Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer (Homo sapiens)

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<?xml version="1.0" encoding="UTF-8"?> <Pathway xmlns="http://pathvisio.org/GPML/2013a" Name="Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer" Organism="Homo sapiens"> <Comment Source="WikiPathways-description">In the nucleus, SMAD2/3:SMAD4 heterotrimer complex acts as a transcriptional regulator. The activity of SMAD2/3 complex is regulated both positively and negatively by association with other transcription factors (Chen et al. 2002, Varelas et al. 2008, Stroschein et al. 1999, Wotton et al. 1999). In addition, the activity of SMAD2/3:SMAD4 complex can be inhibited by nuclear protein phosphatases and ubiquitin ligases (Lin et al. 2006, Dupont et al. 2009). View original pathway at:[http://www.reactome.org/PathwayBrowser/#DIAGRAM=2173793 Reactome].</Comment> <Comment Source="Reactome-Converter">Pathway is converted from Reactome ID: 2173793</Comment> <Comment Source="Reactome-version">Reactome version: 63</Comment> <Comment Source="Reactome Author">Reactome Author: Orlic-Milacic, Marija</Comment> <BiopaxRef>a04</BiopaxRef> <BiopaxRef>fcc</BiopaxRef> <BiopaxRef>fed</BiopaxRef> <BiopaxRef>bc3</BiopaxRef> <BiopaxRef>e8c</BiopaxRef> <BiopaxRef>d2b</BiopaxRef> <Attribute Key="reactome_id" Value="2173793" /> <Graphics BoardWidth="1720.0" BoardHeight="2243.0" /> <DataNode TextLabel="UBC(153-228) " GraphId="a0222" Type="Protein" GroupRef="d6c0f"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-870520" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="800.0" CenterY="1843.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P0CG48" /> </DataNode> <DataNode TextLabel="UBC(609-684) " GraphId="a02a3" Type="Protein" GroupRef="e54f5"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-2186733" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1220.0" CenterY="1623.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P0CG48" /> </DataNode> <DataNode TextLabel="UBB(1-76) " GraphId="a047f" Type="Protein" GroupRef="ac9e2"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-2186778" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1360.0" CenterY="1503.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P0CG47" /> </DataNode> <DataNode TextLabel="RPS27A(1-76) " GraphId="a0793" Type="Protein" GroupRef="b5e40"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-2179273" /> <Attribute Key="copies_num" Value="2" /> <Graphics CenterX="520.0" CenterY="1363.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P62979" /> </DataNode> <DataNode TextLabel="UBC(229-304) " GraphId="a07b8" Type="Protein" GroupRef="e54f5"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-2186733" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1220.0" CenterY="1523.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P0CG48" /> </DataNode> <DataNode TextLabel="SMAD4 " GraphId="a08d2" Type="Protein" GroupRef="c83a1"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-870446" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="240.0" CenterY="1383.0" Width="100.0" Height="20.0" 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Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-2186733" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1220.0" CenterY="1583.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P0CG48" /> </DataNode> <DataNode TextLabel="Signaling by&#xA;TGF-beta Receptor&#xA;Complex" GraphId="cf4f7" Type="Pathway"> <Comment Source="Reactome">The TGF-beta/BMP pathway incorporates several signaling pathways that share most, but not all, components of a central signal transduction engine. The general signaling scheme is rather simple: upon binding of a ligand, an activated plasma membrane receptor complex is formed, which passes on the signal towards the nucleus through a phosphorylated receptor SMAD (R-SMAD). In the nucleus, the activated R-SMAD promotes transcription in complex with a closely related helper molecule termed Co-SMAD (SMAD4). However, this simple linear pathway expands into a network when various regulatory components and mechanisms are taken into account. The signaling pathway includes a great variety of different TGF-beta/BMP superfamily ligands and receptors, several types of the R-SMADs, and functionally critical negative feedback loops. The R-SMAD:Co-SMAD complex can interact with a great number of transcriptional co-activators/co-repressors to regulate positively or negatively effector genes, so that the interpretation of a signal depends on the cell-type and cross talk with other signaling pathways such as Notch, MAPK and Wnt. The pathway plays a number of different biological roles in the control of embryonic and adult cell proliferation and differentiation, and it is implicated in a great number of human diseases.&lt;br&gt;TGF beta (TGFB1) is secreted as a homodimer, and as such it binds to TGF beta receptor II (TGFBR2), inducing its dimerization. Binding of TGF beta enables TGFBR2 to form a stable hetero-tetrameric complex with TGF beta receptor I homodimer (TGFBR1). TGFBR2 acts as a serine/threonine kinase and phosphorylates serine and threonine residues within the short GS domain (glycine-serine rich domain) of TGFBR1.&lt;br&gt;The phosphorylated heterotetrameric TGF beta receptor complex (TGFBR) internalizes into clathrin coated endocytic vesicles where it associates with the endosomal membrane protein SARA. SARA facilitates the recruitment of cytosolic SMAD2 and SMAD3, which act as R-SMADs for TGF beta receptor complex. TGFBR1 phosphorylates recruited SMAD2 and SMAD3, inducing a conformational change that promotes formation of R-SMAD trimers and dissociation of R-SMADs from the TGF beta receptor complex. &lt;br&gt;In the cytosol, phosphorylated SMAD2 and SMAD3 associate with SMAD4 (known as Co-SMAD), forming a heterotrimer which is more stable than the R-SMAD homotrimers. R-SMAD:Co-SMAD heterotrimer translocates to the nucleus where it directly binds DNA and, in cooperation with other transcription factors, regulates expression of genes involved in cell differentiation, in a context-dependent manner. &lt;br&gt;The intracellular level of SMAD2 and SMAD3 is regulated by SMURF ubiquitin ligases, which target R-SMADs for degradation. In addition, nuclear R-SMAD:Co-SMAD heterotrimer stimulates transcription of inhibitory SMADs (I-SMADs), forming a negative feedback loop. I-SMADs bind the phosphorylated TGF beta receptor complexes on caveolin coated vesicles, derived from the lipid rafts, and recruit SMURF ubiquitin ligases to TGF beta receptors, leading to ubiquitination and degradation of TGFBR1. Nuclear R-SMAD:Co-SMAD heterotrimers are targets of nuclear ubiquitin ligases which ubiquitinate SMAD2/3 and SMAD4, causing heterotrimer dissociation, translocation of ubiquitinated SMADs to the cytosol and their proteasome-mediated degradation. For a recent review of TGF-beta receptor signaling, please refer to Kang et al. 2009.</Comment> <BiopaxRef>dbd</BiopaxRef> <Attribute Key="org.pathvisio.DoubleLineProperty" Value="Double" /> <Graphics CenterX="470.0" CenterY="126.0" Width="172.0" Height="52.0" ZOrder="32768" FontSize="10" Valign="Middle" LineThickness="0.0" Color="14961e" /> <Xref Database="Reactome" ID="R-HSA-170834" /> </DataNode> <DataNode TextLabel="UBC(457-532) " GraphId="cf6a5" Type="Protein" GroupRef="bd461"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-68524" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1220.0" CenterY="1943.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P0CG48" /> </DataNode> <DataNode TextLabel="SMAD7 gene" GraphId="d0102" Type="GeneProduct"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="1237.0" CenterY="894.5" Width="90.0" 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GroupRef="c3518"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-870482" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="800.0" CenterY="1383.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P62987" /> </DataNode> <DataNode TextLabel="ATP1B4" GraphId="fdca4" Type="Protein"> <Attribute Key="cellular_location" Value="nuclear envelope" /> <Graphics CenterX="1571.0" CenterY="687.0" Width="56.0" Height="22.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9UN42" /> </DataNode> <DataNode TextLabel="UBC(609-684) " GraphId="fdd9e" Type="Protein" GroupRef="b670e"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-68524" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="660.0" CenterY="2043.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> 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Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P0CG48" /> </DataNode> <DataNode TextLabel="p-S423,S425-SMAD3 " GraphId="ff51e" Type="Protein" GroupRef="db313"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-171175" /> <Attribute Key="copies_num" Value="3" /> <Graphics CenterX="100.0" CenterY="1363.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P84022" /> </DataNode> <DataNode TextLabel="Ub-SMAD4" GraphId="fffa4" Type="Complex"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="306.0" CenterY="613.5" Width="80.0" Height="21.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-870463" /> </DataNode> <Interaction GraphId="a025c"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="734.0" Y="590.0" GraphRef="beddb" RelX="1.0" RelY="0.0" /> <Point X="802.0" Y="576.0" GraphRef="bf960" RelX="3.0" RelY="1.0" ArrowHead="mim-catalysis" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2187325" /> </Interaction> <Interaction GraphId="a088c"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="462.0" Y="616.0" GraphRef="a6585" RelX="-0.017543859649122806" RelY="1.0" /> <Point X="462.0" Y="669.0" GraphRef="bad5b" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-870538" /> </Interaction> <Interaction GraphId="a156d"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="286.0" Y="320.0" GraphRef="b716a" RelX="-0.029999999999972715" RelY="-0.6000000000000227" /> <Point X="287.0" Y="317.0" GraphRef="e25c2" RelX="0.0" RelY="1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-870479" /> </Interaction> <Interaction GraphId="a2591"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1266.0" Y="814.0" GraphRef="ce3a1" RelX="-4.7894736842105265" RelY="2.909090909090909" /> <Point X="1322.0" Y="872.0" GraphRef="d6c3d" RelX="6.5" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2106591" /> </Interaction> <Interaction GraphId="a3e80"> <Comment Source="Reactome">SMURF2 binds SMAD2/3:SMAD4 heterotrimer through ineraction with SMAD3. Phosphorylation of threonine T179 in the linker region of SMAD3 is critical for SMURF2 binding. SMURF2 also interacts with SMAD2 phosphorylated in the linker region. </Comment> <BiopaxRef>b8b</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="793.0" Y="723.0" /> <Point X="832.0" Y="748.0" /> <Anchor Position="0.0" Shape="None" GraphId="e42ce" /> <Anchor Position="0.99" Shape="None" GraphId="a7bdb" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2179274" /> </Interaction> <Interaction GraphId="a4ace"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1282.0" Y="894.0" GraphRef="d0102" RelX="1.0" RelY="-0.0196078431372549" /> <Point X="1291.0" Y="871.0" GraphRef="ab31f" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2106591" /> </Interaction> <Interaction GraphId="a5a79"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="326.0" Y="299.0" GraphRef="e25c2" RelX="1.0" RelY="0.0" /> <Point X="367.0" Y="299.0" GraphRef="a7bb5" RelX="5.0" RelY="-11.0" ArrowHead="mim-catalysis" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-870437" /> </Interaction> <Interaction GraphId="a60ec"> <Comment Source="Reactome">Phosphorylation of the linker region of SMAD2 and SMAD3 by CDK8 or CDK9 creates a docking site for E3-ubiquitin ligase NEDD4L.</Comment> <BiopaxRef>ddb</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="806.0" Y="674.0" /> <Point X="839.0" Y="673.0" /> <Anchor Position="0.0" Shape="None" GraphId="d4e8e" /> <Anchor Position="0.99" Shape="None" GraphId="e0f27" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2176491" /> </Interaction> <Interaction GraphId="a7352"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="688.0" Y="1022.0" GraphRef="d7f50" RelX="0.0" RelY="1.0" /> <Point X="689.0" Y="1053.0" GraphRef="a9119" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2186741" /> </Interaction> <Interaction GraphId="a7830"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="827.0" Y="575.0" GraphRef="f9209" RelX="0.5599999999999454" RelY="0.0" /> <Point X="911.0" Y="570.0" GraphRef="f46a2" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2187325" /> </Interaction> <Interaction GraphId="a80b1"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1462.0" Y="940.0" GraphRef="b1f4c" RelX="0.0" RelY="1.0" /> <Point X="1464.0" Y="962.0" GraphRef="a1ce9" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2186785" /> </Interaction> <Interaction GraphId="a8993"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1499.0" Y="768.0" GraphRef="a35fa" RelX="-0.2899999999999636" RelY="0.40999999999996817" /> <Point X="1493.0" Y="771.0" GraphRef="ce3a1" RelX="-0.010526315789473684" RelY="-1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5252001" /> </Interaction> <Interaction GraphId="a946c"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="593.0" Y="681.0" GraphRef="a4883" RelX="0.9813084112149533" RelY="0.0" /> <Point X="612.0" Y="682.0" GraphRef="a8ad8" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2176475" /> </Interaction> <Interaction GraphId="a95c3"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="734.0" Y="590.0" GraphRef="beddb" RelX="1.0" RelY="0.0" /> <Point X="771.0" Y="575.0" GraphRef="a7c55" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2187325" /> </Interaction> <Interaction GraphId="ab6f4"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="940.0" Y="1094.0" GraphRef="c2f7b" RelX="0.5599999999999454" RelY="-0.13000000000010914" /> <Point X="707.0" Y="919.0" GraphRef="e5802" RelX="0.9692307692307692" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2186747" /> </Interaction> <Interaction GraphId="ac22b"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="546.0" Y="964.0" GraphRef="b9a17" RelX="0.009999999999990905" RelY="0.25" /> <Point X="546.0" Y="967.0" GraphRef="aa6b8" RelX="0.0" RelY="-1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2187309" /> </Interaction> <Interaction GraphId="ac403"> <Comment Source="Reactome">After phosphorylated SMAD2/3 accumulate in the nucleus in response to TGF-beta stimulation, E3 ubiqutin ligases RNF111 (Arkadia) (Levy et al. 2007) and SMURF2 (Bonni et al. 2001) bind SKI/SKIL in complex with SMAD2/3:SMAD4 heterotrimer. The role of RNF111 was inferred from experiments that used recombinant mouse RNF111 and endogenous human SMADs and SKI/SKIL (Levy et al. 2007). 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This interaction involves the C-terminus of WWTR1 (TAZ) and the MH1 domain of SMAD proteins.</Comment> <BiopaxRef>a04</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="997.0" Y="310.0" /> <Point X="1147.0" Y="406.0" /> <Anchor Position="0.0" Shape="None" GraphId="f6945" /> <Anchor Position="0.99" Shape="None" GraphId="cbb7d" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2031355" /> </Interaction> <Interaction GraphId="b4975"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="957.0" Y="737.0" GraphRef="aefdf" RelX="0.0" RelY="0.9047619047619048" /> <Point X="957.0" Y="771.0" GraphRef="b6df7" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2179276" /> </Interaction> <Interaction GraphId="b4fd1"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="286.0" Y="426.0" GraphRef="ce1e8" RelX="-0.160000000000025" RelY="-1.740000000000009" /> <Point X="286.0" Y="422.0" GraphRef="b3aaf" RelX="0.0" RelY="0.9047619047619048" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-870477" /> </Interaction> <Interaction GraphId="b5932"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="628.0" Y="656.0" GraphRef="cd3e8" RelX="0.0" RelY="0.9459459459459459" /> <Point X="629.0" Y="683.0" GraphRef="f55db" RelX="0.0" RelY="0.5" ArrowHead="mim-catalysis" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2176475" /> </Interaction> <Interaction GraphId="b6670"> <Comment Source="Reactome">E3 ubiquitin protein ligase TRIM33 (also known as Ecto, Ectodermin or Tif1-gamma) binds to the SMAD heterotrimer, composed of SMAD4 and two phosphorylated R-SMADs (SMAD2 and/or SMAD3), in the nucleus (Dupont et al. 2009, Dupont et al. 2005, He et al. 2006).</Comment> <BiopaxRef>e8c</BiopaxRef> <BiopaxRef>eaf</BiopaxRef> <BiopaxRef>c43</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="462.0" Y="669.0" /> <Point X="420.0" Y="681.0" /> <Anchor Position="0.0" Shape="None" GraphId="bad5b" /> <Anchor Position="0.99" Shape="None" GraphId="a50e1" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-870538" /> </Interaction> <Interaction GraphId="b84c6"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="407.0" Y="928.0" GraphRef="a1881" RelX="-0.5799999999999841" RelY="0.2799999999999727" /> <Point X="435.0" Y="950.0" GraphRef="b3def" RelX="1.0" RelY="-0.02564102564102564" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2127257" /> </Interaction> <Interaction GraphId="b8f67"> <Comment Source="Reactome">In the nucleus, protein type 2C phosphatase, PPM1A, dephosphorylates SMAD2 and SMAD3, resulting in dissociation of SMAD2/3:SMAD4 heterotrimeric complexes.</Comment> <BiopaxRef>d2b</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="701.0" Y="481.0" /> <Point X="914.0" Y="507.0" /> <Anchor Position="0.0" Shape="None" GraphId="b1a58" /> <Anchor Position="0.99" Shape="None" GraphId="de517" /> <Anchor Position="0.5" Shape="None" GraphId="fcb98" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-209055" /> </Interaction> <Interaction GraphId="b906b"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="960.0" Y="673.0" GraphRef="c6238" RelX="1.0" RelY="0.0" /> <Point X="978.0" Y="670.0" GraphRef="c4353" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2176502" /> </Interaction> <Interaction GraphId="b957c"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="391.0" Y="991.0" GraphRef="f0fe3" RelX="0.34000000000003183" RelY="0.009999999999990905" /> <Point X="394.0" Y="992.0" GraphRef="ed43c" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1484099" /> </Interaction> <Interaction GraphId="ba392"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="940.0" Y="1094.0" GraphRef="c2f7b" RelX="0.5599999999999454" RelY="-0.13000000000010914" /> <Point X="665.0" Y="1065.0" GraphRef="fae91" RelX="0.9692307692307692" RelY="-0.024390243902439025" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2186747" /> </Interaction> <Interaction GraphId="bab31"> <Comment Source="Reactome">Complex formed by RBL1 (p107), E2F4/5, DP1/2 and a trimer of phosphorylated R-SMADs (SMAD2/3) and SMAD4 (Co-SMAD) cooperatively binds to TIE (TGF-beta inhibitory element) and E2F sites in the MYC promoter and promotes cell-cycle independent inhibition of MYC transcription in response to TGF-beta stimulation (Chen et al. 2002).</Comment> <BiopaxRef>fcc</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="357.0" Y="990.0" /> <Point X="391.0" Y="991.0" /> <Anchor Position="0.0" Shape="None" GraphId="fd443" /> <Anchor Position="0.99" Shape="None" GraphId="f0fe3" /> <Anchor Position="0.5" Shape="None" GraphId="e7a38" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1484099" /> </Interaction> <Interaction GraphId="bbf18"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="646.0" Y="683.0" GraphRef="a3ed7" RelX="0.34000000000003183" RelY="0.009999999999990905" /> <Point X="670.0" Y="715.0" GraphRef="ef555" RelX="-0.02857142857142857" RelY="-1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2176475" /> </Interaction> <Interaction GraphId="bcea8"> <Comment Source="Reactome">TRIM33 (also known as Ecto, Ectodermin or Tif1-gamma) monoubiquitinates nuclear SMAD4 on lysine residue K519. This leads to disruption of heterotrimeric complexes composed of SMAD4 and two phosphorylated R-SMADs (SMAD2 and/or SMAD3). TRIM33 inhibits SMAD activity without affecting steady state levels of SMAD4 (Dupont et al. 2009, Dupont et al. 2005). </Comment> <BiopaxRef>e8c</BiopaxRef> <BiopaxRef>eaf</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="377.0" Y="678.0" /> <Point X="378.0" Y="638.0" /> <Anchor Position="0.0" Shape="None" GraphId="f05e6" /> <Anchor Position="0.99" Shape="None" GraphId="fd3e0" /> <Anchor Position="0.5" Shape="None" GraphId="b9e17" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-870449" /> </Interaction> <Interaction GraphId="bcfd3"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="311.0" Y="379.0" GraphRef="e6ccc" RelX="-1.0" RelY="-0.043478260869565216" /> <Point X="289.0" Y="380.0" GraphRef="f2102" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-870479" /> </Interaction> <Interaction GraphId="bdd76"> <Comment Source="Reactome">After dephosphorylation by PPM1A, SMAD2 and SMAD3 translocate to the cytosol.</Comment> <BiopaxRef>d2b</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1008.0" Y="468.0" /> <Point X="1007.0" Y="398.0" /> <Anchor Position="0.0" Shape="None" GraphId="b77d3" /> <Anchor Position="0.99" Shape="None" GraphId="c9f36" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2187395" /> </Interaction> <Interaction GraphId="be0dc"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1164.0" Y="431.0" GraphRef="c177d" RelX="-0.005025125628140704" RelY="1.0" /> <Point X="1164.0" Y="434.0" GraphRef="dce1c" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2106579" /> </Interaction> <Interaction GraphId="beecc"> <Comment Source="Reactome">Knocking down WWTR1 (TAZ) expression by siRNA treatment inhibits TGF-beta-dependent transcription of SMAD7 in human hepatocellular carcinoma cell line Hep G2. Chromatin immunoprecipitation (ChIP) confirmed binding of both WWTR1 and SMAD2/3 to the promoter of SMAD7 gene in response to TGF-beta stimulation (Varelas et al. 2008).&lt;br&gt;In fish, amphibian and avian species, ATP1B4 (aka X,K ATPase subunit beta m) functions as a subunit of Na/K ATPase, located in the plasma membrane. In mammals, this functionality is lost and ATP1B4 accumulates on the nuclear envelope where it can interact with SNW domain containing protein 1 (SNW1 aka Ski interacting protein, SKIP), a transcriptional regulator. This ATP1B4:SNW1 complex is able to modulate TGF beta mediated transcription by increasing mRNA levels of SMAD7, an inhibitor of TGF beta signalling (Pestov et al. 2007).</Comment> <BiopaxRef>a04</BiopaxRef> <BiopaxRef>ae0</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1291.0" Y="871.0" /> <Point X="1340.0" Y="873.0" /> <Anchor Position="0.0" Shape="None" GraphId="ab31f" /> <Anchor Position="0.99" Shape="None" GraphId="ec31f" /> <Anchor Position="0.5" Shape="None" GraphId="d6c3d" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2106591" /> </Interaction> <Interaction GraphId="bfac2"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="540.0" Y="698.0" GraphRef="a4883" RelX="-0.009345794392523364" RelY="1.0" /> <Point X="513.0" Y="701.0" GraphRef="f6b11" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-173545" /> </Interaction> <Interaction GraphId="bfbf2"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="336.0" Y="877.0" GraphRef="c87b1" RelX="1.0" RelY="0.0" /> <Point X="465.0" Y="900.0" GraphRef="ff013" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2127257" /> </Interaction> <Interaction GraphId="c043a"> <Comment Source="Reactome">The nuclear R-SMAD:Co-SMAD complex recruits ubiquitin conjugating enzymes, such as UBE2D1 and UBE2D3, that ubiquitinate the complex and eventually lead to its proteasomal degradation. 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<Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="371.0" Y="969.0" GraphRef="b3def" RelX="0.0" RelY="0.9487179487179487" /> <Point X="372.0" Y="990.0" GraphRef="e7a38" RelX="-2.0" RelY="-0.5" ArrowHead="TBar" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-1484099" /> </Interaction> <Interaction GraphId="cc8df"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="286.0" Y="402.0" GraphRef="b3aaf" RelX="0.0" RelY="-1.0" /> <Point X="289.0" Y="380.0" GraphRef="f2102" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-870479" /> </Interaction> <Interaction GraphId="ccf33"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="914.0" Y="507.0" GraphRef="de517" RelX="2.1299999999999955" RelY="0.2599999999999909" /> <Point X="1110.0" Y="774.0" GraphRef="bedf0" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-209055" /> </Interaction> <Interaction GraphId="cd52c"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="809.0" Y="647.0" GraphRef="ada74" RelX="-0.017543859649122806" RelY="0.9047619047619048" /> <Point X="806.0" Y="674.0" GraphRef="d4e8e" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2176491" /> </Interaction> <Interaction GraphId="cd5d4"> <Comment Source="Reactome">SMAD4 monoubiquitinated by TRIM33 translocates from the nucleus to the cytosol (Dupont et al. 2009, Dupont et al. 2005).</Comment> <BiopaxRef>e8c</BiopaxRef> <BiopaxRef>eaf</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="302.0" Y="600.0" /> <Point X="286.0" Y="426.0" /> <Anchor Position="0.0" Shape="None" GraphId="aabfa" /> <Anchor Position="0.99" Shape="None" GraphId="ce1e8" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-870477" /> </Interaction> <Interaction GraphId="cd7c1"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="914.0" Y="507.0" GraphRef="de517" RelX="2.1299999999999955" RelY="0.2599999999999909" /> <Point X="1059.0" Y="555.0" GraphRef="e9d1b" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-209055" /> </Interaction> <Interaction GraphId="cdb5d"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="537.0" Y="661.0" GraphRef="ffcb6" RelX="0.15999999999996817" RelY="2.2899999999999636" /> <Point X="540.0" Y="664.0" GraphRef="a4883" RelX="-0.009345794392523364" RelY="-1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-173488" /> </Interaction> <Interaction GraphId="ce268"> <Comment Source="Reactome">SKI and SKIL (SNO) are able to recruit NCOR and possibly other transcriptional repressors to SMAD2/3:SMAD4 complex, inhibiting SMAD2/3:SMAD4-mediated transcription (Sun et al. 1999, Luo et al. 1999, Strochein et al. 1999). Experimental findings suggest that SMAD2 and SMAD3 may target SKI and SKIL for degradation (Strochein et al. 1999, Sun et al. 1999 PNAS, Bonni et al. 2001), and that the ratio of SMAD2/3 and SKI/SKIL determines the outcome (inhibition of SMAD2/3:SMAD4-mediated transcription or degradation of SKI/SKIL). SKI and SKIL are overexpressed in various cancer types and their oncogenic effect is connected with their ability to inhibit signaling by TGF-beta receptor complex. </Comment> <BiopaxRef>b53</BiopaxRef> <BiopaxRef>fed</BiopaxRef> <BiopaxRef>e57</BiopaxRef> <BiopaxRef>b40</BiopaxRef> <BiopaxRef>c04</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="615.0" Y="954.0" /> <Point X="660.0" Y="983.0" /> <Anchor Position="0.0" Shape="None" GraphId="ffa35" /> <Anchor Position="0.99" Shape="None" GraphId="f0307" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-173481" /> </Interaction> <Interaction GraphId="ce904"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="787.0" Y="681.0" GraphRef="d877b" RelX="1.0" RelY="0.0" /> <Point X="793.0" Y="723.0" GraphRef="e42ce" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2179274" /> </Interaction> <Interaction GraphId="cee61"> <Comment Source="Reactome">In response to TGF-beta stimulation, a complex composed of SMAD2/3:SMAD4 heterotrimer and RBL1 (p107), E2F4/5 and DP1/2 can be detected in the nucleus. Formation of this complex was confirmed by both co-immunoprecipitation of the endogenous complex from the human keratinocyte cell line HaCat and by protein interaction studies using tagged recombinant proteins. It is possible that cells contain pre-assembled cytosolic complexes of SMAD2/3, RBL1 (p107) and E2F4/5, that translocate to the nucleus after TGF-beta stimulation, when phosphorylated SMAD2/3 recruit SMAD4. The MH2 domain of SMAD3 establishes independent contacts with the N-termini of E2F4 (or E2F5) and unphosphorylated RBL1 (p107). RBL2 (p130), RB1 and E2F1 do not interact with SMAD2/3 (Chen et al. 2002).</Comment> <BiopaxRef>fcc</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="465.0" Y="900.0" /> <Point X="407.0" Y="928.0" /> <Anchor Position="0.0" Shape="None" GraphId="ff013" /> <Anchor Position="0.99" Shape="None" GraphId="a1881" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2127257" /> </Interaction> <Interaction GraphId="cf723"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="844.0" Y="1095.0" GraphRef="dfeb9" RelX="1.0" RelY="-0.0196078431372549" /> <Point X="901.0" Y="1092.0" GraphRef="bfdec" RelX="-11.0" RelY="-8.5" ArrowHead="mim-catalysis" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2186747" /> </Interaction> <Interaction GraphId="cfa7d"> <Comment Source="Reactome">RNF111 (Arkadia) polyubiquitinates SMAD7 (Koinuma et al. 2003). This was inferred from studies using recombinant mouse Smad7 and recombinant mouse Rnf111 expressed in human embryonic kidney cell line HEK293.</Comment> <BiopaxRef>ade</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1464.0" Y="962.0" /> <Point X="1464.0" Y="998.0" /> <Anchor Position="0.0" Shape="None" GraphId="a1ce9" /> <Anchor Position="0.99" Shape="None" GraphId="c5768" /> <Anchor Position="0.5" Shape="None" GraphId="aecf6" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2186785" /> </Interaction> <Interaction GraphId="cfc78"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1358.0" Y="927.0" GraphRef="caf24" RelX="0.9672131147540983" RelY="-0.04" /> <Point X="1392.0" Y="921.0" GraphRef="f8ae3" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2186771" /> </Interaction> <Interaction GraphId="d094b"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="420.0" Y="681.0" GraphRef="a50e1" RelX="-0.4200000000000159" RelY="0.12000000000000455" /> <Point X="425.0" Y="702.0" GraphRef="d7a45" RelX="1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-870538" /> </Interaction> <Interaction GraphId="d127b"> <Comment Source="Reactome">SMURF2 monoubiquitinates SMAD3 on lysine residues in the MH2 domain. Lysines K333 and K378 are likely the major sites for monoubiquitination. Lysine K409 is also monoubiquitinated, and possibly lysine K341. Since lysines K333 and K378 are predicted to stabilize the interaction of SMAD3 with SMAD4, monoubiquitination of these lysine residues is expected to disrupt SMAD2/3:SMAD4 heterotrimer. SMURF2-mediated disruption of endogenous Smad2/3:Smad4 heterotrimers was demonstrated in mouse embryonic fibroblasts. 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are able to phosphorylate the linker region of SMAD2 and SMAD3. In SMAD3, CDK8/CDK9 preferentially targets threonine residue T179, although serine residues S208 and S213 can also be phosphorylated. In SMAD2, CDK8/9 preferentially targets threonine residue T220 (corresponds to T190 in the short isoform of SMAD2, SMAD2-2). Phosphorylation of serine residues that correspond to serines S208 and S213 of SMAD3 has not been examined. Phosphorylation of the linker region of SMAD2 and SMAD3 by CDK8/CDK9 enhances transcriptional activity of SMAD2/3:SMAD4 complex, but also primes SMAD2 and SMAD3 for ubiquitination and subsequent degradation (Alarcon et al. 2009).</Comment> <BiopaxRef>d77</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="612.0" Y="682.0" /> <Point X="646.0" Y="683.0" /> <Anchor Position="0.0" Shape="None" GraphId="a8ad8" /> <Anchor Position="0.99" Shape="None" GraphId="a3ed7" /> <Anchor Position="0.5" Shape="None" GraphId="f55db" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2176475" /> </Interaction> <Interaction GraphId="e160a"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1430.0" Y="922.0" GraphRef="e0a81" RelX="0.38000000000010914" RelY="0.009999999999990905" /> <Point X="1433.0" Y="923.0" GraphRef="b1f4c" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2186771" /> </Interaction> <Interaction GraphId="e163b"> <Comment Source="Reactome">TGF-beta (TGFB1) stimulates formation of a complex of SP1 transcription factor and SMAD2/3:SMAD4 heterotrimer. SMAD2 and SMAD4 bind to SP1 directly, through their C- and N-terminus, respectively (Feng et al. 2000). </Comment> <BiopaxRef>ce2</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="545.0" Y="939.0" /> <Point X="546.0" Y="964.0" /> <Anchor Position="0.0" Shape="None" GraphId="ce91e" /> <Anchor Position="0.99" Shape="None" GraphId="b9a17" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2187309" /> </Interaction> <Interaction GraphId="e2059"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="593.0" Y="681.0" GraphRef="a4883" RelX="0.9813084112149533" RelY="0.0" /> <Point X="677.0" Y="817.0" GraphRef="c6e24" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2186607" /> </Interaction> <Interaction GraphId="e2f88"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="914.0" Y="507.0" GraphRef="de517" RelX="2.1299999999999955" RelY="0.2599999999999909" /> <Point X="626.0" Y="527.0" GraphRef="d0971" RelX="0.9591836734693877" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-209055" /> </Interaction> <Interaction GraphId="e30d4"> <Comment Source="Reactome">TGF-beta-dependent nuclear accumulation of SMAD2/3 and SMAD4 is mediated by WWTR1 (TAZ). 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Initially, RNF111 may enable signal propagation by inhibiting negative regulators of TGF-beta signaling, SKI/SKIL and SMAD7. Subsequent negative regulation of RNF111 expression by TGF-beta may allow the signaling cascade to be turned off (Koinuma et al. 2003).</Comment> <BiopaxRef>ade</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1464.0" Y="1039.0" /> <Point X="1464.0" Y="1073.0" /> <Anchor Position="0.0" Shape="None" GraphId="d22a2" /> <Anchor Position="0.99" Shape="None" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2186780" /> </Interaction> <Interaction GraphId="e4123"> <Comment Source="Reactome">PARP1 ADP-ribosylates SMAD3 and SMAD4 in SMAD2/3:SMAD4 heterotrimer. ADP-ribosyl group is attached to glutamic acid residues E50 and E52 of SMAD3 and unknown amino acid residues of SMAD4. ADP-ribose monomer attached to SMAD3 and SMAD4 is subsequently extended to poly (ADP-ribosyl) chains (i.e. PAR chains) by PARP1, which is not shown here. ADP-ribosylation (PARylation) of SMAD3 and SMAD4 by PARP1 inhibits binding of SMAD2/3:SMAD4 heterotrimers to SMAD binding elements (SBEs) in promoters of SMAD-target genes.</Comment> <BiopaxRef>fd2</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="771.0" Y="575.0" /> <Point X="827.0" Y="575.0" /> <Anchor Position="0.0" Shape="None" GraphId="a7c55" /> <Anchor Position="0.99" Shape="None" GraphId="f9209" /> <Anchor Position="0.5" Shape="None" GraphId="bf960" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2187325" /> </Interaction> <Interaction GraphId="e5127"> <Comment Source="Reactome">E3 ubiqutin ligases RNF111 (Arkadia) (Levy et al. 2007, Nagano et al. 2007) and SMURF2 (Bonni et al. 2001) ubiquitinate SKI/SKIL transcriptional repressors bound to activated SMAD2/3. The role of RNF111 was inferred from experiments that used recombinant mouse RNF111 and endogenous human SMADs and SKI/SKIL. The role of SMURF2 was inferred from experiments involving human proteins only.</Comment> <BiopaxRef>cdd</BiopaxRef> <BiopaxRef>c04</BiopaxRef> <BiopaxRef>e44</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="884.0" Y="1107.0" /> <Point X="940.0" Y="1094.0" /> <Anchor Position="0.0" Shape="None" GraphId="d03e9" /> <Anchor Position="0.99" Shape="None" GraphId="c2f7b" /> <Anchor Position="0.5" Shape="None" GraphId="bfdec" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2186747" /> </Interaction> <Interaction GraphId="e58fd"> <Comment Source="Reactome">MEN1 (menin), a transcription factor tumor suppressor mutated in a familial cancer syndrome multiple endocrine neoplasia type 1, binds SMAD2/3:SMAD4 heterotrimer through interaction with SMAD3. MEN1 likely acts as a trancriptional cofactor for SMAD2/3:SMAD4 and may be involved in transcriptional regulation of some SMAD2/3:SMAD4 target genes (Kaji et al. 2001, Sowa et al. 2004, Canaff et al. 2012).</Comment> <BiopaxRef>a0b</BiopaxRef> <BiopaxRef>fbe</BiopaxRef> <BiopaxRef>bd9</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="455.0" Y="756.0" /> <Point X="416.0" Y="808.0" /> <Anchor Position="0.0" Shape="None" GraphId="e98ce" /> <Anchor Position="0.99" Shape="None" GraphId="d8d75" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2186643" /> </Interaction> <Interaction GraphId="e5d5e"> <Comment Source="Reactome">Knocking down WWTR1 (TAZ) expression by siRNA treatment inhibits TGF-beta-dependent transcription of SERPINE1 (PAI-1 i.e. plasminogen activator inhibitor 1) in hepatocellular carcinoma cell line Hep G2. Chromatin immunoprecipitation (ChIP) confirmed binding of both WWTR1 and SMAD2/3 to the promoter of SERPINE1 gene in response to TGF-beta stimulation (Varelas et al. 2008). Binding of TGIF1 or TGIF2 to SMAD2/3:SMAD4 heterotrimer negatively regulates transcription of SERPINE1 (Wotton et al. 1999, Melhuish et al. 2001). SMAD7 can also bind PAI-1 promoter (and probably other TGF-beta-responsive promoters) and inhibit PAI-1 expression, probably by competing with SMAD2/3:SMAD4 binding (Zhang et al. 2007).</Comment> <BiopaxRef>a04</BiopaxRef> <BiopaxRef>b91</BiopaxRef> <BiopaxRef>bc3</BiopaxRef> <BiopaxRef>b63</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1176.0" Y="949.0" /> <Point X="1196.0" Y="1271.0" /> <Anchor Position="0.0" Shape="None" GraphId="a0e83" /> <Anchor Position="0.99" Shape="None" GraphId="e044b" /> <Anchor Position="0.5" Shape="None" GraphId="a1f32" /> <Anchor Position="0.5" Shape="None" GraphId="b7a38" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2106586" /> </Interaction> <Interaction GraphId="e5df8"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1196.0" Y="1271.0" GraphRef="e044b" RelX="0.20000000000004547" RelY="3.2200000000000273" /> <Point X="1197.0" Y="1274.0" GraphRef="b4437" RelX="-0.014084507042253521" RelY="-1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2106586" /> </Interaction> <Interaction GraphId="e6541"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="540.0" Y="698.0" GraphRef="a4883" RelX="-0.009345794392523364" RelY="1.0" /> <Point X="442.0" Y="1036.0" GraphRef="cdce0" RelX="7.0" RelY="-0.5" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2187293" /> </Interaction> <Interaction GraphId="e6561"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="844.0" Y="1095.0" GraphRef="dfeb9" RelX="1.0" RelY="-0.0196078431372549" /> <Point X="884.0" Y="1107.0" GraphRef="d03e9" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2186747" /> </Interaction> <Interaction GraphId="e65c5"> <Comment Source="Reactome">The phosphorylated R-SMAD:CO-SMAD complex rapidly translocates to the nucleus (Xu et al. 2000, Kurisaki et al. 2001, Xiao et al. 2003) where it binds directly to DNA and interacts with a plethora of transcription co-factors. Regulation of target gene expression can be either positive or negative. A classic example of a target gene of the pathway are the genes encoding for I-SMADs. 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In mammals, this functionality is lost and ATP1B4 accumulates on the nuclear envelope where it can interact with SNW domain-containing protein 1 (SNW1 aka Ski-interacting protein, SKIP), a transcriptional regulator. 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<Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="416.0" Y="808.0" GraphRef="d8d75" RelX="-0.38999999999998636" RelY="0.5199999999999818" /> <Point X="404.0" Y="811.0" GraphRef="c124b" RelX="0.0" RelY="-1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2186643" /> </Interaction> <Interaction GraphId="f1c3a"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="605.0" Y="711.0" GraphRef="fb672" RelX="0.0" RelY="-1.0" /> <Point X="612.0" Y="682.0" GraphRef="a8ad8" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-2176475" /> </Interaction> <Interaction GraphId="f264a"> <Comment Source="Reactome">SKI/SKIL ubiquitinated by RNF111 (Levy et al. 2007, Nagano et al. 2007) or SMURF2 (Bonni et al. 2001) are degraded in a proteasome dependent way, enabling transcription of SMAD2/3:SMAD4 target genes.</Comment> <BiopaxRef>cdd</BiopaxRef> <BiopaxRef>e44</BiopaxRef> <BiopaxRef>c04</BiopaxRef> 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The R-SMAD:Co-SMAD complex (Nakao et al. 1997) most likely is a trimer of two R-SMADs with one Co-SMAD (Kawabata et al. 1998). It is important to note that the Co-SMAD itself cannot be phosphorylated as it lacks the C-terminal serine motif.&lt;br&gt;&lt;br&gt;ZFYVE16 (endofin) promotes SMAD heterotrimer formation. 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assembly of a Smad2-Smurf2 ubiquitin ligase complex that targets SnoN for degradation.</bp:TITLE> <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Bonni S, Wang HR, Causing CG, Kavsak P, Stroschein SL, Luo K, Wrana JL.</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="b7b"> <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">10022869</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">Smad3-Smad4 and AP-1 complexes synergize in transcriptional activation of the c-Jun promoter by transforming growth factor beta.</bp:TITLE> <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Wong C, Rougier-Chapman EM, Frederick JP, Datto MB, Liberati NT, Li JM, Wang XF.</bp:AUTHORS> </bp:PublicationXref> <bp:PublicationXref 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