Prolactin receptor signaling (Homo sapiens)

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<?xml version="1.0" encoding="UTF-8"?> <Pathway xmlns="http://pathvisio.org/GPML/2013a" Name="Prolactin receptor signaling" Organism="Homo sapiens"> <Comment Source="WikiPathways-description">Prolactin (PRL) is a hormone secreted mainly by the anterior pituitary gland. It was originally identified by its ability to stimulate the development of the mammary gland and lactation, but is now known to have numerous and varied functions (Bole-Feysot et al. 1998). Despite this, few pathologies have been associated with abnormalities in prolactin receptor (PRLR) signaling, though roles in various forms of cancer and certain autoimmune disorders have been suggested (Goffin et al. 2002). A vast body of literature suggests effects of PRL in immune cells (Matera 1996) but PRLR KO mice have unaltered immune system development and function (Bouchard et al. 1999). In addition to the pituitary, numerous other tissues produce PRL, including the decidua and myometrium, certain cells of the immune system, brain, skin and exocrine glands such as the mammary, sweat and lacrimal glands (Ben-Jonathan et al. 1996). Pituitary PRL secretion is negatively regulated by inhibitory factors originating from the hypothalamus, the most important of which is dopamine, acting through the D2 subclass of dopamine receptors present in lactotrophs (Freeman et al. 2000). PRL-binding sites or receptors have been identified in numerous cells and tissues of adult mammals. Various forms of PRLR, generated by alternative splicing, have been reported in several species including humans (Kelly et al. 1991, Clevenger et al. 2003).&lt;br&gt;&lt;br&gt;PRLR is a member of the cytokine receptor superfamily. Like many other members of this family, the first step in receptor activation was generally believed to be ligand-induced dimerization whereby one molecule of PRL bound to two molecules of receptor (Elkins et al. 2000). Recent reports suggest that PRLR pre-assembles at the plasma membrane in the absence of ligand (Gadd &amp; Clevenger 2006, Tallet et al. 2011), suggesting that ligand-induced activation involves conformational changes in preformed PRLR dimers (Broutin et al. 2010). &lt;br&gt;&lt;br&gt;PRLR has no intrinsic kinase activity but associates (Lebrun et al. 1994, 1995) with Janus kinase 2 (JAK2) which is activated following receptor activation (Campbell et al. 1994, Rui et al. 1994, Carter-Su et al. 2000, Barua et al. 2009). JAK2-dependent activation of JAK1 has also been reported (Neilson et al. 2007). It is generally accepted that activation of JAK2 occurs by transphosphorylation upon ligand-induced receptor activation, based on JAK activation by chimeric receptors in which various extracellular domains of cytokine or tyrosine kinase receptors were fused to the IL-2 receptor beta chain (see Ihle et al. 1994). This activation step involves the tyrosine phosphorylation of JAK2, which in turn phosphorylates PRLR on specific intracellular tyrosine residues leading to STAT5 recruitment and signaling, considered to be the most important signaling cascade for PRLR. STAT1 and STAT3 activation have also been reported (DaSilva et al. 1996) as have many other signaling pathways; signaling through MAP kinases (Shc/SOS/Grb2/Ras/Raf/MAPK) has been reported as a consequence of PRL stimuilation in many different cellular systems (see Bole-Feysot et al. 1998) though it is not clear how this signal is propagated. Other cascades non exhaustively include Src kinases, Focal adhesion kinase, phospholipase C gamma, PI3 kinase/Akt and Nek3 (Clevenger et al. 2003, Miller et al. 2007). The protein tyrosine phosphatase SHP2 is recruited to the C terminal tyrosine of PRLR and may have a regulatory role (Ali &amp; Ali 2000). PRLR phosphotyrosines can recruit insulin receptor substrates (IRS) and other adaptor proteins to the receptor complex (Bole-Feysot et al. 1998).&lt;br&gt;&lt;br&gt;Female homozygous PRLR knockout mice are completely infertile and show a lack of mammary development (Ormandy et al. 1997). Hemizogotes are unable to lactate following their first pregnancy and depending on the genetic background, this phenotype can persist through subsequent pregnancies (Kelly et al. 2001). 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Height="22.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O60674" /> </DataNode> <DataNode TextLabel="Zn2+ " GraphId="cdef7" Type="Metabolite" GroupRef="e263a"> <Attribute Key="cellular_location" Value="extracellular region" /> <Attribute Key="complex_id" Value="R-HSA-1364054" /> <Attribute Key="copies_num" Value="5" /> <Graphics CenterX="240.0" CenterY="1489.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:29105" /> </DataNode> <DataNode TextLabel="GH1 " GraphId="cefcd" Type="Protein" GroupRef="e263a"> <Comment Source="Reactome">Growth hormone is typically used to refer to the endogenous hormone - somatotropin is reserved for synthetic hormone produced by recombinant technology.</Comment> <Attribute Key="cellular_location" Value="extracellular region" /> <Attribute Key="complex_id" Value="R-HSA-1364054" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="240.0" CenterY="1389.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P01241" /> </DataNode> <DataNode TextLabel="Zn2+ " GraphId="cf047" Type="Metabolite" GroupRef="a896a"> <Attribute Key="cellular_location" Value="extracellular region" /> <Attribute Key="complex_id" Value="R-HSA-1675475" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="660.0" CenterY="1209.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:29105" /> </DataNode> <DataNode TextLabel="p-Y611-PRLR " GraphId="cf179" Type="Protein" GroupRef="df10d"> <Attribute Key="cellular_location" Value="plasma membrane" /> <Attribute Key="complex_id" Value="R-HSA-1369118" /> <Attribute Key="copies_num" Value="2" /> <Graphics CenterX="380.0" CenterY="1389.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P16471" /> </DataNode> <DataNode TextLabel="PRLR&#xA;ligands:p-Y611-PRLR:p-Y1007-JAK2:STAT5" GraphId="cf18c" Type="Complex"> <Attribute Key="cellular_location" Value="plasma membrane" /> <Graphics CenterX="175.5" CenterY="903.0" Width="87.0" Height="78.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-1369095" /> </DataNode> <DataNode TextLabel="ATP" GraphId="d0507" Type="Metabolite"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="326.0" CenterY="398.0" Width="40.0" Height="30.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:15422" /> </DataNode> <DataNode TextLabel="PRLR ligands:p-S349-&#xA;PRLR:JAK2 dimer:SCF&#xA;beta-TrCP complex" GraphId="d14fd" Type="Complex"> <Attribute Key="cellular_location" Value="plasma membrane" /> <Graphics CenterX="613.0" CenterY="400.5" Width="128.0" Height="75.0" ZOrder="32768" FontSize="10" Valign="Middle" 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Key="cellular_location" Value="extracellular region" /> <Attribute Key="complex_id" Value="R-HSA-1671696" /> <Attribute Key="copies_num" Value="3" /> <Graphics CenterX="660.0" CenterY="1589.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P01236" /> </DataNode> <DataNode TextLabel="Zn2+ " GraphId="d655f" Type="Metabolite" GroupRef="a725f"> <Attribute Key="cellular_location" Value="extracellular region" /> <Attribute Key="complex_id" Value="R-HSA-1977946" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="800.0" CenterY="1509.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:29105" /> </DataNode> <DataNode TextLabel="BTRC " GraphId="d6778" Type="Protein" GroupRef="e0531"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-206748" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="520.0" CenterY="1169.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9Y297" /> </DataNode> <DataNode TextLabel="Growth Hormone " GraphId="d69e5" GroupRef="eb6a5"> <Attribute Key="cellular_location" Value="endosome lumen" /> <Attribute Key="complex_id" Value="R-HSA-1370498" /> <Attribute Key="copies_num" Value="5" /> <Graphics CenterX="520.0" CenterY="1469.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Reactome" ID="R-HSA-8942966" /> </DataNode> <DataNode TextLabel="PRL " GraphId="d6ce5" Type="Protein" GroupRef="eb6a5"> <Attribute Key="cellular_location" Value="extracellular region" /> <Attribute Key="complex_id" Value="R-HSA-1370498" /> <Attribute Key="copies_num" Value="3" /> <Graphics CenterX="520.0" CenterY="1329.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P01236" /> </DataNode> <DataNode TextLabel="STAT5A " GraphId="d8603" Type="Protein" GroupRef="ce075"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-1369095" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="380.0" CenterY="1169.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P42229" /> </DataNode> <DataNode TextLabel="p-Y611-PRLR " GraphId="d9105" Type="Protein" GroupRef="e69ec"> <Attribute Key="cellular_location" Value="plasma membrane" /> <Attribute Key="complex_id" Value="R-HSA-1369125" /> <Attribute Key="copies_num" Value="2" /> <Graphics CenterX="800.0" CenterY="1329.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P16471" /> </DataNode> <DataNode TextLabel="Growth Hormone " GraphId="dae09" GroupRef="a896a"> <Attribute Key="cellular_location" Value="extracellular region" /> <Attribute Key="complex_id" 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Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P10912" /> </DataNode> <DataNode TextLabel="PRLR " GraphId="dc29b" Type="Protein" GroupRef="c4ff8"> <Attribute Key="cellular_location" Value="plasma membrane" /> <Attribute Key="complex_id" Value="R-HSA-1671683" /> <Attribute Key="copies_num" Value="4" /> <Graphics CenterX="660.0" CenterY="1449.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P16471" /> </DataNode> <DataNode TextLabel="STAT5A " GraphId="dd81c" Type="Protein" GroupRef="bdd8a"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-452094" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="240.0" CenterY="1609.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P42229" /> </DataNode> <DataNode TextLabel="SKP1 " GraphId="ddb1f" Type="Protein" GroupRef="cb602"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-1369085" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="100.0" CenterY="1429.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P63208" /> </DataNode> <DataNode TextLabel="PRLR&#xA;ligands:p-Y611-PRLR:p-Y1007-JAK2 dimer:SHP2" GraphId="ddcda" Type="Complex"> <Attribute Key="cellular_location" Value="plasma membrane" /> <Graphics CenterX="638.0" CenterY="868.0" Width="146.0" Height="58.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-1369118" /> </DataNode> <DataNode TextLabel="JAK2 " GraphId="de19e" Type="Protein" GroupRef="e4aae"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-976956" /> <Attribute Key="copies_num" Value="3" /> <Graphics CenterX="100.0" CenterY="1329.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O60674" /> </DataNode> <DataNode TextLabel="PRLR&#xA;ligands:p-Y611-PRLR:p-Y1007-JAK2 dimer:p-STAT5" GraphId="de6fe" Type="Complex"> <Attribute Key="cellular_location" Value="plasma membrane" /> <Graphics CenterX="198.0" CenterY="1056.0" Width="90.0" Height="90.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-1671696" /> </DataNode> <DataNode TextLabel="JAK2 " GraphId="de73c" Type="Protein" GroupRef="a725f"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-1977946" /> <Attribute Key="copies_num" Value="4" /> <Graphics CenterX="800.0" CenterY="1589.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O60674" /> </DataNode> <DataNode TextLabel="PRLR " GraphId="df48b" Type="Protein" GroupRef="e263a"> <Attribute Key="cellular_location" Value="plasma membrane" /> <Attribute Key="complex_id" Value="R-HSA-1364054" /> <Attribute Key="copies_num" Value="7" /> <Graphics CenterX="240.0" CenterY="1549.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P16471" /> </DataNode> <DataNode TextLabel="ATP" GraphId="e0087" Type="Metabolite"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="378.5" CenterY="144.0" Width="39.0" Height="30.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:15422" /> </DataNode> <DataNode TextLabel="Growth Hormone " GraphId="e1d9d" GroupRef="ce075"> <Attribute Key="cellular_location" Value="extracellular region" /> <Attribute Key="complex_id" Value="R-HSA-1369095" /> <Attribute Key="copies_num" Value="4" /> <Graphics CenterX="380.0" CenterY="1309.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Reactome" ID="R-HSA-982814" /> </DataNode> <DataNode TextLabel="Zn2+ " GraphId="e2862" Type="Metabolite" GroupRef="e4aae"> <Attribute Key="cellular_location" Value="extracellular region" /> <Attribute Key="complex_id" Value="R-HSA-976956" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="100.0" CenterY="1269.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:29105" /> </DataNode> <DataNode TextLabel="ADP" GraphId="e3019" Type="Metabolite"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="327.0" CenterY="526.0" Width="42.0" Height="30.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:16761" /> </DataNode> <DataNode TextLabel="Zn2+ " GraphId="e3187" Type="Metabolite" GroupRef="fb11e"> <Attribute Key="cellular_location" Value="extracellular region" /> <Attribute Key="complex_id" Value="R-HSA-1671652" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="520.0" CenterY="1549.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:29105" /> </DataNode> <DataNode TextLabel="Zn2+ " GraphId="e37de" Type="Metabolite" GroupRef="e69ec"> <Attribute Key="cellular_location" Value="extracellular region" /> <Attribute Key="complex_id" Value="R-HSA-1369125" /> <Attribute Key="copies_num" Value="3" /> <Graphics CenterX="800.0" CenterY="1389.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:29105" /> </DataNode> <DataNode TextLabel="Zn2+ " GraphId="e3d05" Type="Metabolite" GroupRef="c03f1"> <Attribute Key="cellular_location" Value="extracellular region" /> <Attribute Key="complex_id" Value="R-HSA-1671696" /> <Attribute Key="copies_num" Value="3" /> <Graphics CenterX="660.0" CenterY="1609.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:29105" /> </DataNode> <DataNode TextLabel="Zn2+ " GraphId="e475e" Type="Metabolite" GroupRef="a2cf3"> <Attribute Key="cellular_location" Value="extracellular region" /> <Attribute Key="complex_id" Value="R-HSA-1364055" /> <Attribute Key="copies_num" Value="5" /> <Graphics CenterX="240.0" CenterY="1269.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:29105" /> </DataNode> <DataNode TextLabel="PRLR " GraphId="e5424" Type="Protein" GroupRef="fb11e"> <Attribute Key="cellular_location" Value="plasma membrane" /> <Attribute Key="complex_id" Value="R-HSA-1671652" /> <Attribute Key="copies_num" Value="4" /> <Graphics CenterX="520.0" CenterY="1629.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P16471" /> </DataNode> <DataNode TextLabel="PRL " GraphId="e5a4d" Type="Protein" GroupRef="ce075"> <Attribute Key="cellular_location" Value="extracellular region" /> <Attribute Key="complex_id" Value="R-HSA-1369095" /> <Attribute Key="copies_num" Value="3" /> <Graphics CenterX="380.0" CenterY="1249.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P01236" /> </DataNode> <DataNode TextLabel="CUL1 " GraphId="e7d28" Type="Protein" GroupRef="cb602"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-1369085" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="100.0" CenterY="1449.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q13616" /> </DataNode> <DataNode TextLabel="CSH1 " GraphId="e9cc0" Type="Protein" GroupRef="cb602"> <Attribute Key="cellular_location" Value="extracellular region" /> <Attribute Key="complex_id" Value="R-HSA-1369085" /> <Attribute Key="copies_num" Value="2" /> <Graphics CenterX="100.0" CenterY="1529.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P0DML2" /> </DataNode> <DataNode TextLabel="PRLR " GraphId="ea414" Type="Protein" GroupRef="e4009"> <Attribute Key="cellular_location" Value="plasma membrane" /> <Attribute Key="complex_id" Value="R-HSA-1364076" /> <Attribute Key="copies_num" Value="3" /> <Graphics CenterX="800.0" CenterY="1269.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P16471" /> </DataNode> <DataNode TextLabel="PRLR&#xA;ligands:Activated&#xA;PRLR:JAK2 dimer" GraphId="eb0b2" Type="Complex"> <Attribute Key="cellular_location" Value="plasma membrane" /> <Graphics CenterX="178.0" CenterY="187.0" Width="116.0" Height="52.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-976956" /> </DataNode> <DataNode TextLabel="PRL " GraphId="eb187" Type="Protein" GroupRef="cb602"> <Attribute Key="cellular_location" Value="extracellular region" /> <Attribute Key="complex_id" Value="R-HSA-1369085" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="100.0" CenterY="1489.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P01236" /> </DataNode> <DataNode TextLabel="PRL " GraphId="ee2eb" Type="Protein" GroupRef="e69ec"> <Attribute Key="cellular_location" Value="extracellular region" /> <Attribute Key="complex_id" Value="R-HSA-1369125" /> <Attribute Key="copies_num" Value="3" /> <Graphics CenterX="800.0" CenterY="1369.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P01236" /> </DataNode> <DataNode TextLabel="GH1 " GraphId="ee9d2" Type="Protein" GroupRef="a2cf3"> <Comment Source="Reactome">Growth hormone is typically used to refer to the endogenous hormone - somatotropin is reserved for synthetic hormone produced by recombinant technology.</Comment> <Attribute Key="cellular_location" Value="extracellular region" /> <Attribute Key="complex_id" Value="R-HSA-1364055" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="240.0" CenterY="1169.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P01241" /> </DataNode> <DataNode TextLabel="Zn2+ " GraphId="eeb5e" Type="Metabolite" GroupRef="ce075"> <Attribute Key="cellular_location" Value="extracellular region" /> <Attribute Key="complex_id" Value="R-HSA-1369095" /> <Attribute Key="copies_num" Value="3" /> <Graphics CenterX="380.0" CenterY="1269.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:29105" /> </DataNode> <DataNode TextLabel="CSH1 " GraphId="eee5e" Type="Protein" GroupRef="a725f"> <Attribute Key="cellular_location" Value="extracellular region" /> <Attribute Key="complex_id" Value="R-HSA-1977946" /> <Attribute Key="copies_num" Value="2" /> <Graphics CenterX="800.0" CenterY="1529.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P0DML2" /> </DataNode> <DataNode TextLabel="JAK2 " GraphId="eef98" Type="Protein" GroupRef="a2cf3"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-1364055" /> <Attribute Key="copies_num" Value="4" /> <Graphics CenterX="240.0" CenterY="1209.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O60674" /> </DataNode> <DataNode TextLabel="STAT5B " GraphId="ef5b7" Type="Protein" GroupRef="bdd8a"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-452094" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="240.0" CenterY="1629.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P51692" /> </DataNode> <DataNode TextLabel="ADP" GraphId="efeac" Type="Metabolite"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="318.5" CenterY="750.0" Width="41.0" Height="30.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:16761" /> </DataNode> <DataNode TextLabel="ADP" GraphId="f1a40" Type="Metabolite"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="479.5" CenterY="1013.0" Width="41.0" Height="30.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:16761" /> </DataNode> <DataNode TextLabel="PRLR&#xA;ligands:Activated&#xA;PRLR:p-Y1007-JAK2&#xA;dimer" GraphId="f218f" Type="Complex"> <Attribute Key="cellular_location" Value="plasma membrane" /> <Graphics CenterX="169.0" CenterY="651.5" Width="102.0" Height="67.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-1671683" /> </DataNode> <DataNode TextLabel="ATP" GraphId="f261b" Type="Metabolite"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="483.0" CenterY="898.0" Width="40.0" Height="30.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:15422" /> </DataNode> <DataNode TextLabel="Growth Hormone " GraphId="f27d0" GroupRef="e69ec"> <Attribute Key="cellular_location" Value="extracellular region" /> <Attribute Key="complex_id" Value="R-HSA-1369125" /> <Attribute Key="copies_num" Value="4" /> <Graphics CenterX="800.0" CenterY="1429.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Reactome" ID="R-HSA-982814" /> </DataNode> <DataNode TextLabel="SKP1 " GraphId="f3399" Type="Protein" GroupRef="e0531"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-206748" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="520.0" CenterY="1189.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P63208" /> </DataNode> <DataNode TextLabel="GH2 " GraphId="f3400" Type="Protein" GroupRef="e263a"> <Attribute Key="cellular_location" Value="extracellular region" /> <Attribute Key="complex_id" Value="R-HSA-1364054" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="240.0" CenterY="1409.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P01242" /> </DataNode> <DataNode TextLabel="GH2 " GraphId="f4042" Type="Protein" GroupRef="a2cf3"> <Attribute Key="cellular_location" Value="extracellular region" /> <Attribute Key="complex_id" Value="R-HSA-1364055" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="240.0" CenterY="1189.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P01242" /> </DataNode> <DataNode TextLabel="Zn2+ " GraphId="f499c" Type="Metabolite" GroupRef="cb602"> <Attribute Key="cellular_location" Value="extracellular region" /> <Attribute Key="complex_id" Value="R-HSA-1369085" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="100.0" CenterY="1509.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:29105" /> </DataNode> <DataNode TextLabel="CSH1 " GraphId="f4d32" Type="Protein" GroupRef="c35f1"> <Attribute Key="cellular_location" Value="extracellular region" /> <Attribute Key="complex_id" Value="R-HSA-1172021" /> <Attribute Key="copies_num" Value="2" /> <Graphics CenterX="100.0" CenterY="1169.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P0DML2" /> </DataNode> <DataNode TextLabel="p-Y1007-JAK2 " GraphId="f4dd8" Type="Protein" GroupRef="c03f1"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-1671696" /> <Attribute Key="copies_num" Value="3" /> <Graphics CenterX="660.0" CenterY="1569.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O60674" /> </DataNode> <DataNode TextLabel="PRL " GraphId="f5978" Type="Protein" GroupRef="e263a"> <Attribute Key="cellular_location" Value="extracellular region" /> <Attribute Key="complex_id" Value="R-HSA-1364054" /> <Attribute Key="copies_num" Value="5" /> <Graphics CenterX="240.0" CenterY="1469.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P01236" /> </DataNode> <DataNode TextLabel="PRL " GraphId="f5d5d" Type="Protein" GroupRef="e4aae"> <Attribute Key="cellular_location" Value="extracellular region" /> <Attribute Key="complex_id" Value="R-HSA-976956" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="100.0" CenterY="1249.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P01236" /> </DataNode> <DataNode TextLabel="p-Y1007-JAK2 " GraphId="f612e" Type="Protein" GroupRef="e69ec"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-1369125" /> <Attribute Key="copies_num" Value="3" /> <Graphics CenterX="800.0" CenterY="1349.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O60674" /> </DataNode> <DataNode TextLabel="PRL " GraphId="f6cd8" Type="Protein" GroupRef="fb11e"> <Attribute Key="cellular_location" Value="extracellular region" /> <Attribute Key="complex_id" Value="R-HSA-1671652" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="520.0" CenterY="1529.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P01236" /> </DataNode> <DataNode TextLabel="Zn2+ " GraphId="f7187" Type="Metabolite" GroupRef="c4ff8"> <Attribute Key="cellular_location" Value="extracellular region" /> <Attribute Key="complex_id" Value="R-HSA-1671683" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="660.0" CenterY="1369.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:29105" /> </DataNode> <DataNode TextLabel="PRLR " GraphId="f778f" Type="Protein" GroupRef="a2cf3"> <Attribute Key="cellular_location" Value="plasma membrane" /> <Attribute Key="complex_id" Value="R-HSA-1364055" /> <Attribute Key="copies_num" Value="7" /> <Graphics CenterX="240.0" CenterY="1329.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P16471" /> </DataNode> <DataNode TextLabel="Growth Hormone " GraphId="f7a7a" GroupRef="c4ff8"> <Attribute Key="cellular_location" Value="extracellular region" /> <Attribute Key="complex_id" Value="R-HSA-1671683" /> <Attribute Key="copies_num" Value="2" /> <Graphics CenterX="660.0" CenterY="1409.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Reactome" ID="R-HSA-982814" /> </DataNode> <DataNode TextLabel="p-Y1007-JAK2 " GraphId="f7ed3" Type="Protein" GroupRef="df10d"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-1369118" /> <Attribute Key="copies_num" Value="3" /> <Graphics CenterX="380.0" CenterY="1409.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O60674" /> </DataNode> <DataNode TextLabel="PTPN11" GraphId="f88d7" Type="Protein"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="466.0" CenterY="779.5" Width="64.0" Height="21.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q06124" /> </DataNode> <DataNode TextLabel="CSH1 " GraphId="f8b54" Type="Protein" GroupRef="e4aae"> <Attribute Key="cellular_location" Value="extracellular region" /> <Attribute Key="complex_id" Value="R-HSA-976956" /> <Attribute Key="copies_num" Value="2" /> <Graphics CenterX="100.0" CenterY="1289.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P0DML2" /> </DataNode> <DataNode TextLabel="Growth Hormone " GraphId="f8d3d" GroupRef="e4aae"> <Attribute Key="cellular_location" Value="extracellular region" /> <Attribute Key="complex_id" Value="R-HSA-976956" /> <Attribute Key="copies_num" Value="2" /> <Graphics CenterX="100.0" CenterY="1309.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Reactome" ID="R-HSA-982814" /> </DataNode> <DataNode TextLabel="JAK2 " GraphId="f8e6e" Type="Protein" GroupRef="a896a"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-1675475" /> <Attribute Key="copies_num" Value="3" /> <Graphics CenterX="660.0" CenterY="1269.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O60674" /> </DataNode> <DataNode TextLabel="PRL " GraphId="fa303" Type="Protein" GroupRef="df10d"> <Attribute Key="cellular_location" Value="extracellular region" /> <Attribute Key="complex_id" Value="R-HSA-1369118" /> <Attribute Key="copies_num" Value="3" /> <Graphics CenterX="380.0" CenterY="1429.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P01236" /> </DataNode> <DataNode TextLabel="JAK2 " GraphId="fa754" Type="Protein" GroupRef="fb11e"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-1671652" /> <Attribute Key="copies_num" Value="3" /> <Graphics CenterX="520.0" CenterY="1609.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O60674" /> 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/> </Interaction> <Interaction GraphId="a77be"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="642.0" Y="360.0" GraphRef="f81c3" RelX="-0.42999999999995" RelY="0.9300000000000068" /> <Point X="613.0" Y="363.0" GraphRef="d14fd" RelX="0.0" RelY="-1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1370500" /> </Interaction> <Interaction GraphId="a882c"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="236.0" Y="187.0" GraphRef="eb0b2" RelX="1.0" RelY="0.0" /> <Point X="419.0" Y="184.0" GraphRef="e1510" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1370505" /> </Interaction> <Interaction GraphId="a998b"> <Comment Source="Reactome">Prolactin stimulation leads to tyrosine phosphorylation of the C-terminal SH2 domain of SHP2 and requires JAK2 (Ali et al. 1996). This has a positive regulatory influence on PRLR signaling. SHP2 has a number of signaling-capable interactors such as signal regulatory proteins (SIRPs, Kharitonenkov et al. 1997), SH2-containing inositol phosphatase (SHIP, Liu et al. 1997), insulin receptor substrates 1 and 2 (Myers et al. 1998), JAK2 (Jiao et al. 1996) and GRB2 associated binder 2 (GAB2) an adaptor protein that links activated receptor tyrosine kinase and cytokine receptors to downstream signaling molecules. PRL stimulation leads to SHP2-GAB2 association, GAB2 tyrosine phosphorylation, and GAB2-PI3K p85 subunit association, though it is not clear that this is the order of events, nor that SHP2 serves as a link between PRLR and GAB2 (Ali &amp; Ali 2000).</Comment> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="526.0" Y="932.0" /> <Point X="526.0" Y="985.0" /> <Anchor Position="0.0" Shape="None" GraphId="f2237" /> <Anchor Position="0.99" Shape="None" GraphId="a845a" /> <Anchor Position="0.5" Shape="None" GraphId="f8456" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1369115" /> </Interaction> <Interaction GraphId="aa9c5"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="526.0" Y="985.0" GraphRef="a845a" RelX="0.0" RelY="0.5299999999999727" /> <Point X="499.0" Y="1013.0" GraphRef="f1a40" RelX="0.9512195121951219" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1369115" /> </Interaction> <Interaction GraphId="ac20b"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="511.0" Y="63.0" GraphRef="ccacd" RelX="-1.0" RelY="0.0" /> <Point X="500.0" Y="35.0" GraphRef="e3944" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1302698" /> </Interaction> <Interaction GraphId="ada76"> <Comment Source="Reactome">Ligand binding activates the PRLR, probably by causing a subtle conformational change (Broutin et al. 2010).</Comment> <BiopaxRef>bdd</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="177.0" Y="111.0" /> <Point X="177.0" Y="158.0" /> <Anchor Position="0.0" Shape="None" GraphId="a6e3c" /> <Anchor Position="0.99" Shape="None" GraphId="ae2e2" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1671687" /> </Interaction> <Interaction GraphId="af514"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="280.0" Y="51.0" GraphRef="a3b5b" RelX="-0.014492753623188406" RelY="1.0" /> <Point X="255.0" Y="68.0" GraphRef="fdccb" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-976991" /> </Interaction> <Interaction GraphId="af896"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="231.0" Y="992.0" GraphRef="b20fb" RelX="0.0" RelY="0.37000000000000455" /> <Point X="198.0" Y="1011.0" GraphRef="de6fe" RelX="0.0" RelY="-1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1671691" /> </Interaction> <Interaction GraphId="b1b9b"> <Comment Source="Reactome">Phosphorylation of PRLR on Ser-349 by an unidentified kinase enables recruitment of the SCF beta-TrCP ubiquitin ligase complex, which catalyzes ubiquitination of the receptor (Li et al. 2004). This downregulation mechanism is impaired in some forms of breast cancer (Li et al. 2006).</Comment> <BiopaxRef>fbc</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="685.0" Y="267.0" /> <Point X="642.0" Y="360.0" /> <Anchor Position="0.0" Shape="None" GraphId="b8905" /> <Anchor Position="0.99" Shape="None" GraphId="f81c3" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1370500" /> </Interaction> <Interaction GraphId="b5567"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="549.0" Y="400.0" GraphRef="d14fd" RelX="-1.0" RelY="-0.013333333333333334" /> <Point X="546.0" Y="399.0" GraphRef="c72e9" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1170539" /> </Interaction> <Interaction GraphId="b7c54"> <Comment Source="Reactome">PRLR has no intrinsic kinase activity but associates with Janus kinase 2 (JAK2) (Lebrun et al. 1994, 1995, Campbell et al. 1994, Rui et al. 1994). PRLR to JAK2 binding has been described as constitutive but a recent computational model suggests that roughly half of dimerized Growth Hormone receptors are bound with JAK2 (Barua et al. 2009), a model that may apply to other receptors that promote JAK2 trans-activation. The box 1 region of PRLR is a membrane proximal proline-rich region in the intracellular domain, conserved in all members of the growth hormone rereptor family. This region is critical for JAK2 association; deletion of box 1 virtually abolishes PRLR signaling (Edery et al. 1994). Alanine substitutions of individual residues within box 1 of rat PRLR have shown that the most C-terminal proline (P269 in the Uniprot canonical sequence, 250 in the mature peptide) is critical for association with and subsequent activation of JAK2 (Pezet et al. 1997). It is not known whether the interaction of JAK2 with PRLR is direct or involves an adaptor protein.&lt;br&gt;&lt;br&gt;When the receptor is activated by ligand binding JAK2 (receptor pre-bound or recruited after ligand binding) becomes activated and phosphorylates the dimerized receptor preferentially at Y611 (position 587 in the mature peptide), a consensus tyrosine phosphorylation site. This is followed by the phosphorylation, dimerization and nuclear translocation of STAT5. There are nine other tyrosines in the cytoplasmic domain, some of which may undergo phosphorylation and may participate in signal transduction. </Comment> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="500.0" Y="35.0" /> <Point X="439.0" Y="35.0" /> <Anchor Position="0.0" Shape="None" GraphId="e3944" /> <Anchor Position="0.99" Shape="None" GraphId="ee780" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1302698" /> </Interaction> <Interaction GraphId="b887b"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="306.0" Y="398.0" GraphRef="d0507" RelX="-1.0" RelY="0.0" /> <Point X="275.0" Y="432.0" GraphRef="f9acb" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-982810" /> </Interaction> <Interaction GraphId="b8a55"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="498.0" Y="399.0" GraphRef="ea9fe" RelX="-0.4800000000000182" RelY="0.0" /> <Point X="554.0" Y="268.0" GraphRef="c0242" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1170539" /> </Interaction> <Interaction GraphId="ba2f4"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="178.0" Y="108.0" GraphRef="a090f" RelX="-0.008849557522123894" RelY="1.0" /> <Point X="177.0" Y="111.0" GraphRef="a6e3c" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1671687" /> </Interaction> <Interaction GraphId="ba3ab"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="550.0" Y="35.0" GraphRef="a9abc" RelX="-1.0" RelY="0.0" /> <Point X="500.0" Y="35.0" GraphRef="e3944" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1302698" /> </Interaction> <Interaction GraphId="bb0d2"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="562.0" Y="848.0" GraphRef="d8877" RelX="0.9099999999999682" RelY="0.30999999999994543" /> <Point X="565.0" Y="868.0" GraphRef="ddcda" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1369114" /> </Interaction> <Interaction GraphId="bde1b"> <Comment Source="Reactome">The 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).</Comment> <BiopaxRef>fbc</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="419.0" Y="184.0" /> <Point X="478.0" Y="184.0" /> <Anchor Position="0.0" Shape="None" GraphId="e1510" /> <Anchor Position="0.99" Shape="None" GraphId="bcb65" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1370505" /> </Interaction> <Interaction GraphId="be5a1"> <Comment Source="Reactome">The model for PRL-induced PRLR activation suggests that JAK2 phosphorylates PRLR on specific tyrosine residues. Consistent with this, JAK2 and PRLR are phosphorylated in response to activating ligand (Lebrun et al. 1994) and PRLR tyrosine phosphorylation is required for subsequent Stat signaling (Pezet et al. 1997). Though this evidence is consistent with a role for JAK2, it has not been formally demonstrated that JAK2 is the kinase responsible for PRLR tyrosine phosphorylation.</Comment> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="257.0" Y="677.0" /> <Point X="257.0" Y="724.0" /> <Anchor Position="0.0" Shape="None" GraphId="d60d3" /> <Anchor Position="0.99" Shape="None" GraphId="c7d81" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1364043" /> </Interaction> <Interaction GraphId="be7b5"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="249.0" Y="802.0" GraphRef="c1207" RelX="-1.0" RelY="0.0" /> <Point X="223.0" Y="807.0" GraphRef="f91a4" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1369080" /> </Interaction> <Interaction GraphId="bee5a"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="256.0" Y="209.0" GraphRef="bf8cc" RelX="-1.0" RelY="0.0" /> <Point X="72.0" Y="280.0" GraphRef="f2c3a" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1675473" /> </Interaction> <Interaction GraphId="bf83d"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="177.0" Y="158.0" GraphRef="ae2e2" RelX="0.0" RelY="0.46999999999999886" /> <Point X="178.0" Y="161.0" GraphRef="eb0b2" RelX="0.0" RelY="-1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1671687" /> </Interaction> <Interaction GraphId="bf988"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="123.0" Y="441.0" GraphRef="b7004" RelX="0.5099999999999909" RelY="1.6100000000000136" /> <Point X="149.0" Y="444.0" GraphRef="b47f5" RelX="-0.007633587786259542" RelY="-1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1675473" /> </Interaction> <Interaction GraphId="c1150"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="291.0" Y="660.0" GraphRef="a3e4f" RelX="-1.0" RelY="0.0" /> <Point X="257.0" Y="677.0" GraphRef="d60d3" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1364043" /> </Interaction> <Interaction GraphId="c1708"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="478.0" Y="184.0" GraphRef="bcb65" RelX="0.5900000000000318" RelY="0.0" /> <Point X="501.0" Y="153.0" GraphRef="a1c20" RelX="-0.024390243902439025" RelY="1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1370505" /> </Interaction> <Interaction GraphId="c7337"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="466.0" Y="789.0" GraphRef="f88d7" RelX="0.0" RelY="0.9047619047619048" /> <Point X="471.0" Y="817.0" GraphRef="efcbc" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1369114" /> </Interaction> <Interaction GraphId="c8084"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="275.0" Y="490.0" GraphRef="ae64b" RelX="0.0" RelY="0.5799999999999841" /> <Point X="232.0" Y="539.0" GraphRef="af00c" RelX="0.9900497512437811" RelY="-0.022222222222222223" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-982810" /> </Interaction> <Interaction GraphId="caa91"> <Comment Source="Reactome">PRLR is regulated by ubiquitination of the activated receptor, leading to lysosomal degradation (Djiane et al. 1981, 1982, Lu et al. 2002). Recruitment of the SCFbeta-TrCP ubiquitin ligase complex enables receptor ubiquitination and internalization (Li et al. 2004). This limits the duration and intensity of receptor signaling. Deregulation of this negative control lead to pathological conditions including cancer (Swaminathan et al. 2008). </Comment> <BiopaxRef>fbc</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="546.0" Y="399.0" /> <Point X="498.0" Y="399.0" /> <Anchor Position="0.0" Shape="None" GraphId="c72e9" /> <Anchor Position="0.99" Shape="None" GraphId="ea9fe" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1170539" /> </Interaction> <Interaction GraphId="cb141"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="214.0" Y="469.0" GraphRef="b47f5" RelX="0.9847328244274809" RelY="0.0" /> <Point X="275.0" Y="465.0" GraphRef="dcd31" RelX="0.0" RelY="4.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-982810" /> </Interaction> <Interaction GraphId="cb4af"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="439.0" Y="35.0" GraphRef="ee780" RelX="-0.6100000000000136" RelY="0.0" /> <Point X="436.0" Y="35.0" GraphRef="b2322" RelX="1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1302698" /> </Interaction> <Interaction GraphId="cc4a9"> <Comment Source="Reactome">Co-immunoprecipitation of rat Stat5 and Prlrs mutated to have a single intracellular tyrosine suggests that phosphorylation of these tyrosines is required for Stat5 binding and leads to Stat5 tyrosine phosphorylation (Pezet et al. 1997). STAT1 and STAT3 have both been reported to be activated by PRLR (DaSilva et al. 1996), but the region(s) of PRLR required for activation of these Stats remains poorly documented.</Comment> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="231.0" Y="955.0" /> <Point X="231.0" Y="992.0" /> <Anchor Position="0.0" Shape="None" GraphId="a7a00" /> <Anchor Position="0.99" Shape="None" GraphId="b20fb" /> <Anchor Position="0.5" Shape="None" GraphId="e973e" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1671691" /> </Interaction> <Interaction GraphId="cd288"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="503.0" Y="898.0" GraphRef="f261b" RelX="1.0" RelY="0.0" /> <Point X="526.0" Y="932.0" GraphRef="f2237" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1369115" /> </Interaction> <Interaction GraphId="cf6f5"> <Comment Source="Reactome">Similar models explain JAK activation by the cytokine-like hormone receptors (GHR and PRLR) and interleukin receptors. JAK2 activation is believed to occur as mutual transactivation whereby JAK2 bound to one receptor chain phosphorylates JAK2 bound to the other receptor chain in the dimeric receptor. Transactivation is widely accepted (Herrington &amp; Carter-Su 2001) having been originally proposed in the 1990's (Quelle et al. 1994, Hou et al. 2002). JAK phosphorylation is thought to lock the kinase domain in an active state; prior to this JAK2 is held in an inactive state by interactions between its kinase and pseudokinase domains (Giordanetto &amp; Kroemer 2002). Although there are structures of JAK kinase domains (e.g. Lucet et al. 2006), no complete JAK structures are available and the activation mechanism remains poorly understood (Brooks &amp; Waters 2010). The trigger for JAK activation is believed to be a conformational change in the receptor when ligand is bound, leading to a rotation of the cytoplasmic regions which brings the catalytic domains of bound JAK2 molecules into close proximity and frees them from inhibition by the pseudokinase domains. Supporting observations for cytokine-like hormone receptors include: JAK2 becomes tyrosine phosphorylated as a consequence of GHR activation by GH (Argetsinger et al. 1993); JAK2 is activated following PRLR activation (Campbell et al. 1994, Rui et al. 1994); forced dimerization of GH receptor domains is sufficient to activate signaling (Behncken et al. 2000); phosphorylation of JAK2 at Y1007 is critical for kinase activation (Feng et al. 1997, Lucet et al. 2006); JAK autophosphorylation at several other sites appears to regulate activity (e.g. Feener et al. 2004, Argetsinger et al. 2004, 2010). 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Prlr mutants with a single tyrosine residue at positions 599, 498 or 492 (reported according to their position in the mature peptide as 580, 479 or 473 in Pezet et al. 1997) were all able to activate Stat5; Y599 gave a much stronger response. Short forms of PRLR lacking these tyrosines did not bind STAT5. The equivalent human tyrosine residues are Y509 and Y611; Y492 is not conserved in humans.&lt;br&gt;Activation of STAT1 and STAT3 by PRLR has been reported (Da Silva et al. 1996) but the interaction has been suggested to be indirect and possibly mediated by JAK2.</Comment> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="223.0" Y="807.0" /> <Point X="204.0" Y="861.0" /> <Anchor Position="0.0" Shape="None" GraphId="f91a4" /> <Anchor Position="0.99" Shape="None" GraphId="ed33d" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1369080" /> </Interaction> <Interaction GraphId="de431"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="228.0" Y="32.0" GraphRef="a29b4" RelX="0.9826086956521739" RelY="0.0" /> <Point X="255.0" Y="68.0" GraphRef="fdccb" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-976991" /> </Interaction> <Interaction GraphId="e0945"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="397.0" Y="144.0" GraphRef="e0087" RelX="0.9487179487179487" RelY="0.0" /> <Point X="419.0" Y="184.0" GraphRef="e1510" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1370505" /> </Interaction> <Interaction GraphId="e2fd7"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="218.0" Y="903.0" GraphRef="cf18c" RelX="0.9770114942528736" RelY="0.0" /> <Point X="231.0" Y="955.0" GraphRef="a7a00" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1671691" /> </Interaction> <Interaction GraphId="e4945"> <Comment Source="Reactome">Human PRLR binds at least 3 related peptide ligands namely prolactin, placental lactogen (PL) and growth hormone (GH). In non primates, GH is not able to bind the PRLR. Human GH binding to the PRLR is zinc-dependent (Cunningham et al. 1990). All three ligands bind the extracellular domain and have apparently identical actions. Two disulfide-linked cysteines in the D1 subdomain are involved in ligand binding while the WSXWS motif in the D2 subdomain is probably required for folding and cellular trafficking.</Comment> <BiopaxRef>d6f</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="255.0" Y="68.0" /> <Point X="238.0" Y="88.0" /> <Anchor Position="0.0" Shape="None" GraphId="fdccb" /> <Anchor Position="0.99" Shape="None" GraphId="d6c98" /> <Anchor Position="0.5" Shape="None" GraphId="aaffb" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-976991" /> </Interaction> <Interaction GraphId="e9e04"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="275.0" Y="490.0" GraphRef="ae64b" RelX="0.0" RelY="0.5799999999999841" /> <Point X="306.0" Y="526.0" GraphRef="e3019" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-982810" /> </Interaction> <Interaction GraphId="ec44b"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="240.0" Y="365.0" GraphRef="cbd25" RelX="1.0" RelY="0.0" /> <Point X="275.0" Y="432.0" GraphRef="f9acb" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-982810" /> </Interaction> <Interaction GraphId="f2269"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="664.0" Y="183.0" GraphRef="d543b" RelX="1.0" RelY="0.0" /> <Point X="685.0" Y="267.0" GraphRef="b8905" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1370500" /> </Interaction> <Interaction GraphId="f4e6d"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="202.0" Y="753.0" GraphRef="d307d" RelX="0.978021978021978" RelY="0.0" /> <Point X="223.0" Y="807.0" GraphRef="f91a4" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1369080" /> </Interaction> <Interaction GraphId="f6b42"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="565.0" Y="868.0" GraphRef="ddcda" RelX="-1.0" RelY="0.0" /> <Point X="526.0" Y="964.0" GraphRef="f8456" RelX="0.0" RelY="5.5" ArrowHead="mim-catalysis" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1369115" /> </Interaction> <Interaction GraphId="f88f9"> <Comment Source="Reactome">The SH2 domains of SH2B beta (Uniprot isoform Q9NRF2-2) binds JAK2 at Tyr813. SH2B beta is able to homodimerize while bound to JAK2 molecules, suggesting that SH2B binding and dimerization may help induce JAK2 transactivation (Nishi et al. 2005). Computational modeling suggests that SH2B beta can enhance Jak2 activation (Barua et al. 2009). The relevance of this for PRLR signalling has yet to be demonstrated. </Comment> <BiopaxRef>bf7</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="72.0" Y="280.0" /> <Point X="123.0" Y="441.0" /> <Anchor Position="0.0" Shape="None" GraphId="f2c3a" /> <Anchor Position="0.99" Shape="None" GraphId="b7004" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1675473" /> </Interaction> <Interaction GraphId="faddf"> <Comment Source="Reactome">The prolactin receptor (PRLR) peptide is a single transmembrane domain protein that functions as a dimer. Recent reports suggest that like many other cytokine receptors, the prolactin receptor (PRLR) pre-assembles at the plasma membrane in the absence of ligand (Gadd &amp; Clevenger 2006, Tallet et al. 2011), suggesting that ligand-induced activation involves conformational changes in the preformed receptor dimer (Broutin et al. 2010). </Comment> <BiopaxRef>b49</BiopaxRef> <BiopaxRef>d7f</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="377.0" Y="49.0" /> <Point X="318.0" Y="49.0" /> <Anchor Position="0.0" Shape="None" GraphId="c6a28" /> <Anchor Position="0.99" Shape="None" GraphId="c35c0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1364044" /> </Interaction> <Interaction GraphId="fca66"> <Comment Source="Reactome">Tyrosine-phosphorylated PRLR can bind the protein-tyrosine Phosphatase SHP2 (PTPN11) via its C-terminal SH2 Domain. 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receptor-associated tyrosine kinase.</bp:TITLE> <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Argetsinger LS, Campbell GS, Yang X, Witthuhn BA, Silvennoinen O, Ihle JN, Carter-Su C.</bp:AUTHORS> </bp:PublicationXref> <bp:PublicationXref xmlns:bp="http://www.biopax.org/release/biopax-level3.owl#" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" rdf:id="bf7"> <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">15767667</bp:ID> <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">PubMed</bp:DB> <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Kinase activation through dimerization by human SH2-B.</bp:TITLE> <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Nishi M, Werner ED, Oh BC, Frantz JD, Dhe-Paganon S, Hansen L, Lee J, Shoelson SE.</bp:AUTHORS> </bp:PublicationXref> <bp:PublicationXref xmlns:bp="http://www.biopax.org/release/biopax-level3.owl#" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" 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