Signaling by NOTCH4 (Homo sapiens)

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<?xml version="1.0" encoding="UTF-8"?> <Pathway xmlns="http://pathvisio.org/GPML/2013a" Name="Signaling by NOTCH4" Data-Source="Reactome - http://www.reactome.org" Version="56" Author="Jassal, Bijay" Maintainer="Orlic-Milacic, Marija" Email="morlic-milacic@oicr.on.ca" Organism="Homo sapiens"> <Comment Source="WikiPathways-description">Similar to NOTCH1, NOTCH4 is activated by delta-like and jagged ligands (DLL/JAG) expressed in trans on a neighboring cell. The activation triggers cleavage of NOTCH4, first by ADAM10 at the S2 cleavage site, then by gamma-secretase at the S3 cleavage site, resulting in the release of the intracellular domain of NOTCH4, NICD4, into the cytosol. NICD4 subsequently traffics to the nucleus where it acts as a transcriptional regulator. View original pathway at:[http://www.reactome.org/PathwayBrowser/#DIAGRAM=1980150 Reactome].</Comment> <Comment Source="Reactome Converter">Pathway is converted from Reactome id: </Comment> <Attribute Key="reactome_id" Value="1980150" /> <Graphics BoardWidth="910.0" BoardHeight="1386.0" /> <DataNode TextLabel="DLL/JAG" GraphId="cf476" Type="Complex"> <Attribute Key="cellular_location" Value="plasma membrane" /> <Graphics CenterX="206.0" CenterY="235.5" Width="68.0" Height="21.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="RoundedRectangle" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-157643" /> </DataNode> <DataNode TextLabel="DLL1 " GraphId="bec46" Type="Protein" GroupRef="d5c4c"> <Attribute Key="cellular_location" Value="plasma membrane" /> <Attribute Key="complex_id" Value="R-HSA-157643" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="100.0" CenterY="646.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref 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membrane" /> <Attribute Key="complex_id" Value="R-HSA-157643" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="100.0" CenterY="706.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9Y219" /> </DataNode> <DataNode TextLabel="NOTCH4" GraphId="de784" Type="Complex"> <Attribute Key="cellular_location" Value="plasma membrane" /> <Graphics CenterX="287.5" CenterY="237.5" Width="65.0" Height="23.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-157053" /> </DataNode> <DataNode TextLabel="NOTCH4(1337-2003) " GraphId="f5d0e" Type="Protein" GroupRef="b0e3c"> <Attribute Key="cellular_location" Value="plasma membrane" /> <Attribute Key="complex_id" Value="R-HSA-157053" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="100.0" CenterY="766.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q99466" /> </DataNode> <DataNode TextLabel="12xFucT-11xGlcS-6xFucS-NOTCH4(24-1336) " GraphId="e76c6" Type="Protein" GroupRef="b0e3c"> <Attribute Key="cellular_location" Value="extracellular region" /> <Attribute Key="complex_id" Value="R-HSA-157053" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="100.0" CenterY="806.0" Width="100.0" Height="40.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q99466" /> </DataNode> <DataNode TextLabel="DLL/JAG:NOTCH4" GraphId="d0226" Type="Complex"> <Attribute Key="cellular_location" Value="plasma membrane" /> <Graphics CenterX="250.0" CenterY="310.0" Width="124.0" Height="22.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-157653" /> </DataNode> <DataNode TextLabel="NOTCH4(1337-2003) " GraphId="adb02" Type="Protein" GroupRef="e7328"> <Attribute Key="cellular_location" Value="plasma membrane" /> 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Key="complex_id" Value="R-HSA-157186" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="100.0" CenterY="1206.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:29105" /> </DataNode> <DataNode TextLabel="NICD4" GraphId="faf72" Type="Protein"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="415.0" CenterY="456.0" Width="46.0" Height="22.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q99466" /> </DataNode> <DataNode TextLabel="NOTCH4(1432-1466)" GraphId="a8109" Type="Protein"> <Attribute Key="cellular_location" Value="plasma membrane" /> <Graphics CenterX="248.0" CenterY="463.0" Width="100.0" Height="32.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q99466" /> </DataNode> <DataNode TextLabel="gamma-secretase&#xA;complex" GraphId="ccc3e" Type="Complex"> <Attribute Key="cellular_location" 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Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9NZ42" /> </DataNode> <DataNode TextLabel="APH1B " GraphId="f6fca" Type="Protein" GroupRef="d0de3"> <Attribute Key="cellular_location" Value="plasma membrane" /> <Attribute Key="complex_id" Value="R-HSA-157343" /> <Attribute Key="copies_num" Value="2" /> <Graphics CenterX="100.0" CenterY="1306.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q8WW43" /> </DataNode> <DataNode TextLabel="APH1A " GraphId="fc0e2" Type="Protein" GroupRef="d0de3"> <Attribute Key="cellular_location" Value="plasma membrane" /> <Attribute Key="complex_id" Value="R-HSA-157343" /> <Attribute Key="copies_num" Value="2" /> <Graphics CenterX="100.0" CenterY="1326.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q96BI3" /> </DataNode> <DataNode TextLabel="NCSTN " GraphId="dee12" Type="Protein" GroupRef="d0de3"> <Attribute Key="cellular_location" Value="plasma membrane" /> <Attribute Key="complex_id" Value="R-HSA-157343" /> <Attribute Key="copies_num" Value="2" /> <Graphics CenterX="100.0" CenterY="1346.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q92542" /> </DataNode> <DataNode TextLabel="NICD4" GraphId="f41df" Type="Protein"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="596.0" CenterY="458.0" Width="46.0" Height="22.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q99466" /> </DataNode> <DataNode TextLabel="Pre-NOTCH Expression&#xA;and Processing" GraphId="fa613" Type="Pathway"> <Comment Source="Reactome">In humans and other mammals the NOTCH gene family has four members, NOTCH1, NOTCH2, NOTCH3 and NOTCH4, encoded on four different chromosomes. Their transcription is developmentally regulated and tissue specific, but very little information exists on molecular mechanisms of transcriptional regulation. Translation of NOTCH mRNAs is negatively regulated by a number of recently discovered microRNAs (Li et al. 2009, Pang et al.2010, Ji et al. 2009, Kong et al. 2010, Marcet et al. 2011, Ghisi et al. 2011, Song et al. 2009, Hashimoto et al. 2010, Costa et al. 2009). &lt;br&gt;&lt;br&gt; The nascent forms of NOTCH precursors, Pre-NOTCH1, Pre-NOTCH2, Pre-NOTCH3 and Pre-NOTCH4, undergo extensive posttranslational modifications in the endoplasmic reticulum and Golgi apparatus to become functional. In the endoplasmic reticulum, conserved serine and threonine residues in the EGF repeats of NOTCH extracellular domain are fucosylated and glucosylated by POFUT1 and POGLUT1, respectively (Yao et al. 2011, Stahl et al. 2008, Wang et al. 2001, Shao et al. 2003, Acar et al. 2008, Fernandez Valdivia et al. 2011). &lt;br&gt;&lt;br&gt; In the Golgi apparatus, fucose groups attached to NOTCH EGF repeats can be elongated by additional glycosylation steps initiated by fringe enzymes (Bruckner et al. 2000, Moloney et al. 2000, Cohen et al. 1997, Johnston et al. 1997, Chen et al. 2001). Fringe-mediated modification modulates NOTCH signaling but is not an obligatory step in Pre-NOTCH processing. Typically, processing of Pre-NOTCH in the Golgi involves cleavage by FURIN convertase (Blaumueller et al. 1997, Logeat et al. 1998, Gordon et al. 2009, Rand et al. 2000, Chan et al. 1998). The cleavage of NOTCH results in formation of mature NOTCH heterodimers that consist of NOTCH extracellular domain (NEC i.e. NECD) and NOTCH transmembrane and intracellular domain (NTM i.e. NTMICD). NOTCH heterodimers translocate to the cell surface where they function in cell to cell signaling.</Comment> <BiopaxRef>f87</BiopaxRef> <BiopaxRef>cc3</BiopaxRef> <BiopaxRef>cf8</BiopaxRef> <BiopaxRef>a11</BiopaxRef> <BiopaxRef>c0c</BiopaxRef> <BiopaxRef>a58</BiopaxRef> <BiopaxRef>d49</BiopaxRef> <BiopaxRef>a77</BiopaxRef> <BiopaxRef>f50</BiopaxRef> <BiopaxRef>ad7</BiopaxRef> <BiopaxRef>c57</BiopaxRef> <BiopaxRef>e7a</BiopaxRef> <BiopaxRef>d29</BiopaxRef> <BiopaxRef>cfc</BiopaxRef> <BiopaxRef>fac</BiopaxRef> <BiopaxRef>a80</BiopaxRef> <BiopaxRef>a50</BiopaxRef> <BiopaxRef>cd7</BiopaxRef> <BiopaxRef>ae4</BiopaxRef> <BiopaxRef>a0e</BiopaxRef> <BiopaxRef>f82</BiopaxRef> <BiopaxRef>c09</BiopaxRef> <BiopaxRef>b01</BiopaxRef> <BiopaxRef>ffa</BiopaxRef> <BiopaxRef>a6f</BiopaxRef> <Attribute Key="org.pathvisio.DoubleLineProperty" Value="Double" /> <Graphics CenterX="503.0" CenterY="235.5" Width="256.0" Height="47.0" ZOrder="32768" FontSize="10" Valign="Middle" LineThickness="0.0" Color="14961e" /> <Xref Database="Reactome" ID="R-HSA-1912422" /> </DataNode> <Interaction GraphId="cc388"> <Comment Source="Reactome">The NOTCH4 receptor is activated by binding a Delta-like (DLL) or Jagged (JAG) ligand presented on the plasma membrane of a neighbouring cell. </Comment> <BiopaxRef>c1f</BiopaxRef> <BiopaxRef>b32</BiopaxRef> <BiopaxRef>f5f</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="249.0" Y="261.0" /> <Point X="249.0" Y="296.0" /> <Anchor Position="0.0" Shape="None" GraphId="bd1cb" /> <Anchor Position="0.99" Shape="None" GraphId="b669a" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-157633" /> </Interaction> <Interaction GraphId="fd009"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="240.0" Y="235.0" GraphRef="cf476" RelX="1.0" RelY="-0.047619047619047616" /> <Point X="249.0" Y="261.0" GraphRef="bd1cb" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-157633" /> </Interaction> <Interaction GraphId="dd42a"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="255.0" Y="237.0" GraphRef="de784" RelX="-1.0" RelY="-0.043478260869565216" /> <Point X="249.0" Y="261.0" GraphRef="bd1cb" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-157633" /> </Interaction> <Interaction GraphId="f9ba0"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="249.0" Y="296.0" GraphRef="b669a" RelX="0.0" RelY="0.35000000000002274" /> <Point X="250.0" Y="299.0" GraphRef="d0226" RelX="0.0" RelY="-1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-157633" /> </Interaction> <Interaction GraphId="ad6df"> <Comment Source="Reactome">Ligand binding induces a conformational change in the NOTCH4, probably through mechanical pulling of NOTCH4 triggered by endocytosis of receptor-attached ligand. This conformational change exposes the S2 site in the extracellular region of NOTCH4 and results in cleavage of NOTCH4 by ADAM10 metalloprotease, generating the membrane-anchored NOTCH4 fragment NEXT4. The extracellular NOTCH4 portion remains attached to the ligand presented on the plasma membrane of a neighboring cell. </Comment> <BiopaxRef>b32</BiopaxRef> <BiopaxRef>c1f</BiopaxRef> <BiopaxRef>ee9</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="250.0" Y="324.0" /> <Point X="250.0" Y="362.0" /> <Anchor Position="0.0" Shape="None" GraphId="c8358" /> <Anchor Position="0.99" Shape="None" GraphId="adc99" /> <Anchor Position="0.5" Shape="None" GraphId="d7af4" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-157649" /> </Interaction> <Interaction GraphId="e9d98"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="250.0" Y="321.0" GraphRef="d0226" RelX="0.0" RelY="1.0" /> <Point X="250.0" Y="324.0" GraphRef="c8358" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-157649" /> </Interaction> <Interaction GraphId="c5877"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> 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