RHOBTB GTPase Cycle (Homo sapiens)

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<?xml version="1.0" encoding="UTF-8"?> <Pathway xmlns="http://pathvisio.org/GPML/2013a" Name="RHOBTB GTPase Cycle" Organism="Homo sapiens"> <Comment Source="WikiPathways-description">RHO BTB family belongs to atypical RHO GTPases, which are characterized by the absence of GTPase activity. RhoBTB family includes RHOBTB1, RHOBTB2, and the more divergent RHOBTB3. RHOBTB1 is a component of a signaling cascade that regulates vascular function and blood pressure (Ji and Rivero 2016). RHOBTB2 is involved in COP9 signalosome-regulated and CUL3-dependent protein ubiquitination (Berthold et al. 2008; Ji and Rivero 2016). RHOBTB3 participates in CUL3 dependent protein ubiquitination, vesicle transport, regulation of the cell cycle and modulating the adaptive response to hypoxia (Berthold et al. 2008; Ji and Rivero 2016). View original pathway at [http://www.reactome.org/PathwayBrowser/#DIAGRAM=9706574 Reactome].</Comment> <Comment Source="Reactome-Converter">Pathway is converted from Reactome ID: 9706574</Comment> <Comment Source="Reactome-version">Reactome version: 75</Comment> <Comment Source="Reactome Author">Reactome Author: Orlic-Milacic, Marija</Comment> <BiopaxRef>ec7</BiopaxRef> <BiopaxRef>bdb</BiopaxRef> <Attribute Key="reactome_id" Value="9706574"/> <Graphics BoardWidth="745.0" BoardHeight="1454.0"/> <DataNode TextLabel="ATP " GraphId="a0015" Type="Metabolite" GroupRef="dedac"> <Attribute Key="cellular_location" Value="cytosol"/> <Attribute Key="complex_id" Value="R-HSA-9706391"/> <Attribute Key="copies_num" Value="1"/> <Graphics CenterX="100.0" CenterY="1414.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff"/> <Xref Database="ChEBI" ID="CHEBI:30616"/> </DataNode> <DataNode TextLabel="RHOBTB1 " GraphId="a06ed" Type="Protein" GroupRef="a30a0"> <Attribute Key="cellular_location" Value="endosome membrane"/> <Attribute Key="complex_id" Value="R-HSA-9020317"/> <Attribute Key="copies_num" Value="1"/> <Graphics CenterX="240.0" CenterY="1034.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="O94844"/> </DataNode> <DataNode TextLabel="RHOBTB2 interacting&#10;proteins" GraphId="a1918" Type="Complex"> <Attribute Key="cellular_location" Value="cytosol"/> <Graphics CenterX="439.5" CenterY="363.0" Width="129.0" Height="36.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="RoundedRectangle" Color="a52a2a"/> <Xref Database="Reactome" ID="R-HSA-9020341"/> </DataNode> <DataNode TextLabel="ATP" GraphId="a21af" Type="Metabolite"> <Attribute Key="cellular_location" Value="cytosol"/> <Graphics CenterX="199.0" CenterY="425.0" Width="38.0" Height="30.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff"/> <Xref Database="ChEBI" ID="CHEBI:30616"/> </DataNode> <DataNode TextLabel="RHOBTB3" GraphId="a2870" Type="Protein"> <Attribute Key="cellular_location" Value="trans-Golgi network membrane"/> <Graphics CenterX="162.0" CenterY="474.0" Width="74.0" Height="24.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="O94955"/> </DataNode> <DataNode TextLabel="VHL " GraphId="a30e7" Type="Protein" GroupRef="dedac"> <Attribute Key="cellular_location" Value="cytosol"/> <Attribute Key="complex_id" Value="R-HSA-9706391"/> <Attribute Key="copies_num" Value="1"/> <Graphics CenterX="100.0" CenterY="1374.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="P40337"/> </DataNode> <DataNode TextLabel="Pi" GraphId="a5b33" Type="Metabolite"> <Attribute Key="cellular_location" Value="cytosol"/> <Graphics CenterX="583.5" CenterY="418.0" Width="25.0" Height="30.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff"/> <Xref Database="ChEBI" ID="CHEBI:43474"/> </DataNode> <DataNode TextLabel="ROCK2 " GraphId="a6244" Type="Protein" GroupRef="a30a0"> <Attribute Key="cellular_location" Value="cytosol"/> <Attribute Key="complex_id" Value="R-HSA-9020317"/> <Attribute Key="copies_num" Value="1"/> <Graphics CenterX="240.0" CenterY="994.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="O75116"/> </DataNode> <DataNode TextLabel="RHOBTB2:GTP" GraphId="a6bd9" Type="Complex"> <Attribute Key="cellular_location" Value="endosome membrane"/> <Graphics CenterX="362.0" CenterY="294.0" Width="102.0" Height="24.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a"/> <Xref Database="Reactome" ID="R-HSA-9020344"/> </DataNode> <DataNode TextLabel="ATP " GraphId="a73f1" Type="Metabolite" GroupRef="b143c"> <Attribute Key="cellular_location" Value="cytosol"/> <Attribute Key="complex_id" Value="R-HSA-6814649"/> <Attribute Key="copies_num" Value="1"/> <Graphics CenterX="240.0" 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Key="cellular_location" Value="cytosol"/> <Attribute Key="complex_id" Value="R-HSA-9706391"/> <Attribute Key="copies_num" Value="1"/> <Graphics CenterX="100.0" CenterY="1214.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="Q13618"/> </DataNode> <DataNode TextLabel="PLIN3 " GraphId="c4b78" Type="Protein" GroupRef="dedac"> <Attribute Key="cellular_location" Value="cytosol"/> <Attribute Key="complex_id" Value="R-HSA-9706391"/> <Attribute Key="copies_num" Value="1"/> <Graphics CenterX="100.0" CenterY="1334.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="O60664"/> </DataNode> <DataNode TextLabel="RHOBTB1 " GraphId="c5b38" Type="Protein" GroupRef="b3203"> <Attribute Key="cellular_location" Value="endosome membrane"/> <Attribute Key="complex_id" Value="R-HSA-9020318"/> <Attribute Key="copies_num" Value="1"/> <Graphics CenterX="240.0" CenterY="1114.0" Width="100.0" 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Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="Q13464"/> </DataNode> <DataNode TextLabel="RHOBTB1:GTP" GraphId="d0f07" Type="Complex"> <Attribute Key="cellular_location" Value="endosome membrane"/> <Graphics CenterX="371.5" CenterY="131.0" Width="107.0" Height="22.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a"/> <Xref Database="Reactome" ID="R-HSA-9020318"/> </DataNode> <DataNode TextLabel="RHOBTB3 " GraphId="d292f" Type="Protein" GroupRef="dedac"> <Attribute Key="cellular_location" Value="trans-Golgi network membrane"/> <Attribute Key="complex_id" Value="R-HSA-9706391"/> <Attribute Key="copies_num" Value="1"/> <Graphics CenterX="100.0" CenterY="1394.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="O94955"/> </DataNode> <DataNode TextLabel="CUL3 " GraphId="d3a9d" Type="Protein" GroupRef="e398f"> <Attribute Key="cellular_location" 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ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff"/> <Xref Database="ChEBI" ID="CHEBI:15996"/> </DataNode> <DataNode TextLabel="RHOBTB2:GTP:RHOBTB2&#10;interacting&#10;proteins" GraphId="d6c2f" Type="Complex"> <Attribute Key="cellular_location" Value="endosome membrane"/> <Graphics CenterX="590.5" CenterY="298.0" Width="129.0" Height="50.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a"/> <Xref Database="Reactome" ID="R-HSA-9020346"/> </DataNode> <DataNode TextLabel="RHOBTB2 " GraphId="d77c5" Type="Protein" GroupRef="e398f"> <Attribute Key="cellular_location" Value="endosome membrane"/> <Attribute Key="complex_id" Value="R-HSA-9020346"/> <Attribute Key="copies_num" Value="1"/> <Graphics CenterX="100.0" CenterY="694.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle"/> <Xref Database="Uniprot-TrEMBL" ID="Q9BYZ6"/> </DataNode> <DataNode TextLabel="RHOBTB3:ADP" GraphId="d8a60" Type="Complex"> <Attribute 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</Graphics> <Xref Database="Reactome" ID="R-HSA-9706399"/> </Interaction> <Interaction GraphId="a53dc"> <Comment Source="Reactome">The GTPase domain of RHOBTB3 is considerably divergent and binds and hydrolyzes ATP instead of GTP by virtue of some critical amino acid replacements in the G4 and G5 motifs (Espinosa et al. 2009). 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The following proteins are substrates of RHOBTB3-dependent ubiquitin ligase complexes:&lt;br&gt;RAB9A, RAB9B (Espinosa et al. 2009)&lt;br&gt;Cyclin E1 (Lu and Pfeffer 2013)&lt;br&gt;LRRC41 (MUF1) (Schenková et al. 2012).&lt;br&gt;&lt;br&gt;The following proteins bind directly to RHOBTB3 but there is no evidence that they are substrates of RHOBTB3-dependent ubiquitin ligase complexes:&lt;br&gt;HGS (HRS) (Pridgeon et al. 2009)&lt;br&gt;PLIN3 (TIP47) (Espinosa et al. 2009)&lt;br&gt;5-HT7a serotonin receptor (Matthys et al. 2012)&lt;br&gt;VHL (Zhang et al. 2015).</Comment> <BiopaxRef>f7a</BiopaxRef> <BiopaxRef>fd4</BiopaxRef> <BiopaxRef>ee6</BiopaxRef> <BiopaxRef>a2e</BiopaxRef> <BiopaxRef>fe4</BiopaxRef> <BiopaxRef>dcd</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="358.0" Y="508.0"/> <Point X="293.0" Y="525.0"/> <Anchor Position="0.0" Shape="None" GraphId="e83ef"/> <Anchor Position="0.99" Shape="None" GraphId="a60e7"/> </Graphics> <Xref Database="Reactome" ID="R-HSA-9706390"/> </Interaction> <Interaction GraphId="bdb65"> <Comment Source="Reactome">RHOBTB1 shares 80% sequence identity with RHOBTB2, with close to 95% identity in the GTPase domain (reviewed by Ji and Rivero 2016). Based on studies in RHOBTB2 (Manjarrez et al. 2014), as well as on the primary structure of the GTPase domain, RHOBTB1 is expected to bind to GTP, but not to cycle between GTP- and GDP-bound states. There are no known RHOBTB1 GAPs.</Comment> <BiopaxRef>ec7</BiopaxRef> <BiopaxRef>b47</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="244.0" Y="130.0"/> <Point X="315.0" Y="130.0"/> <Anchor Position="0.0" Shape="None" GraphId="b0e1f"/> <Anchor Position="0.99" Shape="None" GraphId="e19e8"/> </Graphics> <Xref Database="Reactome" ID="R-HSA-9018774"/> </Interaction> <Interaction GraphId="bf245"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="424.0" Y="131.0" GraphRef="d0f07" RelX="0.9813084112149533" RelY="0.0"/> <Point X="462.0" Y="132.0" GraphRef="f4475" RelX="0.0" RelY="0.0"/> </Graphics> <Xref Database="Reactome" ID="R-HSA-9018778"/> </Interaction> <Interaction GraphId="bf586"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="263.0" Y="374.0" GraphRef="bd2ea" RelX="-0.014925373134328358" RelY="-1.0"/> <Point X="266.0" Y="297.0" GraphRef="b1e31" RelX="2.5" RelY="2.0" ArrowHead="mim-catalysis"/> </Graphics> <Xref Database="Reactome" ID="R-HSA-9018785"/> </Interaction> <Interaction GraphId="c4722"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="333.0" Y="472.0" GraphRef="a95a2" RelX="0.8999999999999773" RelY="-0.009999999999990905"/> <Point X="336.0" Y="472.0" GraphRef="be748" RelX="-1.0" RelY="-0.04" ArrowHead="Arrow"/> </Graphics> <Xref Database="Reactome" ID="R-HSA-9706393"/> </Interaction> <Interaction GraphId="c980d"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="315.0" Y="130.0" GraphRef="e19e8" RelX="0.7099999999999795" RelY="0.0"/> <Point X="318.0" Y="131.0" GraphRef="d0f07" RelX="-1.0" RelY="0.0" ArrowHead="Arrow"/> </Graphics> <Xref Database="Reactome" ID="R-HSA-9018774"/> </Interaction> <Interaction GraphId="ced4a"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="199.0" Y="474.0" GraphRef="a2870" RelX="1.0" RelY="0.0"/> <Point X="243.0" Y="473.0" GraphRef="a0991" RelX="0.0" RelY="0.0"/> </Graphics> <Xref Database="Reactome" ID="R-HSA-9706393"/> </Interaction> <Interaction GraphId="d48e8"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="377.0" Y="547.0" GraphRef="b6fcf" RelX="-1.0" RelY="0.0"/> <Point X="358.0" Y="508.0" GraphRef="e83ef" RelX="0.0" RelY="0.0"/> </Graphics> <Xref Database="Reactome" ID="R-HSA-9706390"/> </Interaction> <Interaction GraphId="d539b"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="308.0" Y="295.0" GraphRef="f612c" RelX="0.8899999999999864" RelY="0.0"/> <Point X="311.0" Y="294.0" GraphRef="a6bd9" RelX="-1.0" RelY="0.0" ArrowHead="Arrow"/> </Graphics> <Xref Database="Reactome" ID="R-HSA-9018785"/> </Interaction> <Interaction GraphId="da5fa"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="444.0" Y="427.0" GraphRef="b83ba" RelX="-0.024390243902439025" RelY="1.0"/> <Point X="478.0" Y="468.0" GraphRef="d5e2d" RelX="0.0" RelY="0.0"/> </Graphics> <Xref Database="Reactome" ID="R-HSA-9706399"/> </Interaction> <Interaction GraphId="dc24b"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="439.0" Y="345.0" GraphRef="a1918" RelX="-0.007751937984496124" RelY="-1.0"/> <Point X="437.0" Y="294.0" GraphRef="e3d80" RelX="0.0" RelY="0.0"/> </Graphics> <Xref Database="Reactome" ID="R-HSA-9018787"/> </Interaction> <Interaction GraphId="dd77b"> <Comment Source="Reactome">RHOBTB2 binds to GTP, but does not switch between GDP- and GTP-bound states (Manjarrez et al. 2014). ATP-dependent protein folding chaperone activity of the HSP90:CDC37 complex and binding of RHOBTB2 to the HSP90:CDC37 complex enables RHOBTB2 to bind GTP (Manjarrez et al. 2014). There are no known RHOBTB2 GAPs.</Comment> <BiopaxRef>b47</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="219.0" Y="295.0"/> <Point X="308.0" Y="295.0"/> <Anchor Position="0.0" Shape="None" GraphId="db03c"/> <Anchor Position="0.99" Shape="None" GraphId="f612c"/> <Anchor Position="0.5" Shape="None" GraphId="b1e31"/> </Graphics> <Xref Database="Reactome" ID="R-HSA-9018785"/> </Interaction> <Interaction GraphId="e67db"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="561.0" Y="472.0" GraphRef="cfe32" RelX="0.8300000000000409" RelY="0.040000000000020464"/> <Point X="583.0" Y="433.0" GraphRef="a5b33" RelX="-0.04" RelY="1.0" ArrowHead="Arrow"/> </Graphics> <Xref Database="Reactome" ID="R-HSA-9706399"/> </Interaction> <Interaction GraphId="e714d"> <Comment Source="Reactome">RHOBTB1, like other members of RHOBTB family, RHOBTB2 and RHOBTB3, binds to CUL3 (cullin-3), a core component of the BTB-CUL3-RBX2 E3 ubiquitin ligase complex (Berthold et al. 2008). RHOBTB1 binds to ROCK1 and ROCK2, and ROCK-mediated phosphorylation of RHOBTB1 may regulate its association with CUL3 (Haga et al. 2019). RHOBTB1 has been proposed as a substrate adaptor for PDE5, targeting it to CUL3 complexes for ubiquitination (Mukohda et al. 2019).</Comment> <BiopaxRef>e71</BiopaxRef> <BiopaxRef>a69</BiopaxRef> <BiopaxRef>ba1</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="462.0" Y="132.0"/> <Point X="549.0" Y="134.0"/> <Anchor Position="0.0" Shape="None" GraphId="f4475"/> <Anchor Position="0.99" Shape="None" GraphId="c3436"/> </Graphics> <Xref Database="Reactome" ID="R-HSA-9018778"/> </Interaction> <Interaction GraphId="f02dc"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="389.0" Y="484.0" GraphRef="be748" RelX="0.0" RelY="0.92"/> <Point X="358.0" Y="508.0" GraphRef="e83ef" RelX="0.0" RelY="0.0"/> </Graphics> <Xref Database="Reactome" ID="R-HSA-9706390"/> </Interaction> <Interaction GraphId="f0605"> <Comment Source="Reactome">RHOBTB2, like other RHOBTB family members, RHOBTB1 and RHOBTB3, binds CUL3 (cullin-3) (Berthold et al. 2008), a core component of BTB-CUL3-RBX1 E3 ubiquitin ligase complexes. Binding of GTP to RHOBTB2, facilitated by the HSP90 chaperone complex, enables binding of RHOBTB2 to CUL3 (Manjarrez et al. 2014). RHOBTB2 is thought to act as the regulatory BTB component of the BTB-CUL3-RBX1 complex by recruiting target proteins for ubiquitination and subsequent proteasome-mediated degradation (Wilkins et al. 2004). RHOBTB2 is a substrate adaptor for Musashi 2 (MSI2), targeting it to CUL3 complexes for ubiquitination and proteasomal degradation, thus suppressing tumorigenesis (Choi et al. 2017).</Comment> <BiopaxRef>b47</BiopaxRef> <BiopaxRef>a69</BiopaxRef> <BiopaxRef>f48</BiopaxRef> <BiopaxRef>f6a</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="437.0" Y="294.0"/> <Point X="523.0" Y="295.0"/> <Anchor Position="0.0" Shape="None" GraphId="e3d80"/> <Anchor Position="0.99" Shape="None" GraphId="e436f"/> </Graphics> <Xref Database="Reactome" ID="R-HSA-9018787"/> </Interaction> <Interaction GraphId="f7c52"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="293.0" Y="525.0" GraphRef="a60e7" RelX="-0.6499999999999773" RelY="0.16999999999995907"/> <Point X="289.0" Y="542.0" GraphRef="b473f" RelX="0.986013986013986" RelY="0.0" ArrowHead="Arrow"/> </Graphics> <Xref Database="Reactome" ID="R-HSA-9706390"/> </Interaction> 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