BioPAX pathway converted from "SYK binds IL2RB" in the Reactome database.SYK binds IL2RBSYK binds IL2RBSyk binds to the serine-rich (aa 267 to 322) S region of IL2RB and becomes activated upon IL-2 stimulation (Minami et al. 1995).<br>Syk is shown here binding with the IL2:IL2RB trimer:p-JAK1:JAK3 complex but it may become associated at an earlier stage of receptor activation.Authored: Ray, KP, 2010-05-17Reviewed: Villarino, A, 2011-02-11Reviewed: Dooms, H, 2011-03-17Edited: Jupe, S, 2010-08-06Reactome DB_ID: 4519201plasma membraneGO0005886IL2:IL2R trimer:p-JAK1:JAK3 [plasma membrane]IL2:IL2R trimer:p-JAK1:JAK3Reactome DB_ID: 4519111IL2RG:JAK3 [plasma membrane]IL2RG:JAK3Reactome DB_ID: 4518931cytosolGO0005829UniProt:P52333 JAK3JAK3JAK3FUNCTION Non-receptor tyrosine kinase involved in various processes such as cell growth, development, or differentiation. Mediates essential signaling events in both innate and adaptive immunity and plays a crucial role in hematopoiesis during T-cells development. In the cytoplasm, plays a pivotal role in signal transduction via its association with type I receptors sharing the common subunit gamma such as IL2R, IL4R, IL7R, IL9R, IL15R and IL21R. Following ligand binding to cell surface receptors, phosphorylates specific tyrosine residues on the cytoplasmic tails of the receptor, creating docking sites for STATs proteins. Subsequently, phosphorylates the STATs proteins once they are recruited to the receptor. Phosphorylated STATs then form homodimer or heterodimers and translocate to the nucleus to activate gene transcription. For example, upon IL2R activation by IL2, JAK1 and JAK3 molecules bind to IL2R beta (IL2RB) and gamma chain (IL2RG) subunits inducing the tyrosine phosphorylation of both receptor subunits on their cytoplasmic domain. Then, STAT5A AND STAT5B are recruited, phosphorylated and activated by JAK1 and JAK3. Once activated, dimerized STAT5 translocates to the nucleus and promotes the transcription of specific target genes in a cytokine-specific fashion.SUBUNIT Interacts with STAM2 and MYO18A (By similarity). Interacts with SHB.TISSUE SPECIFICITY In NK cells and an NK-like cell line but not in resting T-cells or in other tissues. The S-form is more commonly seen in hematopoietic lines, whereas the B-form is detected in cells both of hematopoietic and epithelial origins.DOMAIN Possesses two phosphotransferase domains. The second one probably contains the catalytic domain (By similarity), while the presence of slight differences suggest a different role for domain 1.PTM Tyrosine phosphorylated in response to IL-2 and IL-4. Dephosphorylation of Tyr-980 and Tyr-981 by PTPN2 negatively regulates cytokine-mediated signaling (Probable).SIMILARITY Belongs to the protein kinase superfamily. Tyr protein kinase family. JAK subfamily.Reactomehttp://www.reactome.orgHomo sapiensNCBI Taxonomy9606UniProtP52333Chain Coordinates1EQUAL1124EQUALReactome DB_ID: 4491391UniProt:P31785 IL2RGIL2RGIL2RGFUNCTION Common subunit for the receptors for a variety of interleukins. Probably in association with IL15RA, involved in the stimulation of neutrophil phagocytosis by IL15 (PubMed:15123770).SUBUNIT The gamma subunit is common to the IL2, IL4, IL7, IL15, IL21 and probably also the IL13 receptors. Interacts with SHB upon interleukin stimulation.SUBUNIT (Microbial infection) Interacts with HTLV-1 accessory protein p12I.DOMAIN The WSXWS motif appears to be necessary for proper protein folding and thereby efficient intracellular transport and cell-surface receptor binding.DOMAIN The box 1 motif is required for JAK interaction and/or activation.SIMILARITY Belongs to the type I cytokine receptor family. Type 5 subfamily.UniProtP3178523EQUAL369EQUALReactome Database ID Release 75451911Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451911ReactomeR-HSA-4519111Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-451911.1Reactome DB_ID: 4519391IL2RA:IL2RB:p-JAK1:IL2 [plasma membrane]IL2RA:IL2RB:p-JAK1:IL2Reactome DB_ID: 4470991extracellular regionGO0005576UniProt:P60568 IL2IL2IL2FUNCTION Produced by T-cells in response to antigenic or mitogenic stimulation, this protein is required for T-cell proliferation and other activities crucial to regulation of the immune response. Can stimulate B-cells, monocytes, lymphokine-activated killer cells, natural killer cells, and glioma cells.DISEASE A chromosomal aberration involving IL2 is found in a form of T-cell acute lymphoblastic leukemia (T-ALL). Translocation t(4;16)(q26;p13) with involves TNFRSF17.PHARMACEUTICAL Available under the name Proleukin (Chiron). Used in patients with renal cell carcinoma or metastatic melanoma.SIMILARITY Belongs to the IL-2 family.UniProtP6056821EQUAL153EQUALReactome DB_ID: 4519181IL2RA:IL2RB:p-JAK1 [plasma membrane]IL2RA:IL2RB:p-JAK1Interleukin-2 receptor alpha:beta:JAK1Reactome DB_ID: 4500461UniProt:P01589 IL2RAIL2RAIL2RAFUNCTION Receptor for interleukin-2. The receptor is involved in the regulation of immune tolerance by controlling regulatory T cells (TREGs) activity. TREGs suppress the activation and expansion of autoreactive T-cells.SUBUNIT Non-covalent dimer of an alpha and a beta subunit. IL2R exists in 3 different forms: a high affinity dimer, an intermediate affinity monomer (beta subunit), and a low affinity monomer (alpha subunit). The high and intermediate affinity forms also associate with a gamma subunit.UniProtP0158922EQUAL272EQUALReactome DB_ID: 4519431IL2RB:p-JAK1 [plasma membrane]IL2RB:p-JAK1Reactome DB_ID: 4519211UniProt:P23458 JAK1JAK1JAK1BJAK1AJAK1FUNCTION Tyrosine kinase of the non-receptor type, involved in the IFN-alpha/beta/gamma signal pathway (PubMed:7615558). Kinase partner for the interleukin (IL)-2 receptor (PubMed:11909529) as well as interleukin (IL)-10 receptor (PubMed:12133952).SUBUNIT Interacts with IL31RA (PubMed:15194700). Interacts with IFNAR2 (PubMed:7759950). Interacts with IFNGR1 (PubMed:7615558). Interacts with JAKMIP1 (PubMed:15277531). Interacts with SHB (PubMed:12200137). Interacts (via N-terminus) with IL2RB and IL10RA (via its cytoplasmic domain) (PubMed:12133952). Interacts with FER (By similarity).TISSUE SPECIFICITY Expressed at higher levels in primary colon tumors than in normal colon tissue. The expression level in metastatic colon tumors is comparable to the expression level in normal colon tissue.DOMAIN Possesses two phosphotransferase domains. The second one probably contains the catalytic domain, while the presence of slight differences suggest a different role for domain 1.DOMAIN The FERM domain mediates interaction with JAKMIP1.PTM Autophosphorylated (PubMed:7615558). Phosphorylated on tyrosine residues in response to interferon gamma signaling (PubMed:7615558). Dephosphorylation of Tyr-1034 and Tyr-1035 by PTPN2 negatively regulates cytokine-mediated signaling (PubMed:11909529).PTM Ubiquitinated by RNF125; leading to its degradation by the proteasome.SIMILARITY Belongs to the protein kinase superfamily. Tyr protein kinase family. JAK subfamily.UniProtP23458O4'-phospho-L-tyrosine at unknown positionO4'-phospho-L-tyrosine [MOD:00048]1EQUAL1154EQUALReactome DB_ID: 1978761UniProt:P14784 IL2RBIL2RBIL15RBIL2RBFUNCTION Receptor for interleukin-2. This beta subunit is involved in receptor mediated endocytosis and transduces the mitogenic signals of IL2. Probably in association with IL15RA, involved in the stimulation of neutrophil phagocytosis by IL15 (PubMed:15123770, PubMed:31040185).SUBUNIT Non-covalent dimer of an alpha and a beta subunit. IL2R exists in 3 different forms: a high affinity dimer, an intermediate affinity monomer (beta subunit), and a low affinity monomer (alpha subunit). The high and intermediate affinity forms also associate with a gamma subunit. Interacts with SHB upon interleukin stimulation.SUBUNIT (Microbial infection) Interacts with HTLV-1 accessory protein p12I.DOMAIN The WSXWS motif appears to be necessary for proper protein folding and thereby efficient intracellular transport and cell-surface receptor binding.DOMAIN The box 1 motif is required for JAK interaction and/or activation.SIMILARITY Belongs to the type I cytokine receptor family. Type 4 subfamily.UniProtP1478427EQUAL551EQUALReactome Database ID Release 75451943Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451943ReactomeR-HSA-4519431Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-451943.1Reactome Database ID Release 75451918Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451918ReactomeR-HSA-4519181Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-451918.1Reactome Database ID Release 75451939Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451939ReactomeR-HSA-4519391Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-451939.1Reactome Database ID Release 75451920Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451920ReactomeR-HSA-4519201Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-451920.1Reactome DB_ID: 582681UniProt:P43405 SYKSYKSYKFUNCTION Non-receptor tyrosine kinase which mediates signal transduction downstream of a variety of transmembrane receptors including classical immunoreceptors like the B-cell receptor (BCR). Regulates several biological processes including innate and adaptive immunity, cell adhesion, osteoclast maturation, platelet activation and vascular development. Assembles into signaling complexes with activated receptors at the plasma membrane via interaction between its SH2 domains and the receptor tyrosine-phosphorylated ITAM domains. The association with the receptor can also be indirect and mediated by adapter proteins containing ITAM or partial hemITAM domains. The phosphorylation of the ITAM domains is generally mediated by SRC subfamily kinases upon engagement of the receptor. More rarely signal transduction via SYK could be ITAM-independent. Direct downstream effectors phosphorylated by SYK include VAV1, PLCG1, PI-3-kinase, LCP2 and BLNK. Initially identified as essential in B-cell receptor (BCR) signaling, it is necessary for the maturation of B-cells most probably at the pro-B to pre-B transition. Activated upon BCR engagement, it phosphorylates and activates BLNK an adapter linking the activated BCR to downstream signaling adapters and effectors. It also phosphorylates and activates PLCG1 and the PKC signaling pathway. It also phosphorylates BTK and regulates its activity in B-cell antigen receptor (BCR)-coupled signaling. In addition to its function downstream of BCR plays also a role in T-cell receptor signaling. Plays also a crucial role in the innate immune response to fungal, bacterial and viral pathogens. It is for instance activated by the membrane lectin CLEC7A. Upon stimulation by fungal proteins, CLEC7A together with SYK activates immune cells inducing the production of ROS. Also activates the inflammasome and NF-kappa-B-mediated transcription of chemokines and cytokines in presence of pathogens. Regulates neutrophil degranulation and phagocytosis through activation of the MAPK signaling cascade (By similarity). Required for the stimulation of neutrophil phagocytosis by IL15 (PubMed:15123770). Also mediates the activation of dendritic cells by cell necrosis stimuli. Also involved in mast cells activation. Involved in interleukin-3/IL3-mediated signaling pathway in basophils (By similarity). Also functions downstream of receptors mediating cell adhesion. Relays for instance, integrin-mediated neutrophils and macrophages activation and P-selectin receptor/SELPG-mediated recruitment of leukocytes to inflammatory loci. Plays also a role in non-immune processes. It is for instance involved in vascular development where it may regulate blood and lymphatic vascular separation. It is also required for osteoclast development and function. Functions in the activation of platelets by collagen, mediating PLCG2 phosphorylation and activation. May be coupled to the collagen receptor by the ITAM domain-containing FCER1G. Also activated by the membrane lectin CLEC1B that is required for activation of platelets by PDPN/podoplanin. Involved in platelet adhesion being activated by ITGB3 engaged by fibrinogen. Together with CEACAM20, enhances production of the cytokine CXCL8/IL-8 via the NFKB pathway and may thus have a role in the intestinal immune response (By similarity).ACTIVITY REGULATION Autoinhibited. Intramolecular binding of the interdomains A and B (also called linker region) to parts of the catalytic domain keep the catalytic center in an inactive conformation. The phosphorylation of the interdomains or the binding of the SH2 domains with dually phosphorylated ITAM domains on transmembrane proteins disrupt those intramolecular interactions allowing the kinase domain to adopt an active conformation. The phosphorylation of SYK and of the ITAM domains which is responsible for SYK activation is essentially mediated by SRC subfamily kinases, like LYN, upon transmembrane receptors engagement. May also be negatively regulated by PTPN6 through dephosphorylation. Downstream signaling adapters and intermediates like BLNK or RHOH may mediate positive and/or negative feedback regulation. Negatively regulated by CBL and CBLB through ubiquitination and probable degradation. Phosphorylates SH3BP2 which in turn may regulate SYK through LYN (By similarity).SUBUNIT Interacts with LYN; phosphorylates SYK (By similarity). Interacts with RHOH (phosphorylated); regulates mast cells activation (By similarity). Interacts with NFAM1 (phosphorylated); probably involved in BCR signaling (By similarity). Interacts with VAV1 (via SH2 domain); phosphorylates VAV1 upon BCR activation. Interacts with GAB2 (phosphorylated); probably involved in IgE Fc receptor signaling (By similarity). Interacts (via its SH2 domains) with CD79A (via its phosphorylated ITAM domain); the interaction stimulates SYK autophosphorylation and activation (By similarity). Interacts with FCRL3 (PubMed:19843936, PubMed:11162587). Interacts (via SH2 domains) with FCER1G (via ITAM domain); activates SYK and mediates neutrophils and macrophages integrin-mediated activation (By similarity). Interaction with FCER1G in basophils triggers IL3-induced IL4 production (By similarity). Interacts with ITGB2 and FGR; involved in ITGB2 downstream signaling (By similarity). Interacts with ITGB3; upon activation by ITGB3 promotes platelet adhesion. Interacts (via SH2 domains) with TYROBP (via ITAM domain); involved in neutrophils and macrophages integrin-mediated activation (By similarity). Interacts with MSN and SELPLG; mediates the selectin-dependent activation of SYK by SELPLG. Interacts with BLNK (via SH2 domain). Interacts (via the second SH2 domain) with USP25 (via C-terminus); phosphorylates USP25 and regulates USP25 intracellular levels. Interacts (via SH2 domains) with CLEC1B (dimer). Interacts with CLEC7A; participates in leukocyte activation in presence of fungal pathogens. Interacts (phosphorylated) with SLA; may regulate SYK through CBL recruitment. Interacts with YWHAG; attenuates BCR-induced membrane translocation and activation of SYK. Interacts (via SH2 domains) with GCSAM; the interaction increases after B-cell receptor stimulation, resulting in enhanced SYK autophosphorylation and activity. Interacts with TNS2; leading to the phosphorylation of SYK (PubMed:22019427). Interacts with FLNA (via filamin repeat 5); docks SYK to the plasma membrane (PubMed:20713593). Interacts with CEACAM1; lipopolysaccharide activated neutrophils induce phosphorylation of SYK resulting in the formation of a complex including TLR4 and the phosphorylated form of SYK and CEACAM1, which in turn, recruits PTPN6 that dephosphorylates SYK, reducing the production of reactive oxygen species (ROS) and lysosome disruption, leading to a reduction of the inflammasome activity (By similarity). Interacts (via SH2 domains) with CEACAM20 (phosphorylated form); the interaction further enhances CEACAM20 phosphorylation (By similarity). Interacts with IL15RA (PubMed:15123770).SUBUNIT (Microbial infection) Interacts with Epstein-Barr virus LMP2A.TISSUE SPECIFICITY Widely expressed in hematopoietic cells (at protein level) (PubMed:8163536). Expressed in neutrophils (at protein level) (PubMed:15123770). Within the B-cell compartment, expressed from pro- and pre-B cells to plasma cells (PubMed:8163536).DOMAIN The SH2 domains mediate the interaction of SYK with the phosphorylated ITAM domains of transmembrane proteins. Some proteins like CLEC1B have a partial ITAM domain (also called hemITAM) containing a single YxxL motif. The interaction with SYK requires CLEC1B homodimerization.PTM Ubiquitinated by CBLB after BCR activation; which promotes proteasomal degradation.PTM Autophosphorylated. Phosphorylated on tyrosine residues by LYN following receptors engagement. Phosphorylation on Tyr-323 creates a binding site for CBL, an adapter protein that serves as a negative regulator of BCR-stimulated calcium ion signaling. Phosphorylation at Tyr-348 creates a binding site for VAV1. Phosphorylation on Tyr-348 and Tyr-352 enhances the phosphorylation and activation of phospholipase C-gamma and the early phase of calcium ion mobilization via a phosphoinositide 3-kinase-independent pathway (By similarity). Phosphorylated on tyrosine residues in response to IL15 (PubMed:15123770). Phosphorylation on Ser-297 is very common, it peaks 5 minutes after BCR stimulation, and creates a binding site for YWHAG. Phosphorylation at Tyr-630 creates a binding site for BLNK. Dephosphorylated by PTPN6.SIMILARITY Belongs to the protein kinase superfamily. Tyr protein kinase family. SYK/ZAP-70 subfamily.UniProtP434051EQUAL635EQUALReactome DB_ID: 5084491IL2:IL2R trimer:p-JAK1:JAK3:SYK [plasma membrane]IL2:IL2R trimer:p-JAK1:JAK3:SYKReactome DB_ID: 4519201Reactome DB_ID: 5826811EQUAL635EQUALReactome Database ID Release 75508449Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=508449ReactomeR-HSA-5084491Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-508449.1Reactome Database ID Release 75508292Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=508292ReactomeR-HSA-5082924Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-508292.47600304Pubmed1995Protein tyrosine kinase Syk is associated with and activated by the IL-2 receptor: possible link with the c-myc induction pathwayMinami, YNakagawa, YKawahara, AMiyazaki, TSada, KYamamura, HTaniguchi, TImmunity 2:89-100