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
STAP1	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
STON1	two hybrid array, two hybrid prey pooling approach, validated two hybrid	physical association	25416956, (Europe PMC)	0.56	IntAct
SUPT6H	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
SYK	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
SYP	Reconstituted Complex	physical	9890893, (Europe PMC)	NA	BioGRID
TCTE1	proximity-dependent biotin identification	association	26638075, (Europe PMC)	0.35	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
TNS3	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
TNS4	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
TRIM15	PCA	physical	25450970, (Europe PMC)	NA	BioGRID
TUFM	Affinity Capture-MS	physical	28514442, (Europe PMC)	NA	BioGRID
VAV1	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

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GAB1