DEPOD - human DEPhOsphorylation Database

Basic Information
Phosphatases
Pathway
Interacting Proteins
Phosphorylating Kinases

Gene Name	LCK (QuickGO)	Interactive visualization of LCK structures (A quick tutorial to explore the interctive visulaization) Representative structure: 3AC2
Synonyms	LCK
Protein Name	LCK
Alternative Name(s)	Tyrosine-protein kinase Lck;2.7.10.2;Leukocyte C-terminal Src kinase;LSK;Lymphocyte cell-specific protein-tyrosine kinase;Protein YT16;Proto-oncogene Lck;T cell-specific protein-tyrosine kinase;p56-LCK;
Protein Family	Belongs to the protein kinase superfamily Tyr proteinkinase family SRC subfamily
EntrezGene ID	3932 (Comparitive Toxicogenomics)
UniProt AC (Human)	P06239 (protein sequence)
Enzyme Class	2.7.10.2 (BRENDA )
Molecular Weight	58001 Dalton
Protein Length	509 amino acids (AA)
Genome Browsers	NCBI \| ENSG00000182866 (Ensembl) \| UCSC
Crosslinking annotations	Query our ID-mapping table
Orthologues	Quest For Orthologues (QFO) \| GeneTree \| eggNOG - KOG0197 \| 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)
Cytoplasm Cell membrane Note=Present in lipid rafts in aninactive form
Function (UniProt annotation)
Non-receptor tyrosine-protein kinase that plays anessential role in the selection and maturation of developing T-cells in the thymus and in the function of mature T-cells Plays akey role in T-cell antigen receptor (TCR)-linked signaltransduction pathways Constitutively associated with thecytoplasmic portions of the CD4 and CD8 surface receptorsAssociation of the TCR with a peptide antigen-bound MHC complexfacilitates the interaction of CD4 and CD8 with MHC class II andclass I molecules, respectively, thereby recruiting the associatedLCK protein to the vicinity of the TCR/CD3 complex LCK thenphosphorylates tyrosine residues within the immunoreceptortyrosine-based activation motifs (ITAM) of the cytoplasmic tailsof the TCR-gamma chains and CD3 subunits, initiating the TCR/CD3signaling pathway Once stimulated, the TCR recruits the tyrosinekinase ZAP70, that becomes phosphorylated and activated by LCKFollowing this, a large number of signaling molecules arerecruited, ultimately leading to lymphokine production LCK alsocontributes to signaling by other receptor molecules Associatesdirectly with the cytoplasmic tail of CD2, which leads tohyperphosphorylation and activation of LCK Also plays a role inthe IL2 receptor-linked signaling pathway that controls the T-cellproliferative response Binding of IL2 to its receptor results inincreased activity of LCK Is expressed at all stages of thymocytedevelopment and is required for the regulation of maturationevents that are governed by both pre-TCR and mature alpha betaTCR Phosphorylates other substrates including RUNX3, PTK2B/PYK2,the microtubule-associated protein MAPT, RHOH or TYROBP Interactswith FYB2 (PubMed:27335501)
Catalytic Activity (UniProt annotation)
ATP + a [protein]-L-tyrosine = ADP + a[protein]-L-tyrosine phosphate
Protein Sequence
MGCGCSSHPEDDWMENIDVCENCHYPIVPLDGKGTLLIRNGSEVRDPLVTYEGSNPPASPLQDNLVIALHSYEPSHDGDL GFEKGEQLRILEQSGEWWKAQSLTTGQEGFIPFNFVAKANSLEPEPWFFKNLSRKDAERQLLAPGNTHGSFLIRESESTA GSFSLSVRDFDQNQGEVVKHYKIRNLDNGGFYISPRITFPGLHELVRHYTNASDGLCTRLSRPCQTQKPQKPWWEDEWEV PRETLKLVERLGAGQFGEVWMGYYNGHTKVAVKSLKQGSMSPDAFLAEANLMKQLQHQRLVRLYAVVTQEPIYIITEYME NGSLVDFLKTPSGIKLTINKLLDMAAQIAEGMAFIEERNYIHRDLRAANILVSDTLSCKIADFGLARLIEDNEYTAREGA KFPIKWTAPEAINYGTFTIKSDVWSFGILLTEIVTHGRIPYPGMTNPEVIQNLERGYRMVRPDNCPEELYQLMRLCWKER PEDRPTFDYLRSVLEDFFTATEGQYQPQP

Motif information from Eukaryotic Linear Motif atlas (ELM)

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

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GO:0000242	C:pericentriolar material
GO:0001772	C:immunological synapse
GO:0001784	F:phosphotyrosine residue binding
GO:0004713	F:protein tyrosine kinase activity
GO:0004715	F:non-membrane spanning protein tyrosine kinase activity
GO:0004722	F:protein serine/threonine phosphatase activity
GO:0005524	F:ATP binding
GO:0005829	C:cytosol
GO:0005886	C:plasma membrane
GO:0006468	P:protein phosphorylation
GO:0006882	P:cellular zinc ion homeostasis
GO:0006919	P:activation of cysteine-type endopeptidase activity involved in apoptotic process
GO:0007169	P:transmembrane receptor protein tyrosine kinase signaling pathway
GO:0008022	F:protein C-terminus binding
GO:0016301	F:kinase activity
GO:0016477	P:cell migration
GO:0018108	P:peptidyl-tyrosine phosphorylation
GO:0019901	F:protein kinase binding
GO:0019903	F:protein phosphatase binding
GO:0030097	P:hemopoiesis
GO:0030168	P:platelet activation
GO:0030217	P:T cell differentiation
GO:0031234	C:extrinsic component of cytoplasmic side of plasma membrane
GO:0031295	P:T cell costimulation
GO:0034116	P:positive regulation of heterotypic cell-cell adhesion
GO:0038083	P:peptidyl-tyrosine autophosphorylation
GO:0042127	P:regulation of cell proliferation
GO:0042169	F:SH2 domain binding
GO:0042493	P:response to drug
GO:0042608	F:T cell receptor binding
GO:0042609	F:CD4 receptor binding
GO:0042610	F:CD8 receptor binding
GO:0042802	F:identical protein binding
GO:0043548	F:phosphatidylinositol 3-kinase binding
GO:0045087	P:innate immune response
GO:0045121	C:membrane raft
GO:0046934	F:phosphatidylinositol-4,5-bisphosphate 3-kinase activity
GO:0050690	P:regulation of defense response to virus by virus
GO:0050852	P:T cell receptor signaling pathway
GO:0050853	P:B cell receptor signaling pathway
GO:0050862	P:positive regulation of T cell receptor signaling pathway
GO:0050870	P:positive regulation of T cell activation
GO:0050900	P:leukocyte migration
GO:0051117	F:ATPase binding
GO:0051209	P:release of sequestered calcium ion into cytosol
GO:0051249	P:regulation of lymphocyte activation
GO:0051897	P:positive regulation of protein kinase B signaling
GO:0070062	C:extracellular exosome
GO:1903039	P:positive regulation of leukocyte cell-cell adhesion
GO:2001244	P:positive regulation of intrinsic apoptotic signaling pathway

KEGG Pathway
Reactome Pathway

Pathway ID	Pathway Name	Pathway Description (KEGG)
hsa04064	NF-kappa B signaling pathway	Nuclear factor-kappa B (NF-kappa B) is the generic name of a family of transcription factors that function as dimers and regulate genes involved in immunity, inflammation and cell survival. There are several pathways leading to NF-kappa B-activation. The canonical pathway is induced by tumour necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1) or byproducts of bacterial and viral infections. This pathway relies on IKK- mediated IkappaB-alpha phosphorylation on Ser32 and 36, leading to its degradation, which allows the p50/p65 NF-kappa B dimer to enter the nucleus and activate gene transcription. Atypical pathways are IKK-independent and rely on phosphorylation of IkappaB-alpha on Tyr42 or on Ser residues in IkappaB-alpha PEST domain. The non-canonical pathway is triggered by particular members of the TNFR superfamily, such as lymphotoxin-beta (LT-beta) or BAFF. It involves NIK and IKK-alpha-mediated p100 phosphorylation and processing to p52, resulting in nuclear translocation of p52/RelB heterodimers.
hsa04380	Osteoclast differentiation	The osteoclasts, multinucleared cells originating from the hematopoietic monocyte-macrophage lineage, are responsible for bone resorption. Osteoclastogenesis is mainly regulated by signaling pathways activated by RANK and immune receptors, whose ligands are expressed on the surface of osteoblasts. Signaling from RANK changes gene expression patterns through transcription factors like NFATc1 and characterizes the active osteoclast.
hsa04650	Natural killer cell mediated cytotoxicity	Natural killer (NK) cells are lymphocytes of the innate immune system that are involved in early defenses against both allogeneic (nonself) cells and autologous cells undergoing various forms of stress, such as infection with viruses, bacteria, or parasites or malignant transformation. Although NK cells do not express classical antigen receptors of the immunoglobulin gene family, such as the antibodies produced by B cells or the T cell receptor expressed by T cells, they are equipped with various receptors whose engagement allows them to discriminate between target and nontarget cells. Activating receptors bind ligands on the target cell surface and trigger NK cell activation and target cell lysis. However Inhibitory receptors recognize MHC class I molecules (HLA) and inhibit killing by NK cells by overruling the actions of the activating receptors. This inhibitory signal is lost when the target cells do not express MHC class I and perhaps also in cells infected with virus, which might inhibit MHC class I exprssion or alter its conformation. The mechanism of NK cell killing is the same as that used by the cytotoxic T cells generated in an adaptive immune response; cytotoxic granules are released onto the surface of the bound target cell, and the effector proteins they contain penetrate the cell membrane and induce programmed cell death.
hsa04658	Th1 and Th2 cell differentiation	Immunity to different classes of microorganisms is orchestrated by separate lineages of effector T helper (TH)-cells, which differentiate from naive CD4+ precursor cells in response to cues provided by antigen presenting cells (APC) and include T helper type 1 (Th1) and Th2. Th1 cells are characterized by the transcription factor T-bet and signal transducer and activator of transcription (STAT) 4, and the production of IFN-gamma. These cells stimulate strong cell-mediated immune responses, particularly against intracellular pathogens. On the other hand, transcription factors like GATA-3 and STAT6 drive the generation of Th2 cells that produce IL-4, IL-5 and IL-13 and are necessary for inducing the humoral response to combat parasitic helminths (type 2 immunity) and isotype switching to IgG1 and IgE. The balance between Th1/Th2 subsets determines the susceptibility to disease states, where the improper development of Th2 cells can lead to allergy, while an overactive Th1 response can lead to autoimmunity.
hsa04659	Th17 cell differentiation	Interleukin (IL)-17-producing helper T (Th17) cells serve as a subset of CD4+ T cells involved in epithelial cell- and neutrophil mediated immune responses against extracellular microbes and in the pathogenesis of autoimmune diseases. In vivo, Th17 differentiation requires antigen presentation and co-stimulation, and activation of antigen presenting-cells (APCs) to produce TGF-beta, IL-6, IL-1, IL-23 and IL-21. This initial activation results in the activation and up-regulation of STAT3, ROR(gamma)t and other transcriptional factors in CD4+ T cells, which bind to the promoter regions of the IL-17, IL-21 and IL-22 genes and induce IL-17, IL-21 and IL-22. In contrast, the differentiation of Th17 cells and their IL-17 expression are negatively regulated by IL-2, Th2 cytokine IL-4, IL-27 and Th1 cytokine IFN-gamma through STAT5, STAT6 and STAT1 activation, respectively. Retinoid acid and the combination of IL-2 and TGF-beta upregulate Foxp3, which also downregulates cytokines like IL-17 and IL-21. The inhibition of Th17 differentiation may serve as a protective strategy to 'fine-tune' the expression IL-17 so it does not cause excessive inflammation. Thus, balanced differentiation of Th cells is crucial for immunity and host protection.
hsa04660	T cell receptor signaling pathway	Activation of T lymphocytes is a key event for an efficient response of the immune system. It requires the involvement of the T-cell receptor (TCR) as well as costimulatory molecules such as CD28. Engagement of these receptors through the interaction with a foreign antigen associated with major histocompatibility complex molecules and CD28 counter-receptors B7.1/B7.2, respectively, results in a series of signaling cascades. These cascades comprise an array of protein-tyrosine kinases, phosphatases, GTP-binding proteins and adaptor proteins that regulate generic and specialised functions, leading to T-cell proliferation, cytokine production and differentiation into effector cells.
hsa05166	Human T-cell leukemia virus 1 infection	Human T-cell leukemia virus type 1 (HTLV-1) is a pathogenic retrovirus that is associated with adult T-cell leukemia/lymphoma (ATL). It is also strongly implicated in non-neoplastic chronic inflammatory diseases such as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Expression of Tax, a viral regulatory protein is critical to the pathogenesis. Tax is a transcriptional co-factor that interfere several signaling pathways related to anti-apoptosis or cell proliferation. The modulation of the signaling by Tax involve its binding to transcription factors like CREB/ATF, NF-kappa B, SRF, and NFAT.
hsa05340	Primary immunodeficiency	Primary immunodeficiencies (PIs) are a heterogeneous group of disorders, which affect cellular and humoral immunity or non-specific host defense mechanisms mediated by complement proteins, and cells such as phagocytes and natural killer (NK) cells. These disorders of the immune system cause increased susceptibility to infection, autoimmune disease, and malignancy. Most of PIs are due to genetic defects that affect cell maturation or function at different levels during hematopoiesis. Disruption of the cellular immunity is observed in patients with defects in T cells or both T and B cells. These cellular immunodeficiencies comprise 20% of all PIs. Disorders of humoral immunity affect B-cell differentiation and antibody production. They account for 70% of all PIs.

Pathway ID	Pathway Name	Pathway Description (KEGG)
R-HSA-114604	GPVI-mediated activation cascade.	The GPVI receptor is a complex of the GPVI protein with Fc epsilon R1 gamma (FcR). The Src family kinases Fyn and Lyn constitutively associate with the GPVI-FcR complex in platelets and initiate platelet activation through phosphorylation of the immunoreceptor tyrosine-based activation motif (ITAM) in the FcR gamma chain, leading to binding and activation of the tyrosine kinase Syk. Downstream of Syk, a series of adapter molecules and effectors lead to platelet activation. The GPVI receptor signaling cascade is similar to that of T- and B-cell immune receptors, involving the formation of a signalosome composed of adapter and effector proteins. At the core of the T-cell receptor signalosome is the transmembrane adapter LAT and two cytosolic adapters SLP-76 and Gads. While LAT is essential for signalling to PLCgamma1 downstream of the T-cell receptor, the absence of LAT in platelets only impairs the activation of PLCgamma2, the response to collagen and GPVI receptor ligands remains sufficient to elicit a full aggregation response. In contrast, GPVI signalling is almost entirely abolished in the absence of SLP-76
R-HSA-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-1433557	Signaling by SCF-KIT.	Stem cell factor (SCF) is a growth factor with membrane bound and soluble forms. It is expressed by fibroblasts and endothelial cells throughout the body, promoting proliferation, migration, survival and differentiation of hematopoetic progenitors, melanocytes and germ cells.(Linnekin 1999, Ronnstrand 2004, Lennartsson and Ronnstrand 2006). The receptor for SCF is KIT, a tyrosine kinase receptor (RTK) closely related to the receptors for platelet derived growth factor receptor, colony stimulating factor 1 (Linnekin 1999) and Flt3 (Rosnet et al. 1991). Four isoforms of c-Kit have been identified in humans. Alternative splicing results in isoforms of KIT differing in the presence or absence of four residues (GNNK) in the extracellular region. This occurs due to the use of an alternate 5' splice donor site. These GNNK+ and GNNK- variants are co-expressed in most tissues; the GNNK- form predominates and was more strongly tyrosine-phosphorylated and more rapidly internalized (Ronnstrand 2004). There are also splice variants that arise from alternative usage of splice acceptor site resulting in the presence or absence of a serine residue (Crosier et al., 1993). Finally, there is an alternative shorter transcript of KIT expressed in postmeiotic germ cells in the testis which encodes a truncated KIT consisting only of the second part of the kinase domain and thus lackig the extracellular and transmembrane domains as well as the first part of the kinase domain (Rossi et al. 1991). Binding of SCF homodimers to KIT results in KIT homodimerization followed by activation of its intrinsic tyrosine kinase activity. KIT stimulation activates a wide array of signalling pathways including MAPK, PI3K and JAK/STAT (Reber et al. 2006, Ronnstrand 2004). Defects of KIT in humans are associated with different genetic diseases and also in several types of cancers like mast cell leukaemia, germ cell tumours, certain subtypes of malignant melanoma and gastrointestinal tumours
R-HSA-1433559	Regulation of KIT signaling.	SCF induced proliferation is negatively regulated by various proteins including SHP1, PKC, CBL, SOCS1, SOCS6 and LNK
R-HSA-164944	Nef and signal transduction.	Nef interferes with cellular signal transduction pathways in a number of ways. Nef is associated with lipid rafts through its amino-terminal myristoylation and a proline-rich SH3-binding domain. These cholesterol-rich membrane microdomains appear to concentrate potent signaling mediators. Nef was found to complex with and activate serine/threonine protein kinase PAK-2, which may contribute to activation of infected cells. In vitro, HIV-infected T cells produce enhanced levels of interleukin-2 during activation. When expressed in macrophages, Nef intersects the CD40L signaling pathway inducing secretion of chemokines and other factors that attract resting T cells and promote their infection by HIV
R-HSA-167590	Nef Mediated CD4 Down-regulation.	The presence of Nef accelerates endocytosis and lysosomal degradation of the transmembrane glycoprotein CD4. CD4 has its own internalization motif, though this motif is normally concealed by CD4 interaction with Lck, a tyrosine kinase. Nef is known to disrupt this interaction and then facilitate a cascade of protein interactions that ultimately result in the degradation of internalized CD4 protein. The final set of protein interactions that direct Nef to the beta-subunit of the COPI coatomers are at this time unclear.A benefit for the virus from CD4 down-modulation is abolition of interaction between the receptor and the Env protein of the budding virus, which likely increases HIV release from infected cell as well as infectivity of viral particles
R-HSA-202424	Downstream TCR signaling.	Changes in gene expression are required for the T cell to gain full proliferative competence and to produce effector cytokines. Three transcription factors in particular have been found to play a key role in TCR-stimulated changes in gene expression, namely NF-kB, NFAT and AP-1. A key step in NF-kB activation is the stimulation and translocation of PKC theta. The critical element that effects PKC theta activation is PI3K. This enzyme complex translocates to the plasma membrane by interacting with phospho-tyrosines on CD28 via its two SH2 domains located in p85 subunit. The p110 subunit of PI3K phosphorylates the inositol ring of PIP2 to generate PIP3 (steps 17-18). PIP3 may also be dephosphorylated by the phosphatase SHIP to generate PI-3,4-P2. PIP3 and PI-3,4-P2 acts as binding sites to the PH domain of PKB/Akt and PDK1 (steps 19, 21 and 22). PKB is activated in response to PI3K stimulation by PDK1 (step 23). PDK1 has an essential role in regulating the activation of PKC theta and recruitment of CBM complex to the immune synapse. PKC theta is a member of novel class (DAG dependent, Ca++ independent) of PKC and the only member known to translocate to this synapse. Prior to TCR stimulation PKC theta exists in an inactive closed conformation. Upon release of DAG, it binds to PKC theta via the C1 domain and undergoes phosphorylation on tyrosine 90 by Lck to attain an open conformation. PKC theta is further phosphorylated by PDK1 on threonine 538. This step is critical for PKC activity (steps 24-26). CARMA1 translocates to the plasma membrane following the interaction of its SH3 domain with the 'PxxP' motif on PDK1. CARMA1 is phosphorylated by PKC-theta on residue S552, leading to the oligomerization of CARMA1. This complex acts as a scaffold, recruiting Bcl10 to the synapse by interacting with their CARD domains. Bcl10 undergoes phosphorylation mediated by the enzyme RIP2. Activated Bcl10 then mediates the ubiquitination of NEMO by recruiting MALT1 and TRAF6. MALT1 binds to Bcl10 with its Ig-like domains and undergoes oligomerization. TRAF6 binds to the oligomerized MALT1 and also undergoes oligomerization. Oligomerized TRAF6 acts as a ubiquitin-protein ligase, catalyzing auto-K63-linked polyubiquitination (steps 27-33). This K-63 ubiquitinated TRAF6 activates TAK1 kinase bound to TAB2 and also ubiquitinates NEMO/IKK-gamma in the IKK complex. TAK1 undergoes autophosphorylation on residues T184 and T187 and gets activated. Activated TAK1 kinase phosphorylates IKK-beta on residues S177 and S181 in the activation loop and activates the IKK kinase activity. IKK-beta phosphorylates the IkB-alpha bound to the NF-kB heterodimer, on residues S19 and S23 and directs IkB-beta to 26S proteasome degradation (step 34-38 & 40). The NF-kB heterodimer with a free NTS sequence finally migrates to the nucleus to regulate gene transcription (step 39)
R-HSA-202427	Phosphorylation of CD3 and TCR zeta chains.	Prior to T cell receptor (TCR) stimulation, CD4/CD8 associated Lck remains seperated from the TCR and is maintained in an inactive state by the action of Csk. Csk phosphorylates the negative regulatory tyrosine of Lck and inactivates the Lck kinase domain. Upon TCR stimulation, CD4/CD8 associated Lck co-localizes with the TCR leading to the phosphorylation of the CD3 and TCR subunit. Lck becomes activated by way of CD45-mediated dephosphorylation of negative regulatory tyrosine residues. The presence to PAG-bound Csk is further reduced via the dephosphorylation of PAG (step 1). Lck is further activated by trans-autophosphorylation on the tyrosine residue on its activation loop (step 2). Active Lck further phosphorylates the tyrosine residues on CD3 chains. The signal-transducing CD3 delta/epsilon/gamma and TCR zeta chains contain a critical signaling motif known as the immunoreceptor tyrosine-based activation motif (ITAM). The two critical tyrosines of each ITAM motif are phosphorylated by Lck (step 3)
R-HSA-202430	Translocation of ZAP-70 to Immunological synapse.	The dual phosphorylated ITAMs recruit Syk kinase ZAP-70 via their tandem SH2 domains (step 4). ZAP-70 subsequently undergoes phosphorylation on multiple tyrosine residues for further activation. ZAP-70 includes both positive and negative regulatory sites. Tyrosine 493 is a conserved regulatory site found within the activation loop of the kinase domain. This site has shown to be a positive regulatory site required for ZAP-70 kinase activity and is phosphorylated by Lck (step 5). This phosphorylation contributes to the active conformation of the catalytic domain. Later ZAP-70 undergoes trans-autophosphorylation at Y315 and Y319 (step 6). These sites appear to be positive regulatory sites. ZAP-70 achieves its full activation after the trans-autophosphorylation. Activated ZAP-70 along with Lck phosphorylates the multiple tyrosine residues in the adaptor protein LAT (step 7)
R-HSA-202433	Generation of second messenger molecules.	In addition to serving as a scaffold via auto-phosphorylation, ZAP-70 also phosphorylates a restricted set of substrates following TCR stimulation - including LAT and SLP-76. These substrates have been recognized to play pivotal role in TCR signaling by releasing second messengers. When phosphorylated, LAT and SLP-76 act as adaptor proteins which serve as nucleation points for the construction of a higher order signalosome: GADS, PLC-gamma1 and GRB2 bind to the LAT on the phosphorylated tyrosine residues (steps 8 and 13). SLP-76 and SOS are then moved to the signalosome by interacting with the SH3 domains of GRB2 and GADS via their proline rich sequences (step 9). Three SLP-76 acidic domain N-term tyrosine residues are phosphorylated by ZAP-70, once SLP-76 binds to GADS (step 10). These phospho-tyrosine residues act as binding sites to the SH2 domains of PLC-gamma1, Vav and Itk (steps 11 and 12). PLC-gamma1 is activated by dual phosphorylation on the tyrosine residues at positions 771, 783 and 1254 by Itk and ZAP-70 (step 14). Phosphorylated PLC-gamma1 subsequently detaches from LAT and SLP-76 and translocates to the plasma membrane by binding to phosphatidylinositol-4,5-bisphosphate (PIP2) via its PH domain (step 15). PLC-gamma1 goes on to hydrolyse PIP2 to second messengers DAG and IP3. These second messengers are involved in PKC and NF-kB activation and calcium mobilization (step 16)
R-HSA-210990	PECAM1 interactions.	PECAM-1/CD31 is a member of the immunoglobulin superfamily (IgSF) and has been implicated to mediate the adhesion and trans-endothelial migration of T-lymphocytes into the vascular wall, T cell activation and angiogenesis. It has six Ig homology domains within its extracellularly and an ITIM motif within its cytoplasmic region. PECAM-1 mediates cellular interactions by both homophilic and heterophilic interactions. The cytoplasmic domain of PECAM-1 contains tyrosine residues which serves as docking sites for recruitment of cytosolic signaling molecules. Under conditions of platelet activation, PECAM-1 is phosphorylated by Src kinase members. The tyrosine residues 663 and 686 are required for recruitment of the SH2 domain containing PTPs
R-HSA-2219530	Constitutive Signaling by Aberrant PI3K in Cancer.	Signaling by PI3K/AKT is frequently constitutively activated in cancer via gain-of-function mutations in one of the two PI3K subunits - PI3KCA (encoding the catalytic subunit p110alpha) or PIK3R1 (encoding the regulatory subunit p85alpha). Gain-of-function mutations activate PI3K signaling by diverse mechanisms. Mutations affecting the helical domain of PIK3CA and mutations affecting nSH2 and iSH2 domains of PIK3R1 impair inhibitory interactions between these two subunits while preserving their association. Mutations in the catalytic domain of PIK3CA enable the kinase to achieve an active conformation. PI3K complexes with gain-of-function mutations therefore produce PIP3 and activate downstream AKT in the absence of growth factors (Huang et al. 2007, Zhao et al. 2005, Miled et al. 2007, Horn et al. 2008, Sun et al. 2010, Jaiswal et al. 2009, Zhao and Vogt 2010, Urick et al. 2011)
R-HSA-2424491	DAP12 signaling.	In response to receptor ligation, the tyrosine residues in DAP12's immunoreceptor tyrosine-based activation motif (ITAM) are phosphorylated by Src family kinases. These phosphotyrosines form the docking site for the protein tyrosine kinase SYK in myeloid cells and SYK and ZAP70 in NK cells. DAP12-bound SYK autophosphorylates and phosphorylates the scaffolding molecule LAT, recruiting the proximal signaling molecules phosphatidylinositol-3-OH kinase (PI3K), phospholipase-C gamma (PLC-gamma), GADS (GRB2-related adapter downstream of SHC), SLP76 (SH2 domain-containing leukocyte protein of 76 kDa), GRB2:SOS (Growth factor receptor-bound protein 2:Son of sevenless homolog 1) and VAV. All of these intermediate signalling molecules result in the recruitment and activation of kinases AKT, CBL (Casitas B-lineage lymphoma) and ERK (extracellular signal-regulated kinase), and rearrangement of the actin cytoskeleton (actin polymerization) finally leading to cellular activation. PLC-gamma generates the secondary messengers diacylglycerol (DAG) and inositol-1,4,5-trisphosphate (InsP3), leading to activation of protein kinase C (PKC) and calcium mobilization, respectively (Turnbull & Colonna 2007, Klesney-Tait et al. 2006)
R-HSA-389356	CD28 co-stimulation.	In naive T cells, CD28 costimulation enhances cell cycle entry, potently stimulates expression of both the mitogenic lymphokine interleukin-2 (IL-2) and its receptor, and stimulates the activation of an antiapoptotic program. CD28 engages with one or both members of the B7 receptor family, B7.1 and B7.2. Upon ligand binding the tyrosines and proline-rich motifs present in the cytoplasmic tail of CD28 are phosphorylated by Lck or Fyn. Upon phosphorylation CD28 recruits and induces phosphorylation and activation of a more restricted set of intracellular signaling components that, together with those mobilized by the TCR, contribute to convert membrane-based biochemical and biophysical changes into gene activation events. Proteins like PI3K, Vav-1, Tec and Itk kinases, AKT, and the Dok-1 adaptor have been identified as elements of the CD28 signaling pathway by biochemical or genetic approaches or both
R-HSA-389357	CD28 dependent PI3K/Akt signaling.	PI3Ks can be activated by a number of different receptors, including the TcR (T cell receptor), co-stimulatory receptors (CD28), cytokine receptors and chemokine receptors. However, the specific roles of PI3Ks downstream of these receptors vary. CD28 contains the YMNM consensus PI3K-binding motif, and PI3K recruitment by CD28 contributes to or complements TCR-dependent PI3K signaling. Activation of PI3K promotes PIP3 production at the plasma membrane and several potential target molecules for this phospholipid have been implicated in PI3K pathways downstream of the TcR and CD28. Of these targets, at least Vav and Akt have been implicated in CD28 costimulation of T cell activation. AKT/PKB connects PI3K to signaling pathways that promote cytokine transcription, survival, cell-cycle entry and growth
R-HSA-389359	CD28 dependent Vav1 pathway.	CD28 binds to several intracellular proteins including PI3 kinase, Grb-2, Gads and ITK. Grb-2 specifically co-operates with Vav-1 in the up-regulation of NFAT/AP-1 transcription. CD28 costimulation resulted in a prolonged and sustained phosphorylation and membrane localization of Vav1 in comparison to T-cell receptor activation alone. Tyrosine-phosphorylated Vav1 is an early point of integration between the signaling routes triggered by the T-cell receptor and CD28.Vav1 transduces TCR and co-stimulatory signals to multiple biochemical pathways and several cytoskeleton-dependent processes. The products of Vav1 activation, Rac1 and Cdc42, in turn activate the mitogen-activated protein kinases JNK and p38. Vav1 is also required for TCR-induced calcium flux, activation of the ERK MAP kinase pathway, activation of the NF-kB transcription factor, inside-out activation of the integrin LFA-1, TCR clustering, and polarisation of the T cell
R-HSA-389513	CTLA4 inhibitory signaling.	CTLA4 is one of the best studied inhibitory receptors of the CD28 superfamily. CTLA4 inhibits Tcell activation by reducing IL2 production and IL2 expression, and by arresting T cells at the G1 phase of the cell cycle. CTLA-4 expressed by a T cell subpopulation exerts a dominant control on the proliferation of other T cells, which limits autoreactivity. CTLA4 also blocks CD28 signals by competing for the ligands B71 and B72 in the limited space between T cells and antigenpresenting cells. Though the mechanism is obscure, CTLA4 may also propagate inhibitory signals that actively counter those produced by CD28. CTLA4 can also function in a ligand-independent manner.?CTLA-4 regulates the activation of pathogenic T cells by directly modulating T cell receptor signaling (i.e. TCR-zeta chain phosphorylation) as well as downstream biochemical signals (i.e. ERK activation). The cytoplasmic region of CTLA4 contains a tyrosine motif YVKM and a proline rich region. After TCR stimulation, it undergoes tyrosine phosphorylation by src kinases, inducing surface retention
R-HSA-389948	PD-1 signaling.	The Programmed cell death protein 1 (PD-1) is one of the negative regulators of TCR signaling. PD-1 may exert its effects on cell differentiation and survival directly by inhibiting early activation events that are positively regulated by CD28 or indirectly through IL-2. PD-1 ligation inhibits the induction of the cell survival factor Bcl-xL and the expression of transcription factors associated with effector cell function, including GATA-3, Tbet, and Eomes. PD-1 exerts its inhibitory effects by bringing phosphatases SHP-1 and SHP-2 into the immune synapse, leading to dephosphorylation of CD3-zeta chain, PI3K and AKT
R-HSA-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-9020558	Interleukin-2 signaling.	Interleukin-2 (IL-2) is a cytokine that is produced by T cells in response to antigen stimulation. Originally, IL-2 was discovered because of its potent growth factor activity on activated T cells in vitro and was therefore named 'T cell growth factor' (TCGF). However, the generation of IL-2- and IL-2 receptor-deficient mice revealed that IL-2 also plays a regulatory role in the immune system by suppressing autoimmune responses. Two main mechanisms have been identified that explain this suppressive function: (1) IL-2 sensitizes activated T cells for activation-induced cell death (AICD) and (2) IL-2 is critical for the survival and function of regulatory T cells (Tregs), which possess potent immunosuppressive properties.IL-2 signaling occurs when IL-2 binds to the heterotrimeric high-affinity IL-2 receptor (IL-2R), which consists of alpha, beta and gamma chains. The IL-2R was identified in 1981 via radiolabeled ligand binding (Robb et al. 1981). The IL-2R alpha chain was identified in 1982 (Leonard et al.), the beta chain in 1986/7 (Sharon et al. 1986, Teshigawara et al. 1987) and the IL-2R gamma chain in 1992 (Takeshita et al.). The high affinity of IL-2 binding to the IL-2R is created by a very rapid association rate to the IL-2R alpha chain, combined with a much slower dissociation rate contributed by the combination of the IL-2R beta and gamma chains (Wang & Smith 1987). After antigen stimulation, T cells upregulate the high-affinity IL-2R alpha chain; IL-2R alpha captures IL-2 and this complex then associates with the constitutively expressed IL-2R beta and gamma chains. The IL-2R gamma chain is shared by several other members of the cytokine receptor superfamily including IL-4, IL-7, IL-9, IL-15 and IL-21 receptors, and consequently is often referred to as the Common gamma chain (Gamma-c).\nThe tyrosine kinases Jak1 and Jak3, which are constitutively associated with IL-2R beta and Gamma-c respectively, are activated resulting in phosphorylation of three critical tyrosine residues in the IL-2R beta cytoplasmic tail. These phosphorylated residues enable recruitment of the adaptor molecule Shc, activating the MAPK and PI3K pathways, and the transcription factor STAT5. After phosphorylation, STAT5 forms dimers that translocate to the nucleus and initiate gene expression. While STAT5 activation is critical for IL-2 function in most cell types, the contribution of the PI3K/Akt pathway differs between distinct T cell subsets. In Tregs for example, PI3K/Akt is not involved in IL-2 signaling and this may explain some of the different functional outcomes of IL-2 signaling in Tregs vs. effector T cells

BioGRID
IntAct
MINT
ALL

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Interacting partner	Detection method	Interaction type	PubMed IDs	Interaction Score	Source
ADAM15	Affinity Capture-Western, Reconstituted Complex, anti bait coimmunoprecipitation, pull down	physical, physical association	11741929, 16374509, (Europe PMC)	0.52	BioGRID, IntAct, MINT
AJUBA	Two-hybrid	physical	15870274, (Europe PMC)	NA	BioGRID
ARHGAP17	Reconstituted Complex	physical	11431473, (Europe PMC)	NA	BioGRID
AXL	Far Western	physical	9178760, (Europe PMC)	NA	BioGRID
BAG6	Affinity Capture-Western	physical	22863785, (Europe PMC)	NA	BioGRID
BCAR1	Reconstituted Complex	physical	9020138, (Europe PMC)	NA	BioGRID
BRCA1	Two-hybrid	physical	25184681, (Europe PMC)	NA	BioGRID
CBL	Affinity Capture-Western, Reconstituted Complex, coimmunoprecipitation, pull down	direct interaction, physical, physical association	11904433, 16107303, 7721825, 8621719, 8626543, 8900205, (Europe PMC)	0.75	BioGRID, IntAct, MINT
CBLB	Affinity Capture-Western	physical	21453975, (Europe PMC)	NA	BioGRID
CD2	Affinity Capture-Western, Reconstituted Complex, experimental interaction detection	phosphorylation reaction, physical	8551220, 9677430, (Europe PMC)	0.31	BioGRID, IntAct, MINT
CD247	Affinity Capture-Western, protein kinase assay, pull down	phosphorylation reaction, physical, physical association	14523017, 16461343, 24463463, 26390156, 8626561, (Europe PMC)	0.44, 0.61	BioGRID, IntAct, MINT
CD38	Affinity Capture-Western	physical	14523017, (Europe PMC)	NA	BioGRID
CD3E	Affinity Capture-Western, pull down	association, physical	11855827, 14523017, (Europe PMC)	0.35	BioGRID, IntAct, MINT
CD4	Affinity Capture-MS, Affinity Capture-Western, Two-hybrid, anti bait coimmunoprecipitation	physical, physical association	11854499, 12007789, 15047060, 16888650, 17005671, 17653867, 8246987, (Europe PMC)	0.70	BioGRID, IntAct, MINT
CD44	Affinity Capture-Western, Co-fractionation	physical	8576267, 9573028, (Europe PMC)	NA	BioGRID
CD48	Affinity Capture-Western	physical	12007789, (Europe PMC)	NA	BioGRID
CD5	Affinity Capture-Western	physical	21757751, (Europe PMC)	NA	BioGRID
CD55	Co-localization, proximity ligation assay	physical, physical association	25241761, (Europe PMC)	0.40	BioGRID, IntAct
CDKAL1	Two-hybrid, two hybrid array, two hybrid prey pooling approach, validated two hybrid	physical, physical association	25416956, (Europe PMC)	0.56	BioGRID, IntAct
CISH	Affinity Capture-Western	physical	21234523, (Europe PMC)	NA	BioGRID
CSNK2B	Two-hybrid, two hybrid	physical, physical association	21900206, (Europe PMC)	0.37	BioGRID, IntAct, MINT
CTLA4	Affinity Capture-Western	physical	9712716, (Europe PMC)	NA	BioGRID
CTNND1	Biochemical Activity	physical	12835311, (Europe PMC)	NA	BioGRID
DLG1	Affinity Capture-Western, Co-localization, Reconstituted Complex	physical	25241761, 9341123, (Europe PMC)	NA	BioGRID
DOK2	Two-hybrid, two hybrid array, validated two hybrid	physical, physical association	25814554, (Europe PMC)	0.49	BioGRID, IntAct
FAM174A	Protein-peptide	physical	16274251, (Europe PMC)	NA	BioGRID
FAS	Reconstituted Complex, anti bait coimmunoprecipitation	association, physical	20696918, 8864141, (Europe PMC)	0.35	BioGRID, IntAct
FASLG	Reconstituted Complex	physical	11741599, (Europe PMC)	NA	BioGRID
G3BP1	Biochemical Activity, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation	physical, physical association	15743820, (Europe PMC)	0.52	BioGRID, IntAct, MINT
HAVCR2	Affinity Capture-Western, anti bait coimmunoprecipitation, pull down	association, physical	22863785, 26492563, (Europe PMC)	0.46	BioGRID, IntAct
HSP90AA1	Affinity Capture-Luminescence, Affinity Capture-Western, anti bait coimmunoprecipitation	physical, physical association	16888650, 22939624, (Europe PMC)	0.40	BioGRID, IntAct, MINT
IKBKG	Reconstituted Complex, protein array	direct interaction, physical	20098747, (Europe PMC)	0.44	BioGRID, IntAct
IL2RB	Affinity Capture-Western	physical	21834013, (Europe PMC)	NA	BioGRID
KHDRBS1	Affinity Capture-Western, Protein-peptide	physical	16107303, 16274251, 16888650, 9045636, (Europe PMC)	NA	BioGRID
KIT	Affinity Capture-Western, fluorescence polarization spectroscopy	direct interaction, physical	24728074, 9788619, (Europe PMC)	0.44	BioGRID, IntAct
LAT	Affinity Capture-Western, Biochemical Activity, Co-fractionation, anti bait coimmunoprecipitation, protein kinase assay	association, phosphorylation reaction, physical	14523017, 16938345, (Europe PMC)	0.52	BioGRID, IntAct
LCK	Biochemical Activity, cosedimentation in solution, fluorescence technology, protein kinase assay, x-ray crystallography	direct interaction, phosphorylation reaction, physical	17118402, 20372794, 24463463, (Europe PMC)	0.72	BioGRID, IntAct, MINT
LZTS2	Two-hybrid	physical	25416956, (Europe PMC)	NA	BioGRID
MAPK1	Biochemical Activity, anti bait coimmunoprecipitation, pull down	physical, physical association	15967991, 8626561, (Europe PMC)	0.52	BioGRID, IntAct, MINT
MS4A1	Affinity Capture-Western	physical	7545683, (Europe PMC)	NA	BioGRID
NEDD9	Affinity Capture-Western	physical	8879209, (Europe PMC)	NA	BioGRID
NOTCH1	Affinity Capture-Western	physical	14583609, (Europe PMC)	NA	BioGRID
NR3C1	Affinity Capture-Western, anti bait coimmunoprecipitation, imaging technique	colocalization, physical, physical association	16888650, (Europe PMC)	0.46	BioGRID, IntAct, MINT
PAG1	Reconstituted Complex, anti bait coimmunoprecipitation	association, physical	10790433, 18070987, (Europe PMC)	0.35	BioGRID, IntAct, MINT
PAK2	Reconstituted Complex	physical	16374509, (Europe PMC)	NA	BioGRID
PECAM1	Biochemical Activity	physical	9624175, (Europe PMC)	NA	BioGRID
PI4KA	Reconstituted Complex	physical	8246987, (Europe PMC)	NA	BioGRID
PIK3CA	Affinity Capture-Western, Reconstituted Complex	physical	14583609, 8246987, (Europe PMC)	NA	BioGRID
PIK3R1	Reconstituted Complex, pull down	physical, physical association	8246987, 8294442, (Europe PMC)	0.40	BioGRID, IntAct, MINT
PRKCQ	Two-hybrid, anti tag coimmunoprecipitation	association, physical, physical association	10383400, 21964608, (Europe PMC)	0.50	BioGRID, IntAct
PTK2B	Affinity Capture-Western	physical	9091579, (Europe PMC)	NA	BioGRID
PTPN22	Affinity Capture-MS, Affinity Capture-Western, phosphatase assay, pull down	association, dephosphorylation reaction, direct interaction, physical	16461343, 19167335, 21719704, (Europe PMC)	0.78	BioGRID, IntAct
PTPN6	Biochemical Activity, Reconstituted Complex, phosphatase assay, protein kinase assay	dephosphorylation reaction, phosphorylation reaction, physical	10617656, 11294838, 19167335, 8114715, (Europe PMC)	0.62	BioGRID, IntAct, MINT
PTPRC	Affinity Capture-Western, Reconstituted Complex	physical	15085197, 8473339, 8576115, (Europe PMC)	NA	BioGRID
PXN	Affinity Capture-Western	physical	9488700, (Europe PMC)	NA	BioGRID
RAF1	Affinity Capture-Western	physical	8939988, (Europe PMC)	NA	BioGRID
RASA1	Biochemical Activity	physical	11389730, (Europe PMC)	NA	BioGRID
RIN3	Two-hybrid, two hybrid array	physical, physical association	25814554, (Europe PMC)	0.37	BioGRID, IntAct
SH2B3	Affinity Capture-Western	physical	10799879, (Europe PMC)	NA	BioGRID
SH3KBP1	Affinity Capture-Western	physical	15707590, (Europe PMC)	NA	BioGRID
SIT1	Affinity Capture-Western	physical	10209036, (Europe PMC)	NA	BioGRID
SKAP1	Affinity Capture-Western, Reconstituted Complex	physical	10229084, 9195899, (Europe PMC)	NA	BioGRID
SMAD2	Reconstituted Complex	physical	16806069, (Europe PMC)	NA	BioGRID
SMAD3	Reconstituted Complex	physical	16806069, (Europe PMC)	NA	BioGRID
SMURF1	Biochemical Activity	physical	20804422, (Europe PMC)	NA	BioGRID
SOCS1	Affinity Capture-Western	physical	21234523, (Europe PMC)	NA	BioGRID
SOCS2	Affinity Capture-Western	physical	21234523, (Europe PMC)	NA	BioGRID
SOCS3	Affinity Capture-Western	physical	21234523, (Europe PMC)	NA	BioGRID
SOS1	Protein-peptide	physical	16274251, (Europe PMC)	NA	BioGRID
SQSTM1	Reconstituted Complex	physical	8650207, (Europe PMC)	NA	BioGRID
STAT3	Two-hybrid	physical	25814554, (Europe PMC)	NA	BioGRID
SYK	Affinity Capture-Western, Reconstituted Complex, Two-hybrid, coimmunoprecipitation, pull down, two hybrid	association, physical, physical association	15536084, 7539035, 8621719, 8798676, (Europe PMC)	0.75	BioGRID, IntAct, MINT
THY1	Affinity Capture-Western	physical	1351058, (Europe PMC)	NA	BioGRID
TRAT1	Reconstituted Complex	physical	10790433, (Europe PMC)	NA	BioGRID
TRPV4	Affinity Capture-Western	physical	12538589, (Europe PMC)	NA	BioGRID
UBC	Co-crystal Structure, Protein-peptide, nuclear magnetic resonance, pull down	direct interaction, physical, physical association	18539162, (Europe PMC)	0.54	BioGRID, IntAct, MINT
UBE3A	Reconstituted Complex, Two-hybrid	physical	10449731, (Europe PMC)	NA	BioGRID
UHRF2	Far Western, antibody array	physical, physical association	21952639, (Europe PMC)	0.40	BioGRID, IntAct
UNC119	Affinity Capture-Western, Reconstituted Complex	physical	14757743, (Europe PMC)	NA	BioGRID
WAS	Affinity Capture-Western, Biochemical Activity, pull down	physical, physical association	16107303, 16293614, (Europe PMC)	0.40	BioGRID, IntAct, MINT
WASL	Biochemical Activity, protein kinase assay	phosphorylation reaction, physical	16293614, (Europe PMC)	0.44	BioGRID, IntAct
YWHAQ	Affinity Capture-Western	physical	19010391, (Europe PMC)	NA	BioGRID
ZAP70	Affinity Capture-Western, anti tag coimmunoprecipitation, far western blotting, protein kinase assay	association, phosphorylation reaction, physical, physical association	10318843, 10556826, 16461343, 7539035, 8798643, (Europe PMC)	0.70	BioGRID, IntAct, MINT

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Interacting partner	Detection method	Interaction type	PubMed IDs	Interaction Score	Source
ACTB	molecular sieving	physical association	15047060, (Europe PMC)	0.40	IntAct
ADAM15	Affinity Capture-Western, Reconstituted Complex, anti bait coimmunoprecipitation, pull down	physical, physical association	11741929, 16374509, (Europe PMC)	0.52	BioGRID, IntAct, MINT
AR	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
BCL3	anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, pull down	physical association	16099425, (Europe PMC)	0.59	IntAct, MINT
CBL	Affinity Capture-Western, Reconstituted Complex, coimmunoprecipitation, pull down	direct interaction, physical, physical association	11904433, 16107303, 7721825, 8621719, 8626543, 8900205, (Europe PMC)	0.75	BioGRID, IntAct, MINT
CD2	Affinity Capture-Western, Reconstituted Complex, experimental interaction detection	phosphorylation reaction, physical	8551220, 9677430, (Europe PMC)	0.31	BioGRID, IntAct, MINT
CD247	Affinity Capture-Western, protein kinase assay, pull down	phosphorylation reaction, physical, physical association	14523017, 16461343, 24463463, 26390156, 8626561, (Europe PMC)	0.44, 0.61	BioGRID, IntAct, MINT
CD3E	Affinity Capture-Western, pull down	association, physical	11855827, 14523017, (Europe PMC)	0.35	BioGRID, IntAct, MINT
CD4	Affinity Capture-MS, Affinity Capture-Western, Two-hybrid, anti bait coimmunoprecipitation	physical, physical association	11854499, 12007789, 15047060, 16888650, 17005671, 17653867, 8246987, (Europe PMC)	0.70	BioGRID, IntAct, MINT
CD55	Co-localization, proximity ligation assay	physical, physical association	25241761, (Europe PMC)	0.40	BioGRID, IntAct
CDC42	protein kinase assay	phosphorylation reaction	16293614, (Europe PMC)	0.44	IntAct
CDKAL1	Two-hybrid, two hybrid array, two hybrid prey pooling approach, validated two hybrid	physical, physical association	25416956, (Europe PMC)	0.56	BioGRID, IntAct
CSNK2B	Two-hybrid, two hybrid	physical, physical association	21900206, (Europe PMC)	0.37	BioGRID, IntAct, MINT
DLG1	anti bait coimmunoprecipitation, proximity ligation assay, pull down	physical association	25241761, 9341123, (Europe PMC)	0.66	IntAct, MINT
DOK2	Two-hybrid, two hybrid array, validated two hybrid	physical, physical association	25814554, (Europe PMC)	0.49	BioGRID, IntAct
FAS	Reconstituted Complex, anti bait coimmunoprecipitation	association, physical	20696918, 8864141, (Europe PMC)	0.35	BioGRID, IntAct
G3BP1	Biochemical Activity, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation	physical, physical association	15743820, (Europe PMC)	0.52	BioGRID, IntAct, MINT
GAB1	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
GATA3	two hybrid array, two hybrid prey pooling approach, validated two hybrid	physical association	26871637, (Europe PMC)	0.56	IntAct
GRB2	protein kinase assay	phosphorylation reaction	23460737, (Europe PMC)	0.44	IntAct
HAVCR2	Affinity Capture-Western, anti bait coimmunoprecipitation, pull down	association, physical	22863785, 26492563, (Europe PMC)	0.46	BioGRID, IntAct
HSP90AA1	Affinity Capture-Luminescence, Affinity Capture-Western, anti bait coimmunoprecipitation	physical, physical association	16888650, 22939624, (Europe PMC)	0.40	BioGRID, IntAct, MINT
HSP90AB1	anti tag coimmunoprecipitation, luminescence based mammalian interactome mapping	physical association	22939624, (Europe PMC)	0.52	IntAct
IKBKG	Reconstituted Complex, protein array	direct interaction, physical	20098747, (Europe PMC)	0.44	BioGRID, IntAct
KHDRBS1	anti bait coimmunoprecipitation, coimmunoprecipitation, pull down	physical association	11278465, 16107303, 16888650, 7852312, 9045636, (Europe PMC)	0.83	IntAct, MINT
KIT	Affinity Capture-Western, fluorescence polarization spectroscopy	direct interaction, physical	24728074, 9788619, (Europe PMC)	0.44	BioGRID, IntAct
LAT	Affinity Capture-Western, Biochemical Activity, Co-fractionation, anti bait coimmunoprecipitation, protein kinase assay	association, phosphorylation reaction, physical	14523017, 16938345, (Europe PMC)	0.52	BioGRID, IntAct
LCK	Biochemical Activity, cosedimentation in solution, fluorescence technology, protein kinase assay, x-ray crystallography	direct interaction, phosphorylation reaction, physical	17118402, 20372794, 24463463, (Europe PMC)	0.72	BioGRID, IntAct, MINT
LCP2	anti tag coimmunoprecipitation, far western blotting	association, physical association	10556826, 21725281, (Europe PMC)	0.56	IntAct, MINT
LYN	anti bait coimmunoprecipitation	association	18070987, (Europe PMC)	0.35	IntAct, MINT
LZTS2	two hybrid array, two hybrid prey pooling approach, validated two hybrid	physical association	25416956, (Europe PMC)	0.56	IntAct
MAPK1	Biochemical Activity, anti bait coimmunoprecipitation, pull down	physical, physical association	15967991, 8626561, (Europe PMC)	0.52	BioGRID, IntAct, MINT
MED25	classical fluorescence spectroscopy	direct interaction	19290556, (Europe PMC)	0.44	IntAct, MINT
MED28	anti bait coimmunoprecipitation, protein kinase assay, pull down, two hybrid	association, phosphorylation reaction, physical association	10656681, 16899217, (Europe PMC)	0.69	IntAct
MET	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
NR3C1	Affinity Capture-Western, anti bait coimmunoprecipitation, imaging technique	colocalization, physical, physical association	16888650, (Europe PMC)	0.46	BioGRID, IntAct, MINT
PAG1	Reconstituted Complex, anti bait coimmunoprecipitation	association, physical	10790433, 18070987, (Europe PMC)	0.35	BioGRID, IntAct, MINT
PIK3R1	Reconstituted Complex, pull down	physical, physical association	8246987, 8294442, (Europe PMC)	0.40	BioGRID, IntAct, MINT
PRKCQ	Two-hybrid, anti tag coimmunoprecipitation	association, physical, physical association	10383400, 21964608, (Europe PMC)	0.50	BioGRID, IntAct
PTPN12	phosphatase assay	dephosphorylation reaction	19167335, (Europe PMC)	0.44	IntAct
PTPN22	Affinity Capture-MS, Affinity Capture-Western, phosphatase assay, pull down	association, dephosphorylation reaction, direct interaction, physical	16461343, 19167335, 21719704, (Europe PMC)	0.78	BioGRID, IntAct
PTPN6	Biochemical Activity, Reconstituted Complex, phosphatase assay, protein kinase assay	dephosphorylation reaction, phosphorylation reaction, physical	10617656, 11294838, 19167335, 8114715, (Europe PMC)	0.62	BioGRID, IntAct, MINT
PTPRB	phosphatase assay	dephosphorylation reaction	19167335, (Europe PMC)	0.44	IntAct
PTPRC	affinity chromatography technology, anti bait coimmunoprecipitation, phosphatase assay, protein kinase assay, protein phosphatase assay, pull down	dephosphorylation reaction, direct interaction, phosphorylation reaction, physical association	10369126, 19167335, 24463463, 7507203, 8576115, (Europe PMC)	0.44, 0.85	IntAct, MINT
PTPRG	phosphatase assay	dephosphorylation reaction	19167335, (Europe PMC)	0.44	IntAct
PTPRJ	phosphatase assay	dephosphorylation reaction	19167335, (Europe PMC)	0.44	IntAct
PTPRK	phosphatase assay	dephosphorylation reaction	19167335, (Europe PMC)	0.44	IntAct
PTPRM	phosphatase assay	dephosphorylation reaction	19167335, (Europe PMC)	0.44	IntAct
PTPRO	phosphatase assay	dephosphorylation reaction	19167335, (Europe PMC)	0.44	IntAct
PTPRZ1	phosphatase assay	dephosphorylation reaction	19167335, (Europe PMC)	0.44	IntAct
RIN3	Two-hybrid, two hybrid array	physical, physical association	25814554, (Europe PMC)	0.37	BioGRID, IntAct
SH2D1A	anti bait coimmunoprecipitation, two hybrid	association, physical association	15096483, 24688028, (Europe PMC)	0.55	IntAct, MINT
SH2D2A	anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, coimmunoprecipitation, pull down	physical association	10553045, 15827961, 16839418, (Europe PMC)	0.77	IntAct, MINT
SH3BP2	pull down	association	15751964, (Europe PMC)	0.35	IntAct, MINT
SLAMF6	anti bait coimmunoprecipitation	association, physical association	24688028, (Europe PMC)	0.35, 0.40	IntAct
STAT3	anti bait coimmunoprecipitation, two hybrid array, validated two hybrid	association, physical association	18070987, 25814554, (Europe PMC)	0.35, 0.49	IntAct, MINT
SYK	Affinity Capture-Western, Reconstituted Complex, Two-hybrid, coimmunoprecipitation, pull down, two hybrid	association, physical, physical association	15536084, 7539035, 8621719, 8798676, (Europe PMC)	0.75	BioGRID, IntAct, MINT
THEMIS	protein kinase assay, pull down	association, phosphorylation reaction	23460737, (Europe PMC)	0.52	IntAct
UBC	Co-crystal Structure, Protein-peptide, nuclear magnetic resonance, pull down	direct interaction, physical, physical association	18539162, (Europe PMC)	0.54	BioGRID, IntAct, MINT
UHRF2	Far Western, antibody array	physical, physical association	21952639, (Europe PMC)	0.40	BioGRID, IntAct
VAV1	pull down	association	17050525, (Europe PMC)	0.35	IntAct, MINT
WAS	Affinity Capture-Western, Biochemical Activity, pull down	physical, physical association	16107303, 16293614, (Europe PMC)	0.40	BioGRID, IntAct, MINT
WASL	Biochemical Activity, protein kinase assay	phosphorylation reaction, physical	16293614, (Europe PMC)	0.44	BioGRID, IntAct
ZAP70	Affinity Capture-Western, anti tag coimmunoprecipitation, far western blotting, protein kinase assay	association, phosphorylation reaction, physical, physical association	10318843, 10556826, 16461343, 7539035, 8798643, (Europe PMC)	0.70	BioGRID, IntAct, MINT

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Interacting partner	Detection method	Interaction type	PubMed IDs	Interaction Score	Source
ADAM15	Affinity Capture-Western, Reconstituted Complex, anti bait coimmunoprecipitation, pull down	physical, physical association	11741929, 16374509, (Europe PMC)	0.52	BioGRID, IntAct, MINT
BCL3	anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, pull down	physical association	16099425, (Europe PMC)	0.59	IntAct, MINT
CBL	Affinity Capture-Western, Reconstituted Complex, coimmunoprecipitation, pull down	direct interaction, physical, physical association	11904433, 16107303, 7721825, 8621719, 8626543, 8900205, (Europe PMC)	0.75	BioGRID, IntAct, MINT
CD2	Affinity Capture-Western, Reconstituted Complex, experimental interaction detection	phosphorylation reaction, physical	8551220, 9677430, (Europe PMC)	0.31	BioGRID, IntAct, MINT
CD247	Affinity Capture-Western, protein kinase assay, pull down	phosphorylation reaction, physical, physical association	14523017, 16461343, 24463463, 26390156, 8626561, (Europe PMC)	0.44, 0.61	BioGRID, IntAct, MINT
CD3E	Affinity Capture-Western, pull down	association, physical	11855827, 14523017, (Europe PMC)	0.35	BioGRID, IntAct, MINT
CD4	Affinity Capture-MS, Affinity Capture-Western, Two-hybrid, anti bait coimmunoprecipitation	physical, physical association	11854499, 12007789, 15047060, 16888650, 17005671, 17653867, 8246987, (Europe PMC)	0.70	BioGRID, IntAct, MINT
CSNK2B	Two-hybrid, two hybrid	physical, physical association	21900206, (Europe PMC)	0.37	BioGRID, IntAct, MINT
DLG1	anti bait coimmunoprecipitation, proximity ligation assay, pull down	physical association	25241761, 9341123, (Europe PMC)	0.66	IntAct, MINT
G3BP1	Biochemical Activity, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation	physical, physical association	15743820, (Europe PMC)	0.52	BioGRID, IntAct, MINT
HSP90AA1	Affinity Capture-Luminescence, Affinity Capture-Western, anti bait coimmunoprecipitation	physical, physical association	16888650, 22939624, (Europe PMC)	0.40	BioGRID, IntAct, MINT
KHDRBS1	anti bait coimmunoprecipitation, coimmunoprecipitation, pull down	physical association	11278465, 16107303, 16888650, 7852312, 9045636, (Europe PMC)	0.83	IntAct, MINT
LCK	Biochemical Activity, cosedimentation in solution, fluorescence technology, protein kinase assay, x-ray crystallography	direct interaction, phosphorylation reaction, physical	17118402, 20372794, 24463463, (Europe PMC)	0.72	BioGRID, IntAct, MINT
LCP2	anti tag coimmunoprecipitation, far western blotting	association, physical association	10556826, 21725281, (Europe PMC)	0.56	IntAct, MINT
LYN	anti bait coimmunoprecipitation	association	18070987, (Europe PMC)	0.35	IntAct, MINT
MAPK1	Biochemical Activity, anti bait coimmunoprecipitation, pull down	physical, physical association	15967991, 8626561, (Europe PMC)	0.52	BioGRID, IntAct, MINT
MED25	classical fluorescence spectroscopy	direct interaction	19290556, (Europe PMC)	0.44	IntAct, MINT
NR3C1	Affinity Capture-Western, anti bait coimmunoprecipitation, imaging technique	colocalization, physical, physical association	16888650, (Europe PMC)	0.46	BioGRID, IntAct, MINT
PAG1	Reconstituted Complex, anti bait coimmunoprecipitation	association, physical	10790433, 18070987, (Europe PMC)	0.35	BioGRID, IntAct, MINT
PIK3R1	Reconstituted Complex, pull down	physical, physical association	8246987, 8294442, (Europe PMC)	0.40	BioGRID, IntAct, MINT
PTPN6	Biochemical Activity, Reconstituted Complex, phosphatase assay, protein kinase assay	dephosphorylation reaction, phosphorylation reaction, physical	10617656, 11294838, 19167335, 8114715, (Europe PMC)	0.62	BioGRID, IntAct, MINT
PTPRC	affinity chromatography technology, anti bait coimmunoprecipitation, phosphatase assay, protein kinase assay, protein phosphatase assay, pull down	dephosphorylation reaction, direct interaction, phosphorylation reaction, physical association	10369126, 19167335, 24463463, 7507203, 8576115, (Europe PMC)	0.44, 0.85	IntAct, MINT
SH2D1A	anti bait coimmunoprecipitation, two hybrid	association, physical association	15096483, 24688028, (Europe PMC)	0.55	IntAct, MINT
SH2D2A	anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, coimmunoprecipitation, pull down	physical association	10553045, 15827961, 16839418, (Europe PMC)	0.77	IntAct, MINT
SH3BP2	pull down	association	15751964, (Europe PMC)	0.35	IntAct, MINT
STAT3	anti bait coimmunoprecipitation, two hybrid array, validated two hybrid	association, physical association	18070987, 25814554, (Europe PMC)	0.35, 0.49	IntAct, MINT
SYK	Affinity Capture-Western, Reconstituted Complex, Two-hybrid, coimmunoprecipitation, pull down, two hybrid	association, physical, physical association	15536084, 7539035, 8621719, 8798676, (Europe PMC)	0.75	BioGRID, IntAct, MINT
UBC	Co-crystal Structure, Protein-peptide, nuclear magnetic resonance, pull down	direct interaction, physical, physical association	18539162, (Europe PMC)	0.54	BioGRID, IntAct, MINT
VAV1	pull down	association	17050525, (Europe PMC)	0.35	IntAct, MINT
WAS	Affinity Capture-Western, Biochemical Activity, pull down	physical, physical association	16107303, 16293614, (Europe PMC)	0.40	BioGRID, IntAct, MINT
ZAP70	Affinity Capture-Western, anti tag coimmunoprecipitation, far western blotting, protein kinase assay	association, phosphorylation reaction, physical, physical association	10318843, 10556826, 16461343, 7539035, 8798643, (Europe PMC)	0.70	BioGRID, IntAct, MINT

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Interacting partner	Detection method	Interaction type	PubMed IDs	Interaction Score	Source
ACTB	molecular sieving	physical association	15047060, (Europe PMC)	0.40	IntAct
ADAM10	Affinity Capture-Western	physical	11741929, (Europe PMC)	NA	BioGRID
ADAM15	Affinity Capture-Western, Reconstituted Complex, anti bait coimmunoprecipitation, pull down	physical, physical association	11741929, 16374509, (Europe PMC)	0.52	BioGRID, IntAct, MINT
AJUBA	Two-hybrid	physical	15870274, (Europe PMC)	NA	BioGRID
AR	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
ARHGAP17	Reconstituted Complex	physical	11431473, (Europe PMC)	NA	BioGRID
AXL	Far Western	physical	9178760, (Europe PMC)	NA	BioGRID
BAG6	Affinity Capture-Western	physical	22863785, (Europe PMC)	NA	BioGRID
BCAR1	Reconstituted Complex	physical	9020138, (Europe PMC)	NA	BioGRID
BCL3	anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, pull down	physical association	16099425, (Europe PMC)	0.59	IntAct, MINT
BRCA1	Two-hybrid	physical	25184681, (Europe PMC)	NA	BioGRID
CBL	Affinity Capture-Western, Reconstituted Complex, coimmunoprecipitation, pull down	direct interaction, physical, physical association	11904433, 16107303, 7721825, 8621719, 8626543, 8900205, (Europe PMC)	0.75	BioGRID, IntAct, MINT
CBLB	Affinity Capture-Western	physical	21453975, (Europe PMC)	NA	BioGRID
CD2	Affinity Capture-Western, Reconstituted Complex, experimental interaction detection	phosphorylation reaction, physical	8551220, 9677430, (Europe PMC)	0.31	BioGRID, IntAct, MINT
CD247	Affinity Capture-Western, protein kinase assay, pull down	phosphorylation reaction, physical, physical association	14523017, 16461343, 24463463, 26390156, 8626561, (Europe PMC)	0.44, 0.61	BioGRID, IntAct, MINT
CD38	Affinity Capture-Western	physical	14523017, (Europe PMC)	NA	BioGRID
CD3E	Affinity Capture-Western, pull down	association, physical	11855827, 14523017, (Europe PMC)	0.35	BioGRID, IntAct, MINT
CD4	Affinity Capture-MS, Affinity Capture-Western, Two-hybrid, anti bait coimmunoprecipitation	physical, physical association	11854499, 12007789, 15047060, 16888650, 17005671, 17653867, 8246987, (Europe PMC)	0.70	BioGRID, IntAct, MINT
CD44	Affinity Capture-Western, Co-fractionation	physical	8576267, 9573028, (Europe PMC)	NA	BioGRID
CD48	Affinity Capture-Western	physical	12007789, (Europe PMC)	NA	BioGRID
CD5	Affinity Capture-Western	physical	21757751, (Europe PMC)	NA	BioGRID
CD55	Co-localization, proximity ligation assay	physical, physical association	25241761, (Europe PMC)	0.40	BioGRID, IntAct
CDC42	protein kinase assay	phosphorylation reaction	16293614, (Europe PMC)	0.44	IntAct
CDKAL1	Two-hybrid, two hybrid array, two hybrid prey pooling approach, validated two hybrid	physical, physical association	25416956, (Europe PMC)	0.56	BioGRID, IntAct
CISH	Affinity Capture-Western	physical	21234523, (Europe PMC)	NA	BioGRID
CSNK2B	Two-hybrid, two hybrid	physical, physical association	21900206, (Europe PMC)	0.37	BioGRID, IntAct, MINT
CTLA4	Affinity Capture-Western	physical	9712716, (Europe PMC)	NA	BioGRID
CTNND1	Biochemical Activity	physical	12835311, (Europe PMC)	NA	BioGRID
DLG1	Affinity Capture-Western, Co-localization, Reconstituted Complex	physical	25241761, 9341123, (Europe PMC)	NA	BioGRID
DLG1	anti bait coimmunoprecipitation, proximity ligation assay, pull down	physical association	25241761, 9341123, (Europe PMC)	0.66	IntAct, MINT
DOK2	Two-hybrid, two hybrid array, validated two hybrid	physical, physical association	25814554, (Europe PMC)	0.49	BioGRID, IntAct
FAM174A	Protein-peptide	physical	16274251, (Europe PMC)	NA	BioGRID
FAS	Reconstituted Complex, anti bait coimmunoprecipitation	association, physical	20696918, 8864141, (Europe PMC)	0.35	BioGRID, IntAct
FASLG	Reconstituted Complex	physical	11741599, (Europe PMC)	NA	BioGRID
G3BP1	Biochemical Activity, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation	physical, physical association	15743820, (Europe PMC)	0.52	BioGRID, IntAct, MINT
GAB1	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
GATA3	two hybrid array, two hybrid prey pooling approach, validated two hybrid	physical association	26871637, (Europe PMC)	0.56	IntAct
GRB2	protein kinase assay	phosphorylation reaction	23460737, (Europe PMC)	0.44	IntAct
HAVCR2	Affinity Capture-Western, anti bait coimmunoprecipitation, pull down	association, physical	22863785, 26492563, (Europe PMC)	0.46	BioGRID, IntAct
HSP90AA1	Affinity Capture-Luminescence, Affinity Capture-Western, anti bait coimmunoprecipitation	physical, physical association	16888650, 22939624, (Europe PMC)	0.40	BioGRID, IntAct, MINT
HSP90AB1	anti tag coimmunoprecipitation, luminescence based mammalian interactome mapping	physical association	22939624, (Europe PMC)	0.52	IntAct
IKBKG	Reconstituted Complex, protein array	direct interaction, physical	20098747, (Europe PMC)	0.44	BioGRID, IntAct
IL2RB	Affinity Capture-Western	physical	21834013, (Europe PMC)	NA	BioGRID
KHDRBS1	Affinity Capture-Western, Protein-peptide	physical	16107303, 16274251, 16888650, 9045636, (Europe PMC)	NA	BioGRID
KHDRBS1	anti bait coimmunoprecipitation, coimmunoprecipitation, pull down	physical association	11278465, 16107303, 16888650, 7852312, 9045636, (Europe PMC)	0.83	IntAct, MINT
KIT	Affinity Capture-Western, fluorescence polarization spectroscopy	direct interaction, physical	24728074, 9788619, (Europe PMC)	0.44	BioGRID, IntAct
LAT	Affinity Capture-Western, Biochemical Activity, Co-fractionation, anti bait coimmunoprecipitation, protein kinase assay	association, phosphorylation reaction, physical	14523017, 16938345, (Europe PMC)	0.52	BioGRID, IntAct
LCK	Biochemical Activity, cosedimentation in solution, fluorescence technology, protein kinase assay, x-ray crystallography	direct interaction, phosphorylation reaction, physical	17118402, 20372794, 24463463, (Europe PMC)	0.72	BioGRID, IntAct, MINT
LCP2	anti tag coimmunoprecipitation, far western blotting	association, physical association	10556826, 21725281, (Europe PMC)	0.56	IntAct, MINT
LYN	anti bait coimmunoprecipitation	association	18070987, (Europe PMC)	0.35	IntAct, MINT
LZTS2	Two-hybrid	physical	25416956, (Europe PMC)	NA	BioGRID
LZTS2	two hybrid array, two hybrid prey pooling approach, validated two hybrid	physical association	25416956, (Europe PMC)	0.56	IntAct
MAPK1	Biochemical Activity, anti bait coimmunoprecipitation, pull down	physical, physical association	15967991, 8626561, (Europe PMC)	0.52	BioGRID, IntAct, MINT
MED25	classical fluorescence spectroscopy	direct interaction	19290556, (Europe PMC)	0.44	IntAct, MINT
MED28	anti bait coimmunoprecipitation, protein kinase assay, pull down, two hybrid	association, phosphorylation reaction, physical association	10656681, 16899217, (Europe PMC)	0.69	IntAct
MET	fluorescence polarization spectroscopy	direct interaction	24728074, (Europe PMC)	0.44	IntAct
MS4A1	Affinity Capture-Western	physical	7545683, (Europe PMC)	NA	BioGRID
NEDD9	Affinity Capture-Western	physical	8879209, (Europe PMC)	NA	BioGRID
NOTCH1	Affinity Capture-Western	physical	14583609, (Europe PMC)	NA	BioGRID
NR3C1	Affinity Capture-Western, anti bait coimmunoprecipitation, imaging technique	colocalization, physical, physical association	16888650, (Europe PMC)	0.46	BioGRID, IntAct, MINT
PAG1	Reconstituted Complex, anti bait coimmunoprecipitation	association, physical	10790433, 18070987, (Europe PMC)	0.35	BioGRID, IntAct, MINT
PAK2	Reconstituted Complex	physical	16374509, (Europe PMC)	NA	BioGRID
PECAM1	Biochemical Activity	physical	9624175, (Europe PMC)	NA	BioGRID
PI4KA	Reconstituted Complex	physical	8246987, (Europe PMC)	NA	BioGRID
PIK3CA	Affinity Capture-Western, Reconstituted Complex	physical	14583609, 8246987, (Europe PMC)	NA	BioGRID
PIK3R1	Reconstituted Complex, pull down	physical, physical association	8246987, 8294442, (Europe PMC)	0.40	BioGRID, IntAct, MINT
PRKCQ	Two-hybrid, anti tag coimmunoprecipitation	association, physical, physical association	10383400, 21964608, (Europe PMC)	0.50	BioGRID, IntAct
PTK2B	Affinity Capture-Western	physical	9091579, (Europe PMC)	NA	BioGRID
PTPN12	phosphatase assay	dephosphorylation reaction	19167335, (Europe PMC)	0.44	IntAct
PTPN22	Affinity Capture-MS, Affinity Capture-Western, phosphatase assay, pull down	association, dephosphorylation reaction, direct interaction, physical	16461343, 19167335, 21719704, (Europe PMC)	0.78	BioGRID, IntAct
PTPN6	Biochemical Activity, Reconstituted Complex, phosphatase assay, protein kinase assay	dephosphorylation reaction, phosphorylation reaction, physical	10617656, 11294838, 19167335, 8114715, (Europe PMC)	0.62	BioGRID, IntAct, MINT
PTPRB	phosphatase assay	dephosphorylation reaction	19167335, (Europe PMC)	0.44	IntAct
PTPRC	Affinity Capture-Western, Reconstituted Complex	physical	15085197, 8473339, 8576115, (Europe PMC)	NA	BioGRID
PTPRC	affinity chromatography technology, anti bait coimmunoprecipitation, phosphatase assay, protein kinase assay, protein phosphatase assay, pull down	dephosphorylation reaction, direct interaction, phosphorylation reaction, physical association	10369126, 19167335, 24463463, 7507203, 8576115, (Europe PMC)	0.44, 0.85	IntAct, MINT
PTPRG	phosphatase assay	dephosphorylation reaction	19167335, (Europe PMC)	0.44	IntAct
PTPRJ	phosphatase assay	dephosphorylation reaction	19167335, (Europe PMC)	0.44	IntAct
PTPRK	phosphatase assay	dephosphorylation reaction	19167335, (Europe PMC)	0.44	IntAct
PTPRM	phosphatase assay	dephosphorylation reaction	19167335, (Europe PMC)	0.44	IntAct
PTPRO	phosphatase assay	dephosphorylation reaction	19167335, (Europe PMC)	0.44	IntAct
PTPRZ1	phosphatase assay	dephosphorylation reaction	19167335, (Europe PMC)	0.44	IntAct
PXN	Affinity Capture-Western	physical	9488700, (Europe PMC)	NA	BioGRID
RAF1	Affinity Capture-Western	physical	8939988, (Europe PMC)	NA	BioGRID
RASA1	Biochemical Activity	physical	11389730, (Europe PMC)	NA	BioGRID
RIN3	Two-hybrid, two hybrid array	physical, physical association	25814554, (Europe PMC)	0.37	BioGRID, IntAct
SH2B3	Affinity Capture-Western	physical	10799879, (Europe PMC)	NA	BioGRID
SH2D1A	anti bait coimmunoprecipitation, two hybrid	association, physical association	15096483, 24688028, (Europe PMC)	0.55	IntAct, MINT
SH2D2A	anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, coimmunoprecipitation, pull down	physical association	10553045, 15827961, 16839418, (Europe PMC)	0.77	IntAct, MINT
SH3BP2	pull down	association	15751964, (Europe PMC)	0.35	IntAct, MINT
SH3KBP1	Affinity Capture-Western	physical	15707590, (Europe PMC)	NA	BioGRID
SIT1	Affinity Capture-Western	physical	10209036, (Europe PMC)	NA	BioGRID
SKAP1	Affinity Capture-Western, Reconstituted Complex	physical	10229084, 9195899, (Europe PMC)	NA	BioGRID
SLAMF6	anti bait coimmunoprecipitation	association, physical association	24688028, (Europe PMC)	0.35, 0.40	IntAct
SMAD2	Reconstituted Complex	physical	16806069, (Europe PMC)	NA	BioGRID
SMAD3	Reconstituted Complex	physical	16806069, (Europe PMC)	NA	BioGRID
SMURF1	Biochemical Activity	physical	20804422, (Europe PMC)	NA	BioGRID
SOCS1	Affinity Capture-Western	physical	21234523, (Europe PMC)	NA	BioGRID
SOCS2	Affinity Capture-Western	physical	21234523, (Europe PMC)	NA	BioGRID
SOCS3	Affinity Capture-Western	physical	21234523, (Europe PMC)	NA	BioGRID
SOS1	Protein-peptide	physical	16274251, (Europe PMC)	NA	BioGRID
SQSTM1	Reconstituted Complex	physical	8650207, (Europe PMC)	NA	BioGRID
STAT3	Two-hybrid	physical	25814554, (Europe PMC)	NA	BioGRID
STAT3	anti bait coimmunoprecipitation, two hybrid array, validated two hybrid	association, physical association	18070987, 25814554, (Europe PMC)	0.35, 0.49	IntAct, MINT
SYK	Affinity Capture-Western, Reconstituted Complex, Two-hybrid, coimmunoprecipitation, pull down, two hybrid	association, physical, physical association	15536084, 7539035, 8621719, 8798676, (Europe PMC)	0.75	BioGRID, IntAct, MINT
THEMIS	protein kinase assay, pull down	association, phosphorylation reaction	23460737, (Europe PMC)	0.52	IntAct
THY1	Affinity Capture-Western	physical	1351058, (Europe PMC)	NA	BioGRID
TRAT1	Reconstituted Complex	physical	10790433, (Europe PMC)	NA	BioGRID
TRPV4	Affinity Capture-Western	physical	12538589, (Europe PMC)	NA	BioGRID
UBC	Co-crystal Structure, Protein-peptide, nuclear magnetic resonance, pull down	direct interaction, physical, physical association	18539162, (Europe PMC)	0.54	BioGRID, IntAct, MINT
UBE3A	Reconstituted Complex, Two-hybrid	physical	10449731, (Europe PMC)	NA	BioGRID
UHRF2	Far Western, antibody array	physical, physical association	21952639, (Europe PMC)	0.40	BioGRID, IntAct
UNC119	Affinity Capture-Western, Reconstituted Complex	physical	14757743, (Europe PMC)	NA	BioGRID
VAV1	pull down	association	17050525, (Europe PMC)	0.35	IntAct, MINT
WAS	Affinity Capture-Western, Biochemical Activity, pull down	physical, physical association	16107303, 16293614, (Europe PMC)	0.40	BioGRID, IntAct, MINT
WASL	Biochemical Activity, protein kinase assay	phosphorylation reaction, physical	16293614, (Europe PMC)	0.44	BioGRID, IntAct
YWHAQ	Affinity Capture-Western	physical	19010391, (Europe PMC)	NA	BioGRID
ZAP70	Affinity Capture-Western, anti tag coimmunoprecipitation, far western blotting, protein kinase assay	association, phosphorylation reaction, physical, physical association	10318843, 10556826, 16461343, 7539035, 8798643, (Europe PMC)	0.70	BioGRID, IntAct, MINT

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LCK