BioPAX pathway converted from "PRLR is phosphorylated at Ser-349" in the Reactome database.LEFT-TO-RIGHTPRLR is phosphorylated at Ser-349The PRL responsiveness of target cells is negatively regulated by receptor internalization, ubiquitination and degradation, which limit the duration and intensity of receptor signaling (Djiane et al. 1981, 1982, Lu et al. 2002). The PRLR is phosphorylated on Ser-349 by an unidentified kinase (Li et al. 2006) enabling subsequent recruitment of the SCF beta-TrCP ubiquitin ligase complex (Li et al. 2004).Authored: Jupe, S, 2011-06-13Reviewed: Goffin, V, 2011-11-08Edited: Jupe, S, 2011-10-17PRLR ligands:Activated PRLR:JAK2 dimerReactome DB_ID: 976956plasma membraneGENE ONTOLOGYGO:0005886Activated PRLR:JAK2 dimerReactome DB_ID: 1671734Activated PRLR:JAK2Reactome DB_ID: 1977936JAK2Tyrosine-protein kinase JAK2Reactome DB_ID: 210620cytosolGENE ONTOLOGYGO:0005829UniProt:O60674 JAK2JAK2FUNCTION Non-receptor tyrosine kinase involved in various processes such as cell growth, development, differentiation or histone modifications. Mediates essential signaling events in both innate and adaptive immunity. In the cytoplasm, plays a pivotal role in signal transduction via its association with type I receptors such as growth hormone (GHR), prolactin (PRLR), leptin (LEPR), erythropoietin (EPOR), thrombopoietin (THPO); or type II receptors including IFN-alpha, IFN-beta, IFN-gamma and multiple interleukins (PubMed:7615558). Following ligand-binding to cell surface receptors, phosphorylates specific tyrosine residues on the cytoplasmic tails of the receptor, creating docking sites for STATs proteins (PubMed:9618263). 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, cell stimulation with erythropoietin (EPO) during erythropoiesis leads to JAK2 autophosphorylation, activation, and its association with erythropoietin receptor (EPOR) that becomes phosphorylated in its cytoplasmic domain. Then, STAT5 (STAT5A or STAT5B) is recruited, phosphorylated and activated by JAK2. Once activated, dimerized STAT5 translocates into the nucleus and promotes the transcription of several essential genes involved in the modulation of erythropoiesis. Part of a signaling cascade that is activated by increased cellular retinol and that leads to the activation of STAT5 (STAT5A or STAT5B) (PubMed:21368206). In addition, JAK2 mediates angiotensin-2-induced ARHGEF1 phosphorylation (PubMed:20098430). Plays a role in cell cycle by phosphorylating CDKN1B (PubMed:21423214). Cooperates with TEC through reciprocal phosphorylation to mediate cytokine-driven activation of FOS transcription. In the nucleus, plays a key role in chromatin by specifically mediating phosphorylation of 'Tyr-41' of histone H3 (H3Y41ph), a specific tag that promotes exclusion of CBX5 (HP1 alpha) from chromatin (PubMed:19783980).ACTIVITY REGULATION Regulated by autophosphorylation, can both activate or decrease activity (By similarity). Heme regulates its activity by enhancing the phosphorylation on Tyr-1007 and Tyr-1008 (PubMed:21036157).SUBUNIT Interacts with EPOR, LYN, SIRPA, SH2B1 and TEC (By similarity). Interacts with IL23R (PubMed:12023369). Interacts with SKB1 (PubMed:10531356). Interacts with STAM2 (PubMed:10899310). Interacts with IFNGR2 (via intracellular domain) (PubMed:7673114, PubMed:7615558). Interacts with LEPR (Isoform B) (By similarity). Interacts with HSP90AB1; promotes functional activation in a heat shock-dependent manner (PubMed:20353823). Interacts with STRA6 (PubMed:21368206). Interacts with RHEX; this interaction occurs in a erythropoietin (EPO)-dependent manner (PubMed:25092874).TISSUE SPECIFICITY Ubiquitously expressed throughout most tissues.DOMAIN Possesses 2 protein kinase domains. The second one probably contains the catalytic domain, while the presence of slight differences suggest a different role for protein kinase 1 (By similarity).PTM Autophosphorylated, leading to regulate its activity. Leptin promotes phosphorylation on tyrosine residues, including phosphorylation on Tyr-813 (By similarity). Autophosphorylation on Tyr-119 in response to EPO down-regulates its kinase activity (By similarity). Autophosphorylation on Tyr-868, Tyr-966 and Tyr-972 in response to growth hormone (GH) are required for maximal kinase activity (By similarity). Also phosphorylated by TEC (By similarity). Phosphorylated on tyrosine residues in response to interferon gamma signaling (PubMed:7615558, PubMed:7673114). Phosphorylated on tyrosine residues in response to a signaling cascade that is activated by increased cellular retinol (PubMed:21368206).DISEASE Chromosomal aberrations involving JAK2 are found in both chronic and acute forms of eosinophilic, lymphoblastic and myeloid leukemia. Translocation t(8;9)(p22;p24) with PCM1 links the protein kinase domain of JAK2 to the major portion of PCM1. Translocation t(9;12)(p24;p13) with ETV6.SIMILARITY Belongs to the protein kinase superfamily. Tyr protein kinase family. JAK subfamily.Homo sapiensNCBI Taxonomy9606UniProtO606741EQUAL1132EQUALReactome Database ID Release 76210620Database 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=210620ReactomeR-HSA-2106202Reactome 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-210620.2Reactomehttp://www.reactome.org1PRLRActivated PRLRProlactin receptorPRLR_HUMANReactome DB_ID: 1977933UniProt:P16471 PRLRPRLRFUNCTION This is a receptor for the anterior pituitary hormone prolactin (PRL). Acts as a prosurvival factor for spermatozoa by inhibiting sperm capacitation through suppression of SRC kinase activation and stimulation of AKT. Isoform 4 is unable to transduce prolactin signaling. Isoform 6 is unable to transduce prolactin signaling.SUBUNIT Homodimer upon hormone binding. Interacts with SMARCA1. Interacts with GH1. Interacts with CSH. Interacts with NEK3 and VAV2 and this interaction is prolactin-dependent.TISSUE SPECIFICITY Expressed in breast, placenta, kidney, liver and pancreas.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 1 subfamily.UniProtP1647125EQUAL622EQUALReactome Database ID Release 761977933Database 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=1977933ReactomeR-HSA-19779331Reactome 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-1977933.11Reactome Database ID Release 761977936Database 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=1977936ReactomeR-HSA-19779361Reactome 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-1977936.12Reactome Database ID Release 761671734Database 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=1671734ReactomeR-HSA-16717341Reactome 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-1671734.11Converted from EntitySet in ReactomeProlactin receptor ligandsReactome DB_ID: 1172021PRLProlactinPRL_HUMANReactome DB_ID: 976984extracellular regionGENE ONTOLOGYGO:0005576UniProt:P01236 PRLPRLFUNCTION Prolactin acts primarily on the mammary gland by promoting lactation.SUBUNIT Interacts with PRLR.SIMILARITY Belongs to the somatotropin/prolactin family.UniProtP0123629EQUAL227EQUALReactome Database ID Release 76976984Database 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=976984ReactomeR-HSA-9769841Reactome 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-976984.1Placental lactogenReactome DB_ID: 1172022CSH1Chorionic somatomammotropin hormone 1CSH1_HUMANReactome DB_ID: 5622079UniProt:P0DML2 CSH1CSH1FUNCTION Produced only during pregnancy and is involved in stimulating lactation, fetal growth and metabolism. Does not interact with GHR but only activates PRLR through zinc-induced dimerization.SUBUNIT Can be found in a monomeric as well as dimeric form.MISCELLANEOUS CSH1 sequence only differs from CSH2 sequence in 1 aa.SIMILARITY Belongs to the somatotropin/prolactin family.UniProtP0DML227EQUAL217EQUALReactome Database ID Release 765622079Database 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=5622079ReactomeR-HSA-56220791Reactome 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-5622079.12Zn2+Zn++zinc(2+)Zinc ionZn(II)Reactome DB_ID: 158417zinc(2+) [ChEBI:29105]zinc(2+)ChEBICHEBI:29105Reactome Database ID Release 76158417Database 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=158417ReactomeR-ALL-1584173Reactome 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-ALL-158417.3COMPOUNDC00038additional informationMIMI:03611Reactome Database ID Release 761172022Database 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=1172022ReactomeR-HSA-11720221Reactome 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-1172022.1Converted from EntitySet in ReactomeGrowth HormoneReactome DB_ID: 982814GH1Growth HormoneSomatotropinSOMA_HUMANGrowth hormone 1Reactome DB_ID: 422070UniProt:P01241 GH1GH1FUNCTION Plays an important role in growth control. Its major role in stimulating body growth is to stimulate the liver and other tissues to secrete IGF-1. It stimulates both the differentiation and proliferation of myoblasts. It also stimulates amino acid uptake and protein synthesis in muscle and other tissues.SUBUNIT Monomer, dimer, trimer, tetramer and pentamer, disulfide-linked or non-covalently associated, in homopolymeric and heteropolymeric combinations. Can also form a complex either with GHBP or with the alpha2-macroglobulin complex.PHARMACEUTICAL Available under the names Nutropin or Protropin (Genentech), Norditropin (Novo Nordisk), Genotropin (Pharmacia Upjohn), Humatrope (Eli Lilly) and Saizen or Serostim (Serono). Used for the treatment of growth hormone deficiency and for Turner's syndrome.MISCELLANEOUS Circulating GH shows a great heterogeneity due to alternative splicing, differential post-translational modifications of monomeric forms, oligomerization, optional binding to 2 different GH-binding proteins, and potentially proteolytic processing.SIMILARITY Belongs to the somatotropin/prolactin family.UniProtP0124127EQUAL217EQUALReactome Database ID Release 76422070Database 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=422070ReactomeR-HSA-4220701Reactome 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-422070.1GH2Growth Hormone variantGrowth hormone 2SOM2_HUMANReactome DB_ID: 982809UniProt:P01242 GH2GH2FUNCTION Plays an important role in growth control. Its major role in stimulating body growth is to stimulate the liver and other tissues to secrete IGF-1. It stimulates both the differentiation and proliferation of myoblasts. It also stimulates amino acid uptake and protein synthesis in muscle and other tissues.SUBUNIT Monomer, dimer, trimer, tetramer and pentamer, disulfide-linked or non-covalently associated, in homopolymeric and heteropolymeric combinations. Can also form a complex either with GHBP or with the alpha2-macroglobulin complex.TISSUE SPECIFICITY Expressed in the placenta.SIMILARITY Belongs to the somatotropin/prolactin family.UniProtP0124227EQUAL217EQUALReactome Database ID Release 76982809Database 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=982809ReactomeR-HSA-9828091Reactome 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-982809.1Reactome Database ID Release 76982814Database 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=982814ReactomeR-HSA-9828141Reactome 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-982814.1Reactome Database ID Release 761172021Database 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=1172021ReactomeR-HSA-11720211Reactome 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-1172021.11Reactome Database ID Release 76976956Database 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=976956ReactomeR-HSA-9769561Reactome 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-976956.1ATPAdenosine 5'-triphosphateATP(4-)Reactome DB_ID: 113592ATP(4-) [ChEBI:30616]ATP(4-)ATPatpAdenosine 5'-triphosphateChEBICHEBI:30616Reactome Database ID Release 76113592Database 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=113592ReactomeR-ALL-1135925Reactome 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-ALL-113592.5COMPOUNDC000022ADPAdenosine 5'-diphosphateADP(3-)Reactome DB_ID: 29370ADP(3-) [ChEBI:456216]ADP(3-)ADP5'-O-[(phosphonatooxy)phosphinato]adenosineADP trianionChEBICHEBI:456216Reactome Database ID Release 7629370Database 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=29370ReactomeR-ALL-293705Reactome 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-ALL-29370.5COMPOUNDC000082PRLR ligands:p-S349-PRLR:JAK2 dimerReactome DB_ID: 19779461p(S349)-PRLR:JAK2 dimerReactome DB_ID: 1675474p(S349)-PRLR:JAK2Reactome DB_ID: 1370506PRLRp-Y611-PRLRp(S349)-PRLRProlactin receptorPRLR_HUMANReactome DB_ID: 1370503611EQUALO4'-phospho-L-tyrosineMODMOD:0004825EQUAL622EQUALReactome Database ID Release 761370503Database 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=1370503ReactomeR-HSA-13705031Reactome 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-1370503.111Reactome Database ID Release 761370506Database 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=1370506ReactomeR-HSA-13705061Reactome 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-1370506.12Reactome Database ID Release 761675474Database 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=1675474ReactomeR-HSA-16754741Reactome 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-1675474.11Reactome Database ID Release 761977946Database 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=1977946ReactomeR-HSA-19779462Reactome 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-1977946.2Reactome Database ID Release 761370505Database 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=1370505ReactomeR-HSA-13705051Reactome 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-1370505.16276249Pubmed1982Prolactin receptor turnover in explants of pseudopregnant rabbit mammary glandDjiane, JDelouis, CKelly, PAMol Cell Endocrinol 25:163-7015082796Pubmed2004Negative regulation of prolactin receptor stability and signaling mediated by SCF(beta-TrCP) E3 ubiquitin ligaseLi, YKumar, KGTang, WSpiegelman, VSFuchs, SYMol Cell Biol 24:4038-486275396Pubmed1981Down-regulation of prolactin receptors in rabbit mammary gland: differential subcellular localizationDjiane, JHoudebine, LMKelly, PAProc Soc Exp Biol Med 168:378-8116278670Pubmed2006Stabilization of prolactin receptor in breast cancer cellsLi, YClevenger, CVMinkovsky, NKumar, KGRaghunath, PNTomaszewski, JESpiegelman, VSFuchs, SYOncogene 25:1896-90212403840Pubmed2002Multiple internalization motifs differentially used by prolactin receptor isoforms mediate similar endocytic pathwaysLu, JCScott, PStrous, GJSchuler, LAMol Endocrinol 16:2515-27