BioPAX pathway converted from "IL15:IL15RA binds IL2RB:JAK1 and IL2RG:JAK3" in the Reactome database.LEFT-TO-RIGHTIL15:IL15RA binds IL2RB:JAK1 and IL2RG:JAK3The Interleukin-15 (IL15) / Interleukin-15 receptor subunit alpha (IL15RA, IL15Rα) complex binds Interleukin-2 receptor subunit beta (IL2RB, IL2Rβ), which is associated with Tyrosine-protein kinase JAK1 (JAK1) and Cytokine receptor common subunit gamma (IL2RG, IL2Rγ), which is associated with Tyrosine-protein kinase JAK3 (JAK3) (Johnston et al. 1995). The heterodimer of IL2RB and IL2RG can bind IL15 with low affinity but high affinity binding requires a third component, IL15RA (Giri et al. 1994, 1995, Anderson et al. 1995). This is a Black Box Event because it is not clear whether the beta and gamma subunits pre-associate before binding IL15:IL15RA.Authored: Jupe, Steve, 2014-06-04Reviewed: Meldal, Birgit, 2016-01-28Reviewed: Patidar, Manoj, 2017-08-07Edited: Jupe, Steve, 2016-01-28Edited: Duenas, Corina, 2017-08-09IL2RG:JAK3Reactome DB_ID: 451911plasma membraneGENE ONTOLOGYGO:0005886JAK3Tyrosine-protein kinase JAK3JAK3_HUMANJanus kinase 3Reactome DB_ID: 451893cytosolGENE ONTOLOGYGO:0005829UniProt:P52333 JAK3JAK3FUNCTION 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.Homo sapiensNCBI Taxonomy9606UniProtP523331EQUAL1124EQUALReactome Database ID Release 75451893Database 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=451893ReactomeR-HSA-4518931Reactome 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-451893.1Reactomehttp://www.reactome.org1IL2RGCytokine receptor common gamma chainInterleukin-2 receptor gamma chainIL2RG_HUMANGamma cReactome DB_ID: 449139UniProt:P31785 IL2RGIL2RGFUNCTION 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 75449139Database 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=449139ReactomeR-HSA-4491393Reactome 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-449139.31Reactome 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-451911.1IL15:IL15RAReactome DB_ID: 8983124IL15Interleukin-15IL15_HUMANReactome DB_ID: 447242extracellular regionGENE ONTOLOGYGO:0005576UniProt:P40933 IL15IL15FUNCTION Cytokine that stimulates the proliferation of T-lymphocytes (PubMed:8178155). Stimulation by IL15 requires interaction of IL15 with components of the IL2 receptor, including IL2RB and probably IL2RG but not IL2RA (PubMed:8178155). In neutrophils, stimulates phagocytosis probably by signaling through the IL15 receptor, composed of the subunits IL15RA, IL2RB and IL2RG, which results in kinase SYK activation (PubMed:15123770).TISSUE SPECIFICITY Most abundant in placenta and skeletal muscle. It is also detected in the heart, lung, liver and kidney. IL15-S21AA is preferentially expressed in tissues such as testis and thymus.SIMILARITY Belongs to the IL-15/IL-21 family.UniProtP4093349EQUAL162EQUALReactome Database ID Release 75447242Database 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=447242ReactomeR-HSA-4472422Reactome 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-447242.21IL15RAInterleukin-15 receptor subunit alphaI15RA_HUMANReactome DB_ID: 449122UniProt:Q13261 IL15RAIL15RAFUNCTION High-affinity receptor for interleukin-15 (PubMed:8530383). Can signal both in cis and trans where IL15R from one subset of cells presents IL15 to neighboring IL2RG-expressing cells (By similarity). In neutrophils, binds and activates kinase SYK in response to IL15 stimulation (PubMed:15123770). In neutrophils, required for IL15-induced phagocytosis in a SYK-dependent manner (PubMed:15123770). Expression of different isoforms may alter or interfere with signal transduction (PubMed:10480910).SUBUNIT The interleukin-15 receptor IL15R is a heterotrimer of IL15RA, IL2RB and IL2RG. IL15RA also self-associates (PubMed:17643103). Interacts with SYK (PubMed:15123770).TISSUE SPECIFICITY Expressed in neutrophils (at protein level) (PubMed:15123770). Expressed in fetal brain with higher expression in the hippocampus and cerebellum than in cortex and thalamus (PubMed:12114302). Higher levels of soluble sIL-15RA form in comparison with membrane-bound forms is present in all brain structures (PubMed:12114302). Isoforms 1, 3, 4, 5, 6, 7, 8 and 9: Widely expressed (PubMed:10480910, PubMed:8530383).PTM N-glycosylated and O-glycosylated.PTM A soluble form (sIL-15RA) arises from proteolytic shedding of the membrane-anchored receptor (PubMed:15265897). It also binds IL-15 and thus interferes with IL-15 binding to the membrane receptor (PubMed:15265897).UniProtQ1326131EQUAL267EQUALReactome Database ID Release 75449122Database 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=449122ReactomeR-HSA-4491222Reactome 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-449122.21Reactome Database ID Release 758983124Database 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=8983124ReactomeR-HSA-89831241Reactome 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-8983124.1IL2RB:JAK1Reactome DB_ID: 451905IL2RBInterleukin-2 receptor beta chainIL2B_HUMANReactome DB_ID: 197876UniProt:P14784 IL2RBIL2RBIL15RBFUNCTION 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 75197876Database 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=197876ReactomeR-HSA-1978762Reactome 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-197876.21JAK1Tyrosine-protein kinase JAK1JAK1_HUMANJanus kinase 1Reactome DB_ID: 451898UniProt:P23458 JAK1JAK1JAK1AJAK1BFUNCTION 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.UniProtP234581EQUAL1154EQUALReactome Database ID Release 75451898Database 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=451898ReactomeR-HSA-4518982Reactome 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-451898.21Reactome Database ID Release 75451905Database 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=451905ReactomeR-HSA-4519051Reactome 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-451905.1IL15RA:IL15:IL2RB:JAK1:IL2RG:JAK3Interleukin-15 receptor:Interleukin-15Reactome DB_ID: 449120111Reactome Database ID Release 75449120Database 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=449120ReactomeR-HSA-4491202Reactome 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-449120.2Reactome Database ID Release 75449115Database 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=449115ReactomeR-HSA-4491153Reactome 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-449115.38530383Pubmed1995Functional characterization of the human interleukin-15 receptor alpha chain and close linkage of IL15RA and IL2RA genesAnderson, DMKumaki, SAhdieh, MBertles, JTometsko, MLoomis, AGiri, JCopeland, NGGilbert, DJJenkins, NAJ Biol Chem 270:29862-97641685Pubmed1995Identification and cloning of a novel IL-15 binding protein that is structurally related to the alpha chain of the IL-2 receptorGiri, JGKumaki, SAhdieh, MFriend, DJLoomis, AShanebeck, KDuBose, RCosman, DPark, LSAnderson, DMEMBO J 14:3654-638026467Pubmed1994Utilization of the beta and gamma chains of the IL-2 receptor by the novel cytokine IL-15Giri, J GAhdieh, MEisenman, JShanebeck, KGrabstein, KKumaki, SNamen, APark, L SCosman, DAnderson, DEMBO J. 13:2822-307568001Pubmed1995Tyrosine phosphorylation and activation of STAT5, STAT3, and Janus kinases by interleukins 2 and 15Johnston, JABacon, CMFinbloom, DSRees, RCKaplan, DShibuya, KOrtaldo, JRGupta, SChen, YQGiri, JDProc Natl Acad Sci U S A 92:8705-9