BioPAX pathway converted from "Phosphorylated STAT5 is released" in the Reactome database.LEFT-TO-RIGHTPhosphorylated STAT5 is releasedDeletion mutants have demonstrated that STAT dimerization can occur independently of the binding of 2 STAT molecules by a dimeric receptor. Although this does not exclude the possibility that STATs may dimerize while still associated with the receptor complex, dimerization is believe to occur following the release of phosphorylated monomers (e.g. Turkson & Jove 2000).Authored: Ray, KP, 2010-05-17Reviewed: Villarino, A, 2011-02-11Reviewed: Dooms, H, 2011-03-17Edited: Jupe, S, 2010-08-06IL2:IL2R trimer p-(Y338,Y392, Y510) beta subunit:p-JAK1:JAK3:p-STAT5Reactome DB_ID: 507943plasma membraneGENE ONTOLOGYGO:0005886IL2:IL2R trimer p-(Y338,392,510) beta subunit:p-JAK1:JAK3Reactome DB_ID: 452119IL2RG:JAK3Reactome DB_ID: 451911JAK3Tyrosine-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-451911.11IL2Interleukin-2IL2_HUMANReactome DB_ID: 447099extracellular regionGENE ONTOLOGYGO:0005576UniProt:P60568 IL2IL2FUNCTION 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 Database ID Release 75447099Database 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=447099ReactomeR-HSA-4470991Reactome 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-447099.11p-JAK1p-Y-JAK1Phosphorylated tyrosine-protein kinase JAK1JAK1_HUMANJanus kinase 1Reactome DB_ID: 451921UniProt: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.UniProtP23458O4'-phospho-L-tyrosineMODMOD:000481EQUAL1154EQUALReactome Database ID Release 75451921Database 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=451921ReactomeR-HSA-4519211Reactome 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-451921.11CD25IL2RAInterleukin-2 receptor alpha chainIL2RA_HUMANReactome DB_ID: 450046UniProt:P01589 IL2RAIL2RAFUNCTION 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 Database ID Release 75450046Database 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=450046ReactomeR-HSA-4500462Reactome 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-450046.21IL2B_HUMANp-Y364,Y418,Y536-IL2RBp(Y338,392,510)-IL2RBInterleukin-2 receptor beta chainReactome DB_ID: 452093UniProt: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.UniProtP14784364EQUAL418EQUAL536EQUAL27EQUAL551EQUALReactome Database ID Release 75452093Database 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=452093ReactomeR-HSA-4520931Reactome 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-452093.11Reactome Database ID Release 75452119Database 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=452119ReactomeR-HSA-4521191Reactome 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-452119.11Converted from EntitySet in Reactomep-STAT5p-STAT5A, p-STAT5BReactome DB_ID: 507929STA5A_HUMANp-Y694-STAT5Ap(Y694)-STAT5ASignal transducer and activator of transcription 5AReactome DB_ID: 507936UniProt:P42229 STAT5ASTAT5ASTAT5FUNCTION Carries out a dual function: signal transduction and activation of transcription. Mediates cellular responses to the cytokine KITLG/SCF and other growth factors. Mediates cellular responses to ERBB4. May mediate cellular responses to activated FGFR1, FGFR2, FGFR3 and FGFR4. Binds to the GAS element and activates PRL-induced transcription. Regulates the expression of milk proteins during lactation.SUBUNIT Forms a homodimer or a heterodimer with a related family member. Binds NR3C1 (By similarity). Interacts with NCOA1 and SOCS7. Interacts with ERBB4.PTM Tyrosine phosphorylated in response to KITLG/SCF, IL2, IL3, IL7, IL15, CSF2/GMCSF, GH1, PRL, EPO and THPO (By similarity). Activated KIT promotes phosphorylation on tyrosine residues and subsequent translocation to the nucleus (PubMed:21135090). Tyrosine phosphorylated in response to constitutively activated FGFR1, FGFR2, FGFR3 and FGFR4 (By similarity). Tyrosine phosphorylation is required for DNA-binding activity and dimerization. Serine phosphorylation is also required for maximal transcriptional activity (By similarity). Tyrosine phosphorylated in response to signaling via activated FLT3; wild-type FLT3 results in much weaker phosphorylation than constitutively activated mutant FLT3 (PubMed:14504097). Alternatively, can be phosphorylated by JAK2 at Tyr-694 (PubMed:12529425).PTM ISGylated.SIMILARITY Belongs to the transcription factor STAT family.CAUTION It was reported that dephosphorylation on tyrosine residues by PTPN2 would negatively regulate prolactin signaling pathway (PubMed:11773439). However, the corresponding article has been retracted (PubMed:24319783).UniProtP42229694EQUAL1EQUAL794EQUALReactome Database ID Release 75507936Database 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=507936ReactomeR-HSA-5079361Reactome 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-507936.1STA5B_HUMANp-Y699-STAT5Bp(Y699)-STAT5BSignal transducer and activator of transcription 5BReactome DB_ID: 507939UniProt:P51692 STAT5BSTAT5BFUNCTION Carries out a dual function: signal transduction and activation of transcription. Mediates cellular responses to the cytokine KITLG/SCF and other growth factors. Binds to the GAS element and activates PRL-induced transcription. Positively regulates hematopoietic/erythroid differentiation.SUBUNIT Forms a homodimer or a heterodimer with a related family member. Binds NR3C1 (By similarity). Interacts with NCOA1 (PubMed:12954634). Interacts with NMI (PubMed:9989503). Interacts with SOCS7 (PubMed:15677474). Interacts (via SH2 domain) with INSR (PubMed:9428692). Interacts with CPEB3; this inhibits STAT5B-mediated transcriptional activation (PubMed:20639532).PTM Tyrosine phosphorylated in response to signaling via activated KIT, resulting in translocation to the nucleus. Tyrosine phosphorylated in response to signaling via activated FLT3; wild-type FLT3 results in much weaker phosphorylation than constitutively activated mutant FLT3. Alternatively, can be phosphorylated by JAK2. Phosphorylation at Tyr-699 by PTK6 or HCK leads to an increase of its transcriptional activity.SIMILARITY Belongs to the transcription factor STAT family.CAUTION It was reported that dephosphorylation on tyrosine residues by PTPN2 would negatively regulate prolactin signaling pathway (PubMed:11773439). However, the corresponding article has been retracted (PubMed:24319783).UniProtP51692699EQUAL1EQUAL787EQUALReactome Database ID Release 75507939Database 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=507939ReactomeR-HSA-5079391Reactome 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-507939.1Reactome Database ID Release 75507929Database 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=507929ReactomeR-HSA-5079293Reactome 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-507929.31Reactome Database ID Release 75507943Database 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=507943ReactomeR-HSA-5079431Reactome 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-507943.1Reactome Database ID Release 75919404Database 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=919404ReactomeR-HSA-9194043Reactome 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-919404.39030599Pubmed1997A single STAT recruitment module in a chimeric cytokine receptor complex is sufficient for STAT activationBehrmann, IJanzen, CGerhartz, CSchmitz-Van de Leur, HHermanns, HHeesel, BGraeve, LHorn, FTavernier, JHeinrich, PCJ Biol Chem 272:5269-7411426647Pubmed2000STAT proteins: novel molecular targets for cancer drug discoveryTurkson, JJove, ROncogene 19:6613-26