Regulation of mitotic cell cycle (Homo sapiens)

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<?xml version="1.0" encoding="UTF-8"?> <Pathway xmlns="http://pathvisio.org/GPML/2013a" Name="Regulation of mitotic cell cycle" Organism="Homo sapiens"> <Comment Source="WikiPathways-description">Regulation of mitotic cell cycle currently covers APC/C-mediated degradation of cell cycle proteins. View original pathway at:[http://www.reactome.org/PathwayBrowser/#DIAGRAM=453276 Reactome].</Comment> <Comment Source="Reactome-Converter">Pathway is converted from Reactome ID: 453276</Comment> <Comment Source="Reactome-version">Reactome version: 63</Comment> <Attribute Key="reactome_id" Value="453276" /> <Graphics BoardWidth="3820.0" BoardHeight="2829.0" /> <DataNode TextLabel="CDC16 " GraphId="a0001" Type="Protein" GroupRef="c5168"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-188192" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="3600.0" CenterY="1949.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q13042" /> </DataNode> <DataNode TextLabel="CDC20 " GraphId="a00a3" Type="Protein" GroupRef="c0199"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-174140" /> <Attribute Key="copies_num" Value="1" /> <Graphics 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This allows the stabilization of proteins required for subsequent cell cycle progression.</Comment> <BiopaxRef>a1f</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="772.0" Y="316.0" /> <Point X="683.0" Y="317.0" /> <Anchor Position="0.0" Shape="None" GraphId="af9b5" /> <Anchor Position="0.99" Shape="None" GraphId="f2580" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174139" /> </Interaction> <Interaction GraphId="a6d99"> <Comment Source="Reactome">The APC/C:Cdh1 complex recognizes substrates containing a D box, a KEN box (Pfleger and Kirschner, 2000) or a D box activated (DAD) domain (Castro et al., 2002).</Comment> <BiopaxRef>f78</BiopaxRef> <BiopaxRef>a45</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="172.0" Y="1216.0" /> <Point X="218.0" Y="1217.0" /> <Anchor Position="0.0" Shape="None" GraphId="eab69" /> <Anchor Position="0.99" Shape="None" GraphId="ac3cc" /> </Graphics> <Xref 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RelX="0.9701492537313433" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174058" /> </Interaction> <Interaction GraphId="a8f3f"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="862.0" Y="1298.0" GraphRef="f100f" RelX="0.9863945578231292" RelY="-0.04" /> <Point X="925.0" Y="1354.0" GraphRef="fc715" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174171" /> </Interaction> <Interaction GraphId="a9054"> <Comment Source="Reactome">Securin is thought to be recognized by the APC/C:Cdc20 complex through its conserved D-box sequence.</Comment> <BiopaxRef>f6c</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1191.0" Y="953.0" /> <Point X="1189.0" Y="885.0" /> <Anchor Position="0.0" Shape="None" GraphId="d5ceb" /> <Anchor Position="0.99" Shape="None" GraphId="b64f8" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174121" /> </Interaction> <Interaction 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ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1040.0" Y="1184.0" GraphRef="e729c" RelX="0.0" RelY="-1.0" /> <Point X="1038.0" Y="1181.0" GraphRef="e5b66" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174157" /> </Interaction> <Interaction GraphId="aebdf"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1035.0" Y="1104.0" GraphRef="f319c" RelX="-0.029999999999972715" RelY="-0.7699999999999818" /> <Point X="868.0" Y="1124.0" GraphRef="a6dcf" RelX="0.9801980198019802" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174157" /> </Interaction> <Interaction GraphId="aec32"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="717.0" Y="759.0" GraphRef="cc0c4" RelX="0.9726027397260274" RelY="0.0" /> <Point X="937.0" Y="840.0" GraphRef="d2429" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174144" /> </Interaction> <Interaction GraphId="af107"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="465.0" Y="982.0" GraphRef="f3a94" RelX="1.0299999999999727" RelY="1.9600000000000364" /> <Point X="524.0" Y="963.0" GraphRef="be43f" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174203" /> </Interaction> <Interaction GraphId="af210"> <Comment Source="Reactome">At the onset of mitosis, Cdh1 is phosphorylated by Cyclin B-Cdc2 resulting in a conformational change that prevents Cdh1 from activating the APC/C. </Comment> <BiopaxRef>de0</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="563.0" Y="440.0" /> <Point X="564.0" Y="387.0" /> <Anchor Position="0.0" Shape="None" GraphId="fc34a" /> <Anchor Position="0.99" Shape="None" GraphId="a7f19" /> <Anchor Position="0.5" Shape="None" GraphId="d4d07" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174251" /> </Interaction> <Interaction 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Database="Reactome" ID="R-HSA-174088" /> </Interaction> <Interaction GraphId="b2be6"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="317.0" Y="1218.0" GraphRef="bf63f" RelX="1.0" RelY="0.0" /> <Point X="366.0" Y="1193.0" GraphRef="b9782" RelX="0.0" RelY="-2.0" ArrowHead="mim-catalysis" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174195" /> </Interaction> <Interaction GraphId="b3875"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="386.0" Y="614.0" GraphRef="f83d8" RelX="0.7300000000000182" RelY="0.0" /> <Point X="426.0" Y="593.0" GraphRef="c0952" RelX="-1.0" RelY="-0.0196078431372549" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174174" /> </Interaction> <Interaction GraphId="b3fff"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="92.0" Y="1496.0" GraphRef="d8ecf" RelX="0.010000000000005116" RelY="-0.6700000000000728" /> <Point X="72.0" Y="1469.0" GraphRef="dbaa1" RelX="0.9354838709677419" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174124" /> </Interaction> <Interaction GraphId="b43b6"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="872.0" Y="250.0" GraphRef="e3d6a" RelX="-1.0" RelY="0.0" /> <Point X="869.0" Y="248.0" GraphRef="a5ad1" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174058" /> </Interaction> <Interaction GraphId="b45d0"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="247.0" Y="1136.0" GraphRef="cbe83" RelX="-0.5" RelY="-0.009999999999990905" /> <Point X="233.0" Y="1090.0" GraphRef="d5b57" RelX="-0.015384615384615385" RelY="1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174105" /> </Interaction> <Interaction GraphId="b5c7e"> <Comment Source="Reactome">In late mitosis, Cdc20 dissociates from the APC/C and is replaced by the activator Cdh1 (Ballabeni et al. 2011).</Comment> <BiopaxRef>cd7</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1220.0" Y="1006.0" /> <Point X="1441.0" Y="1011.0" /> <Anchor Position="0.0" Shape="None" GraphId="a23f5" /> <Anchor Position="0.99" Shape="None" GraphId="fa2b5" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174224" /> </Interaction> <Interaction GraphId="b5d96"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="206.0" Y="428.0" GraphRef="c982d" RelX="0.0" RelY="-1.0" /> <Point X="223.0" Y="327.0" GraphRef="ecf05" RelX="-22.0" RelY="10.0" ArrowHead="mim-catalysis" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174119" /> </Interaction> <Interaction GraphId="b6ab0"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1335.0" Y="1063.0" GraphRef="ab48d" RelX="0.0" RelY="1.0" /> <Point X="1303.0" Y="1091.0" GraphRef="a831b" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174120" /> </Interaction> <Interaction GraphId="b802b"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1302.0" Y="1186.0" GraphRef="f4a5e" RelX="-0.009999999999990905" RelY="0.9500000000000455" /> <Point X="1303.0" Y="1189.0" GraphRef="aa004" RelX="-0.007633587786259542" RelY="-1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174120" /> </Interaction> <Interaction GraphId="b8388"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="404.0" Y="216.0" GraphRef="d8b64" RelX="0.983739837398374" RelY="0.0" /> <Point X="431.0" Y="200.0" GraphRef="e1232" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174079" /> </Interaction> <Interaction GraphId="b87e0"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1013.0" Y="1485.0" GraphRef="a3fc5" RelX="-0.009009009009009009" RelY="-1.0" /> <Point X="996.0" Y="1482.0" GraphRef="cb881" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-179421" /> </Interaction> <Interaction GraphId="b8f50"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="767.0" Y="894.0" GraphRef="a6147" RelX="0.0" RelY="1.0" /> <Point X="767.0" Y="897.0" GraphRef="aa27f" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174202" /> </Interaction> <Interaction GraphId="b91b9"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1189.0" Y="885.0" GraphRef="b64f8" RelX="-0.01999999999998181" RelY="-0.6800000000000637" /> <Point X="1189.0" Y="882.0" GraphRef="cebc9" RelX="-0.009174311926605505" RelY="1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174121" /> </Interaction> <Interaction GraphId="b945d"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="810.0" Y="861.0" GraphRef="cb93f" RelX="-1.2699999999999818" RelY="0.21000000000003638" /> <Point X="807.0" Y="862.0" GraphRef="a6147" RelX="1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174144" /> </Interaction> <Interaction GraphId="ba33b"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="759.0" Y="248.0" GraphRef="f5bca" RelX="-1.1000000000000227" RelY="0.0" /> <Point X="404.0" Y="306.0" GraphRef="a673b" RelX="1.0" RelY="-0.013333333333333334" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174058" /> </Interaction> <Interaction GraphId="baf9d"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="862.0" Y="1298.0" GraphRef="f100f" RelX="0.9863945578231292" RelY="-0.04" /> <Point X="866.0" Y="1297.0" GraphRef="f4344" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174238" /> </Interaction> <Interaction GraphId="bc9af"> <Comment Source="Reactome">Emi1 is also believed to be phosphorylated by Cyclin B:Cdc2 on a CDK consensus site at Ser 182. While Plk1 mediated phosphorylation of Emi1 at the DSGxxS (ßTrCP recognition) motif is essential for Emi1 destruction in mitosis, Cdk phosphorylation has been shown to play an important regulatory role.</Comment> <BiopaxRef>eb7</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="309.0" Y="526.0" /> <Point X="365.0" Y="526.0" /> <Anchor Position="0.0" Shape="None" GraphId="a9139" /> <Anchor Position="0.99" Shape="None" GraphId="d7ab4" /> <Anchor Position="0.5" Shape="None" GraphId="b210a" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174122" /> </Interaction> <Interaction GraphId="bcc2e"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="178.0" Y="1034.0" GraphRef="c5450" RelX="-0.5699999999999932" RelY="0.650000000000091" /> <Point X="201.0" Y="1080.0" GraphRef="d5b57" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-188191" /> </Interaction> <Interaction GraphId="bd975"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="420.0" Y="1059.0" GraphRef="c0b4e" RelX="0.9823008849557522" RelY="0.0" /> <Point X="745.0" Y="1191.0" GraphRef="ad9f7" RelX="3.0" RelY="0.5" ArrowHead="mim-catalysis" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174255" /> </Interaction> <Interaction GraphId="be07e"> <Comment Source="Reactome">At the beginning of this reaction, 1 molecule of 'multiubiquitinated Cdh1 associated with APC/C' is present. At the end of this reaction, 1 molecule of 'phosphorylated anaphase promoting complex (APC/C)', and 3 molecules of 'ubiquitin' are present.&lt;br&gt;&lt;br&gt; This reaction takes place in the 'nucleoplasm' and is mediated by the 'endopeptidase activity' of '26S proteasome'.&lt;br&gt;</Comment> <BiopaxRef>c7a</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="869.0" Y="248.0" /> <Point X="759.0" Y="248.0" /> <Anchor Position="0.0" Shape="None" GraphId="a5ad1" /> <Anchor Position="0.99" Shape="None" GraphId="f5bca" /> <Anchor Position="0.5" Shape="None" GraphId="cc45f" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174058" /> </Interaction> <Interaction GraphId="be85a"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="801.0" Y="1499.0" GraphRef="cdd67" RelX="0.979381443298969" RelY="-0.018867924528301886" /> <Point X="910.0" Y="1499.0" GraphRef="d49bc" RelX="2.0" RelY="-1.0" ArrowHead="mim-catalysis" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-179417" /> </Interaction> <Interaction GraphId="bec85"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1216.0" Y="998.0" GraphRef="f809d" RelX="0.9805825242718447" RelY="0.0" /> <Point X="1303.0" Y="1091.0" GraphRef="a831b" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174120" /> </Interaction> <Interaction GraphId="bfaf3"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="576.0" Y="462.0" GraphRef="f5da9" RelX="-1.0" RelY="0.0" /> <Point X="563.0" Y="440.0" GraphRef="fc34a" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174251" /> </Interaction> <Interaction GraphId="bfe8e"> <Comment Source="Reactome">Nek2A is degraded by the 26S proteasome following ubiquitylation by the E3 ubiquitin ligase APC/C: Cdc20.</Comment> <BiopaxRef>ba4</BiopaxRef> <BiopaxRef>e5f</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="996.0" Y="1482.0" /> <Point X="905.0" Y="1394.0" /> <Anchor Position="0.0" Shape="None" GraphId="cb881" /> <Anchor Position="0.99" Shape="None" GraphId="dcb0e" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-179421" /> </Interaction> <Interaction GraphId="c020d"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="190.0" Y="308.0" GraphRef="c0ab4" RelX="1.0" RelY="0.0" /> <Point X="193.0" Y="320.0" GraphRef="e1ec7" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174119" /> </Interaction> <Interaction GraphId="c0c7b"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="515.0" Y="916.0" GraphRef="ae68e" RelX="0.9805825242718447" RelY="0.0" /> <Point X="465.0" Y="758.0" GraphRef="ee9db" RelX="-30.5" RelY="0.0" ArrowHead="mim-catalysis" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174159" /> </Interaction> <Interaction GraphId="c1d92"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1135.0" Y="857.0" GraphRef="cebc9" RelX="-1.0" RelY="0.0" /> <Point X="937.0" Y="840.0" GraphRef="d2429" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174144" /> </Interaction> <Interaction GraphId="c1f91"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="518.0" Y="1561.0" GraphRef="a6b26" RelX="-1.0" RelY="0.0" /> <Point X="509.0" Y="1505.0" GraphRef="dac5f" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-141437" /> </Interaction> <Interaction GraphId="c265e"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="789.0" Y="1310.0" GraphRef="f100f" RelX="-0.006802721088435374" RelY="0.92" /> <Point X="753.0" Y="1339.0" GraphRef="a1831" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-179410" /> </Interaction> <Interaction GraphId="c2c50"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1216.0" Y="998.0" GraphRef="f809d" RelX="0.9805825242718447" RelY="0.0" /> <Point X="1220.0" Y="1006.0" GraphRef="a23f5" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174224" /> </Interaction> <Interaction GraphId="c52ac"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="774.0" Y="1190.0" GraphRef="fedf4" RelX="0.6399999999999864" RelY="-0.009999999999990905" /> <Point X="877.0" Y="1191.0" GraphRef="d935e" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174255" /> </Interaction> <Interaction GraphId="c6338"> <Comment Source="Reactome">Cdh1 is multiubiquitinated by the APC/C:Cdh1 complex prior to degradation by the 26S proteasome.</Comment> <BiopaxRef>c7a</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="936.0" Y="367.0" /> <Point X="936.0" Y="278.0" /> <Anchor Position="0.0" Shape="None" GraphId="a9729" /> <Anchor Position="0.99" Shape="None" GraphId="f3c18" /> <Anchor Position="0.5" Shape="None" GraphId="ab33d" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174057" /> </Interaction> <Interaction GraphId="c66a1"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="858.0" Y="525.0" GraphRef="ceb7d" RelX="-1.0" RelY="0.0" /> <Point X="825.0" Y="574.0" GraphRef="b289d" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174235" /> </Interaction> <Interaction GraphId="c6e76"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1108.0" Y="1214.0" GraphRef="d91c8" RelX="-0.7799999999999727" RelY="-0.009999999999990905" /> <Point X="1105.0" Y="1216.0" GraphRef="e729c" RelX="1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174227" /> </Interaction> <Interaction GraphId="c79c5"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point 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Consequently, Mad2 indirectly inhibits the APC/C by sequestering its activator, Cdc20. This requires interaction between Mad1 and Mad2. Cdc20 and Mad1 bind to the same site on Mad2.</Comment> <BiopaxRef>dd0</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="441.0" Y="1427.0" /> <Point X="384.0" Y="1429.0" /> <Anchor Position="0.0" Shape="None" GraphId="b89a6" /> <Anchor Position="0.99" Shape="None" GraphId="d8f48" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-141429" /> </Interaction> <Interaction GraphId="dae7f"> <Comment Source="Reactome">Emi1 promotes the accumulation of Cyclin A and entry into S phase by associating with and inhibiting the APC/C:Cdh1 complex at G1/S.</Comment> <BiopaxRef>ff4</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="750.0" Y="481.0" /> <Point X="844.0" Y="481.0" /> <Anchor Position="0.0" Shape="None" GraphId="ad749" /> <Anchor Position="0.99" Shape="None" GraphId="fa166" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174097" /> </Interaction> <Interaction GraphId="db020"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="774.0" Y="1190.0" GraphRef="fedf4" RelX="0.6399999999999864" RelY="-0.009999999999990905" /> <Point X="768.0" Y="1124.0" GraphRef="a6dcf" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174255" /> </Interaction> <Interaction GraphId="db3e8"> <Comment Source="Reactome">Nek2A does not appear to be recruited to the APC/C by Cdc20 but rather binds directly to the APC/C in an interaction involving the NEK2A C-terminal methionine–arginine (MR) dipeptide tail (Hayes et al., 2006).</Comment> <BiopaxRef>ba4</BiopaxRef> <BiopaxRef>e5f</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="753.0" Y="1339.0" /> <Point X="753.0" Y="1470.0" /> <Anchor Position="0.0" Shape="None" GraphId="a1831" /> <Anchor Position="0.99" Shape="None" GraphId="cb951" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-179410" /> </Interaction> <Interaction GraphId="dd1be"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="259.0" Y="503.0" GraphRef="f1be0" RelX="1.0" RelY="0.0" /> <Point X="309.0" Y="526.0" GraphRef="a9139" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174122" /> </Interaction> <Interaction GraphId="dd3dc"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="728.0" Y="1335.0" GraphRef="dc513" RelX="0.9636363636363636" RelY="0.0" /> <Point X="753.0" Y="1339.0" GraphRef="a1831" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-179410" /> </Interaction> <Interaction GraphId="dd512"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="483.0" Y="1389.0" GraphRef="af730" RelX="-1.0" RelY="0.0" /> <Point X="441.0" Y="1427.0" GraphRef="b89a6" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-141429" /> </Interaction> <Interaction GraphId="ddb79"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="190.0" Y="308.0" GraphRef="c0ab4" RelX="1.0" RelY="0.0" /> <Point X="193.0" Y="304.0" GraphRef="f834b" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174132" /> </Interaction> <Interaction GraphId="dde2b"> <Comment Source="Reactome">Skp2 is degraded by the anaphase promoting complex/Cyclosome and its activator Cdh1 [APC/C(Cdh1)] (Bashir et al, 2004; Wei et al, 2004). The tight regulation of APC/C(Cdh1) activity ensures the timely elimination Skp2 and, thus, plays a critical role in controlling the G1/S transition.</Comment> <BiopaxRef>e7a</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="235.0" Y="969.0" /> <Point X="178.0" Y="1034.0" /> <Anchor Position="0.0" Shape="None" GraphId="daba9" /> <Anchor Position="0.99" Shape="None" GraphId="c5450" /> <Anchor Position="0.5" Shape="None" GraphId="d40ae" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-188191" /> </Interaction> <Interaction GraphId="de0f2"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1441.0" Y="1011.0" GraphRef="fa2b5" RelX="2.2100000000000364" RelY="0.049999999999954525" /> <Point X="613.0" Y="1306.0" GraphRef="a7c95" RelX="0.9858156028368794" RelY="-0.018867924528301886" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174224" /> </Interaction> <Interaction GraphId="de6b1"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="465.0" Y="982.0" GraphRef="f3a94" RelX="1.0299999999999727" RelY="1.9600000000000364" /> <Point X="417.0" Y="1336.0" GraphRef="bdb79" RelX="-0.010526315789473684" RelY="-1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174203" /> </Interaction> <Interaction GraphId="dff3d"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="862.0" Y="1298.0" GraphRef="f100f" RelX="0.9863945578231292" RelY="-0.04" /> <Point X="814.0" Y="1237.0" GraphRef="f232f" RelX="36.5" RelY="22.0" ArrowHead="mim-catalysis" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174104" /> </Interaction> <Interaction GraphId="dff86"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="706.0" Y="1193.0" GraphRef="fee95" RelX="0.9891891891891892" RelY="0.0" /> <Point X="710.0" Y="1191.0" GraphRef="f6234" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174255" /> </Interaction> <Interaction GraphId="e0131"> <Comment Source="Reactome">Following its association with SCF-ßTrCP, phospho-Emi1 is poly-ubiquitinated.</Comment> <BiopaxRef>e0f</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="563.0" Y="758.0" /> <Point X="428.0" Y="758.0" /> <Anchor Position="0.0" Shape="None" GraphId="fdc6f" /> <Anchor Position="0.99" Shape="None" GraphId="e0de3" /> <Anchor Position="0.5" Shape="None" GraphId="ee9db" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174159" /> </Interaction> <Interaction GraphId="e01aa"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="825.0" Y="635.0" GraphRef="a73ca" RelX="0.0" RelY="0.6100000000000136" /> <Point X="825.0" Y="638.0" GraphRef="e8233" RelX="-0.010526315789473684" RelY="-1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174235" /> </Interaction> <Interaction GraphId="e039a"> <Comment Source="Reactome">In the direct inhibition model, association of the MCC with APCC results in the inactivation of APC/C. However, the affinity between MCC and APC/C is not high, so that the inhibition is readily reversible. The role of unattached kinetochores is to sensitize the APC/C to prolonged inhibition by the MCC.</Comment> <BiopaxRef>cd2</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="635.0" Y="1301.0" /> <Point X="713.0" Y="1299.0" /> <Anchor Position="0.0" Shape="None" GraphId="ec85c" /> <Anchor Position="0.99" Shape="None" GraphId="aa56a" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-141423" /> </Interaction> <Interaction GraphId="e05dc"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="252.0" Y="439.0" GraphRef="c982d" RelX="1.0" RelY="0.0" /> <Point X="342.0" Y="614.0" GraphRef="bd3ea" RelX="-7.5" RelY="0.0" ArrowHead="mim-catalysis" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174174" /> </Interaction> <Interaction GraphId="e07cb"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="713.0" Y="1299.0" GraphRef="aa56a" RelX="0.7799999999999727" RelY="-0.01999999999998181" /> <Point X="716.0" Y="1298.0" GraphRef="f100f" RelX="-1.0" RelY="-0.04" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-141423" /> </Interaction> <Interaction GraphId="e1324"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="269.0" Y="417.0" GraphRef="bbe68" RelX="-1.0" RelY="-0.030303030303030304" /> <Point X="251.0" Y="302.0" GraphRef="e122f" RelX="6.0" RelY="-1.5" ArrowHead="mim-catalysis" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174132" /> </Interaction> <Interaction GraphId="e1401"> <Comment Source="Reactome">One model ( the direct inhibition model) describing the inhibition of the APC/C during the mitotic spindle checkpoint suggests that the association of the hBUBR1:hBUB3:MAD2*:CDC20 mitotic checkpoint complex (MCC) with APC/C results in the inactivation of APC/C. The affinity between MCC and APC/C is not high, thus inhibition is readily reversible when the mitotic spindle checkpoint has been satisfied.</Comment> <BiopaxRef>cd2</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="866.0" Y="1297.0" /> <Point X="1168.0" Y="1296.0" /> <Anchor Position="0.0" Shape="None" GraphId="f4344" /> <Anchor Position="0.99" Shape="None" GraphId="a2591" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174238" /> </Interaction> <Interaction GraphId="e144f"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="515.0" Y="916.0" GraphRef="ae68e" RelX="0.9805825242718447" RelY="0.0" /> <Point X="563.0" Y="911.0" GraphRef="e651d" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174209" /> </Interaction> <Interaction GraphId="e20c9"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="486.0" Y="202.0" GraphRef="db94a" RelX="0.5500000000000114" RelY="0.020000000000010232" /> <Point X="509.0" Y="218.0" GraphRef="e2931" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174079" /> </Interaction> <Interaction GraphId="e2b29"> <Comment Source="Reactome">Cyclin B is believed to be recognized by the APC/C:Cdc20 complex through its D-box sequence.</Comment> <BiopaxRef>e86</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1303.0" Y="1091.0" /> <Point X="1302.0" Y="1186.0" /> <Anchor Position="0.0" Shape="None" GraphId="a831b" /> <Anchor Position="0.99" Shape="None" GraphId="f4a5e" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174120" /> </Interaction> <Interaction GraphId="e2ef7"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="297.0" Y="314.0" GraphRef="cdf46" RelX="1.0400000000000205" RelY="-0.060000000000002274" /> <Point X="300.0" Y="306.0" GraphRef="a673b" RelX="-1.0" RelY="-0.013333333333333334" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174119" /> </Interaction> <Interaction GraphId="e4cab"> <Comment Source="Reactome">Mulitubiquitinated Cyclin B is targeted for degradation by the 26S proteasome.</Comment> <BiopaxRef>e86</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1038.0" Y="1181.0" /> <Point X="1035.0" Y="1104.0" /> <Anchor Position="0.0" Shape="None" GraphId="e5b66" /> <Anchor Position="0.99" Shape="None" GraphId="f319c" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174157" /> </Interaction> <Interaction GraphId="e5ee7"> <Comment Source="Reactome">Phosphorylation by mitotic kinases is believed to alter the conformation of Cdh1 preventing it from associating with the APC/C. Cdc14 is thought to contribute to the dephosphorylation of Cdh1 in late mitosis. Dephosphorylated Cdh1 then associates with and activates the APC/C.</Comment> <BiopaxRef>de0</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="91.0" Y="1563.0" /> <Point X="92.0" Y="1496.0" /> <Anchor Position="0.0" Shape="None" GraphId="e43fe" /> <Anchor Position="0.99" Shape="None" GraphId="d8ecf" /> <Anchor Position="0.5" Shape="None" GraphId="a6c09" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174124" /> </Interaction> <Interaction GraphId="e74fb"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="362.0" Y="783.0" GraphRef="aca7e" RelX="0.0" RelY="1.0" /> <Point X="362.0" Y="786.0" GraphRef="c7bf6" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174203" /> </Interaction> <Interaction GraphId="e76b5"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="221.0" Y="181.0" GraphRef="de1bf" RelX="0.0" RelY="1.0" /> <Point X="218.0" Y="216.0" GraphRef="fa2f6" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-188371" /> </Interaction> <Interaction GraphId="e7ad2"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1035.0" Y="1104.0" GraphRef="f319c" RelX="-0.029999999999972715" RelY="-0.7699999999999818" /> <Point X="1114.0" Y="998.0" GraphRef="f809d" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174157" /> </Interaction> <Interaction GraphId="e8478"> <Comment Source="Reactome">Upon release from the kinetochore, Mad2 associates with Cdc20, hBUBR1, and hBUB3 to form the Mitotic Checkpoint Complex (MCC). Assembly of this complex does not depend on kinetochores but this complex can only inhibit APC/C that has undergone mitotic modifications.</Comment> <BiopaxRef>cd2</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="509.0" Y="1505.0" /> <Point X="630.0" Y="1425.0" /> <Anchor Position="0.0" Shape="None" GraphId="dac5f" /> <Anchor Position="0.99" Shape="None" GraphId="a9cc0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-141437" /> </Interaction> <Interaction GraphId="e881a"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="563.0" Y="797.0" GraphRef="f7e8a" RelX="-0.009900990099009901" RelY="-1.0" /> <Point X="563.0" Y="758.0" GraphRef="fdc6f" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174159" /> </Interaction> <Interaction GraphId="e8a75"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="366.0" Y="1172.0" GraphRef="b7188" RelX="0.0" RelY="-0.4600000000000364" /> <Point X="366.0" Y="1169.0" GraphRef="efa40" RelX="-0.007518796992481203" RelY="1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174195" /> </Interaction> <Interaction GraphId="e959d"> <Comment Source="Reactome">Following multiubiquitination, Cyclin A is targeted for destruction by the 26S proteasome.</Comment> <BiopaxRef>e86</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="710.0" Y="1191.0" /> <Point X="774.0" Y="1190.0" /> <Anchor Position="0.0" Shape="None" GraphId="f6234" /> <Anchor Position="0.99" Shape="None" GraphId="fedf4" /> <Anchor Position="0.5" Shape="None" GraphId="ad9f7" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174255" /> </Interaction> <Interaction GraphId="e9722"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1011.0" Y="1422.0" GraphRef="eb396" RelX="-1.0" RelY="0.0" /> <Point X="925.0" Y="1354.0" GraphRef="fc715" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174171" /> </Interaction> <Interaction GraphId="e9a5e"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="365.0" Y="526.0" GraphRef="d7ab4" RelX="0.5600000000000023" RelY="0.0" /> <Point X="433.0" Y="536.0" GraphRef="ae8a7" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174122" /> </Interaction> <Interaction GraphId="e9bd2"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="428.0" Y="758.0" GraphRef="e0de3" RelX="-1.3500000000000227" RelY="0.0" /> <Point X="425.0" Y="758.0" GraphRef="aca7e" RelX="1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174159" /> </Interaction> <Interaction GraphId="ea7b5"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="308.0" Y="1059.0" GraphRef="c0b4e" RelX="-1.0" RelY="0.0" /> <Point X="275.0" Y="1137.0" GraphRef="bbee3" RelX="3.0" RelY="0.5" ArrowHead="mim-catalysis" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174105" /> </Interaction> <Interaction GraphId="ea903"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="562.0" Y="855.0" GraphRef="f60f0" RelX="-0.009999999999990905" RelY="-0.5599999999999454" /> <Point X="563.0" Y="851.0" GraphRef="f7e8a" RelX="-0.009900990099009901" RelY="0.9636363636363636" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174209" /> </Interaction> <Interaction GraphId="eabb9"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="656.0" Y="1372.0" GraphRef="bc042" RelX="-0.009345794392523364" RelY="-1.0" /> <Point X="635.0" Y="1301.0" GraphRef="ec85c" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-141423" /> </Interaction> <Interaction GraphId="eb439"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="247.0" Y="1136.0" GraphRef="cbe83" RelX="-0.5" RelY="-0.009999999999990905" /> <Point X="189.0" Y="1141.0" GraphRef="ecfd8" RelX="1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174105" /> </Interaction> <Interaction GraphId="ec985"> <Comment Source="Reactome">Phosphorylation of the APC/C is believed to be required for its activation. While the identity of the essential phosphorylation sites and the kinase(s) responsible are not known with certainty, in vitro studies have shown that the Apc1 and the tetratricopeptide repeat (TPR) subunits Cdc27, Cdc16, Cdc23 and Apc7 are phosphorylated and that the Cdk1 and Plk1 kinases may play a role.</Comment> <BiopaxRef>e8c</BiopaxRef> <BiopaxRef>a26</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="193.0" Y="304.0" /> <Point X="297.0" Y="303.0" /> <Anchor Position="0.0" Shape="None" GraphId="f834b" /> <Anchor Position="0.99" Shape="None" GraphId="f10d0" /> <Anchor Position="0.5" Shape="None" GraphId="e122f" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174132" /> </Interaction> <Interaction GraphId="ed3d0"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="881.0" Y="317.0" GraphRef="c5cef" RelX="1.0" RelY="0.0" /> <Point X="936.0" Y="315.0" GraphRef="ab33d" RelX="0.0" RelY="-7.5" ArrowHead="mim-catalysis" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174057" /> </Interaction> <Interaction GraphId="ed864"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="482.0" Y="1564.0" GraphRef="c03d7" RelX="1.0" RelY="0.0" /> <Point X="509.0" Y="1505.0" GraphRef="dac5f" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-141437" /> </Interaction> <Interaction GraphId="eec7a"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="844.0" Y="481.0" GraphRef="fa166" RelX="0.9400000000000546" RelY="0.0" /> <Point X="847.0" Y="481.0" GraphRef="f7b9d" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174097" /> </Interaction> <Interaction GraphId="ef7d5"> <Comment Source="Reactome">Rape et al. have recently demonstrated that the order in which APC/C targeted proteins are degraded is determined by the processivity of multiubiquitination of these substrates. Processive substrates acquire a polyubiquitin chain upon binding to the APC/C once and are degraded. Distributive substrates bind, dissociate and reassociate with the APC/C multiple times before acquiring an ubiquitin chain of sufficient length to insure degradation. In addition, distributive substrates that dissociate from the APC/C with short ubiquitin chains are targeted for deubiquitination (Rape et al., 2006). Paradoxically, although the multiubiquitination of cyclin A is distributive and later substrates of APC-Cdc20 such as Securin are processive (Rape et al., 2006), Cyclin A is degraded prior to Securin and Cyclin B. 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Plk1 phosphorylates serine residues in the DSGxxS degron sequence of Emi1 recruiting the SCF(betaTrCP) ubiquitin ligase.</Comment> <BiopaxRef>e0f</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="313.0" Y="614.0" /> <Point X="386.0" Y="614.0" /> <Anchor Position="0.0" Shape="None" GraphId="b2124" /> <Anchor Position="0.99" Shape="None" GraphId="f83d8" /> <Anchor Position="0.5" Shape="None" GraphId="bd3ea" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174174" /> </Interaction> <Interaction GraphId="f7927"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="768.0" Y="995.0" GraphRef="adc76" RelX="0.009999999999990905" RelY="0.9800000000000182" /> <Point X="769.0" Y="1047.0" GraphRef="ac7cb" RelX="-0.012345679012345678" RelY="-1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174202" /> </Interaction> <Interaction GraphId="f7cdf"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="341.0" Y="433.0" GraphRef="bbe68" RelX="-0.006896551724137931" RelY="0.9393939393939394" /> <Point X="337.0" Y="526.0" GraphRef="b210a" RelX="0.0" RelY="0.0" ArrowHead="mim-catalysis" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174122" /> </Interaction> <Interaction GraphId="f7e5e"> <Comment Source="Reactome">At the beginning of this reaction, 1 molecule of 'Cdc20:phospho-APC/C:Cyclin B:Cdc2 complex', and 3 molecules of 'ubiquitin' are present. At the end of this reaction, 1 molecule of 'multiubiquitinated Cyclin B:Cdc2:Cdc20:phospho-APC/C complex' is present.&lt;br&gt;&lt;br&gt; This reaction takes place in the 'cytosol' and is mediated by the 'ubiquitin-protein ligase activity' of 'Cdc20:Phospho-APC/C'.&lt;br&gt;</Comment> <BiopaxRef>e86</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1186.0" Y="1215.0" /> <Point X="1108.0" Y="1214.0" /> <Anchor Position="0.0" Shape="None" GraphId="a8f21" /> <Anchor Position="0.99" Shape="None" GraphId="d91c8" /> <Anchor Position="0.5" Shape="None" GraphId="b9f66" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174227" /> </Interaction> <Interaction GraphId="f7e6c"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1244.0" Y="968.0" GraphRef="b0527" RelX="-1.0" RelY="0.0" /> <Point X="1191.0" Y="953.0" GraphRef="d5ceb" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174121" /> </Interaction> <Interaction GraphId="f8d2c"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="683.0" Y="317.0" GraphRef="f2580" RelX="-0.8899999999999864" RelY="0.009999999999990905" /> <Point X="699.0" Y="351.0" GraphRef="d4454" RelX="1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174139" /> </Interaction> <Interaction GraphId="f914d"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="123.0" Y="1162.0" GraphRef="d41a6" RelX="0.3499999999999943" RelY="-1.4300000000000637" /> <Point X="135.0" Y="1159.0" GraphRef="ecfd8" RelX="0.0" RelY="1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174070" /> </Interaction> <Interaction GraphId="f9763"> <Comment Source="Reactome">At the beginning of this reaction, 3 molecules of 'ubiquitin', and 1 molecule of 'cell cycle proteins:phospho-APC/C:Cdh1 complex' are present. At the end of this reaction, 1 molecule of 'multiubiquitinated cell cycle protein:APC/C:Cdh1 complex' is present.&lt;br&gt;&lt;br&gt; This reaction takes place in the 'cytosol' and is mediated by the 'ubiquitin-protein ligase activity' of 'cell cycle proteins:phospho-APC/C:Cdh1 complex' (Rape et al.1996).&lt;br&gt;</Comment> <BiopaxRef>c37</BiopaxRef> <BiopaxRef>a1c</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="366.0" Y="1218.0" /> <Point X="366.0" Y="1172.0" /> <Anchor Position="0.0" Shape="None" GraphId="e8650" /> <Anchor Position="0.99" Shape="None" GraphId="b7188" /> <Anchor Position="0.5" Shape="None" GraphId="b9782" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174195" /> </Interaction> <Interaction GraphId="f9874"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="836.0" Y="1439.0" GraphRef="a44db" RelX="0.0" RelY="1.0" /> <Point X="861.0" Y="1500.0" GraphRef="e83df" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-179417" /> </Interaction> <Interaction GraphId="fb726"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="564.0" Y="387.0" GraphRef="a7f19" RelX="0.009999999999990905" RelY="-0.5299999999999727" /> <Point X="537.0" Y="357.0" GraphRef="bbef0" RelX="0.9487179487179487" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174251" /> </Interaction> <Interaction GraphId="fb90c"> <Comment Source="Reactome">Cell cycle proteins mulitubiquitinated by the APC/C are targeted for degradation by the 26S proteasome.</Comment> <BiopaxRef>c37</BiopaxRef> <BiopaxRef>a1c</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="297.0" Y="1137.0" /> <Point X="247.0" Y="1136.0" /> <Anchor Position="0.0" Shape="None" GraphId="f9eb6" /> <Anchor Position="0.99" Shape="None" GraphId="cbe83" /> <Anchor Position="0.5" Shape="None" GraphId="bbee3" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174105" /> </Interaction> <Interaction GraphId="fbf36"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="508.0" Y="1400.0" GraphRef="af730" RelX="-0.0196078431372549" RelY="1.0" /> <Point X="509.0" Y="1505.0" GraphRef="dac5f" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-141437" /> </Interaction> <Interaction GraphId="fc131"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1168.0" Y="1296.0" GraphRef="a2591" RelX="3.019999999999982" RelY="-0.009999999999990905" /> <Point X="1168.0" Y="1360.0" GraphRef="cf84d" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-174238" /> </Interaction> <Interaction GraphId="fc223"> <Comment Source="Reactome">Securin is ubiquitinated by APC/C:Cdc20 (Hagting et al., 2002; Jin et al. 2008).</Comment> <BiopaxRef>f6c</BiopaxRef> <BiopaxRef>b5d</BiopaxRef> <Graphics ConnectorType="Segmented" 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Width="59.0" Height="33.0" ZOrder="28672" FillColor="ffffff" FontSize="10" Valign="Middle" /> </Label> <Shape GraphId="c3aac" GroupRef="b9f7d"> <Graphics CenterX="539.0" CenterY="400.5" Width="1002.0" Height="615.0" ZOrder="16384" FontSize="10" Valign="Middle" ShapeType="RoundedRectangle" LineThickness="3.0" Color="c0c0c0" Rotation="0.0" /> </Shape> <Shape GraphId="ebf5b" GroupRef="f0fd3"> <Graphics CenterX="771.0" CenterY="863.0" Width="1526.0" Height="1596.0" ZOrder="16384" FontSize="10" Valign="Middle" ShapeType="RoundedRectangle" LineThickness="3.0" Color="c0c0c0" Rotation="0.0" /> </Shape> <Group GroupId="c3fd0" GraphId="a047f" Style="Complex"> <Attribute Key="complex_id" Value="R-HSA-188374" /> </Group> <Group GroupId="b052e" GraphId="a356a" Style="Complex"> <Attribute Key="complex_id" Value="R-HSA-174095" /> </Group> <Group GroupId="a7433" GraphId="a42f2" Style="Complex"> <Attribute Key="complex_id" Value="R-HSA-174107" /> </Group> <Group GroupId="f37ab" GraphId="a74e9" 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xmlns:bp="http://www.biopax.org/release/biopax-level3.owl#" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" rdf:id="f6c"> <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">12070128</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">Human securin proteolysis is controlled by the spindle checkpoint and reveals when the APC/C switches from activation by Cdc20 to Cdh1.</bp:TITLE> <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Hagting A, Den Elzen N, Vodermaier HC, Waizenegger IC, Peters JM, Pines J.</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="a1f"> <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">10548110</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">Accumulation of cyclin B1 requires E2F and cyclin-A-dependent rearrangement of the anaphase-promoting complex.</bp:TITLE> <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Lukas C, Sørensen CS, Kramer E, Santoni-Rugiu E, Lindeneg C, Peters JM, Bartek J, Lukas J.</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="ba4"> <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">11742988</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">APC/C-mediated destruction of the centrosomal kinase Nek2A occurs in early mitosis and depends upon a cyclin A-type D-box.</bp:TITLE> <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Hames RS, Wattam SL, Yamano H, Bacchieri R, Fry 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rdf:datatype="http://www.w3.org/2001/XMLSchema#string">E2F-dependent accumulation of hEmi1 regulates S phase entry by inhibiting APC(Cdh1).</bp:TITLE> <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Hsu JY, Reimann JD, Sørensen CS, Lukas J, Jackson PK.</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="e0f"> <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">15469984</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">Plk1 regulates activation of the anaphase promoting complex by phosphorylating and triggering SCFbetaTrCP-dependent destruction of the APC Inhibitor Emi1.</bp:TITLE> <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Hansen DV, Loktev AV, Ban KH, Jackson PK.</bp:AUTHORS> </bp:PublicationXref> 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rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Mammalian Cdh1/Fzr mediates its own degradation.</bp:TITLE> <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Listovsky T, Oren YS, Yudkovsky Y, Mahbubani HM, Weiss AM, Lebendiker M, Brandeis M.</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="de0"> <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">11598127</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">Regulation of the anaphase-promoting complex by the dual specificity phosphatase human Cdc14a.</bp:TITLE> <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Bembenek J, Yu H.</bp:AUTHORS> </bp:PublicationXref> <bp:PublicationXref xmlns:bp="http://www.biopax.org/release/biopax-level3.owl#" 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