Hedgehog 'off' state (Homo sapiens)

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<?xml version="1.0" encoding="UTF-8"?> <Pathway xmlns="http://pathvisio.org/GPML/2013a" Name="Hedgehog 'off' state" Organism="Homo sapiens"> <Comment Source="WikiPathways-description">Hedgehog is a secreted morphogen that has evolutionarily conserved roles in body organization by regulating the activity of the Ci/Gli transcription factor family. In Drosophila in the absence of Hh signaling, full-length Ci is partially degraded by the proteasome to generate a truncated repressor form that translocates to the nucleus to represses Hh-responsive genes. Binding of Hh ligand to the Patched (PTC) receptor allows the 7-pass transmembrane protein Smoothened (SMO) to be activated in an unknown manner, disrupting the partial proteolysis of Ci and allowing the full length activator form to accumulate (reviewed in Ingham et al, 2011; Briscoe and Therond, 2013). &lt;br&gt;While many of the core components of Hh signaling are conserved from flies to humans, the pathways do show points of significant divergence. Notably, the human genome encodes three Ci homologues, GLI1, 2 and 3 that each play slightly different roles in regulating Hh responsive genes. GLI3 is the primary repressor of Hh signaling in vertebrates, and is converted to the truncated GLI3R repressor form in the absence of Hh. GLI2 is a potent activator of transcription in the presence of Hh but contributes only minimally to the repression function. While a minor fraction of GLI2 protein is processed into the repressor form in the absence of Hh, the majority is either fully degraded by the proteasome or sequestered in the full-length form in the cytosol by protein-protein interactions. GLI1 lacks the repression domain and appears to be an obligate transcriptional activator (reviewed in Briscoe and Therond, 2013).&lt;br&gt; Vertebrate but not fly Hh signaling also depends on the movement of pathway components through the primary cilium. The primary cilium is a non-motile microtubule based structure whose construction and maintenance depends on intraflagellar transport (IFT). Anterograde IFT moves molecules from the ciliary base along the axoneme to the ciliary tip in a manner that requires the microtubule-plus-end directed kinesin KIF3 motor complex and the IFT-B protein complex, while retrograde IFT back to the ciliary base depends on the minus-end directed dynein motor and the IFT-A complex. Genetic screens have identified a number of cilia-related proteins that are required both to maintain Hh in the 'off' state and to transduce the signal when the pathway is activated (reviewed in Hui and Angers, 2011; Goetz and Anderson, 2010). 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<Attribute Key="complex_id" Value="R-HSA-5610571" /> <Attribute Key="copies_num" Value="5" /> <Graphics CenterX="1080.0" CenterY="1965.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P10644" /> </DataNode> <DataNode TextLabel="SUFU " GraphId="c2dd6" Type="Protein" GroupRef="cafd7"> <Attribute Key="cellular_location" Value="ciliary base" /> <Attribute Key="complex_id" Value="R-HSA-5610542" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="800.0" CenterY="1745.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9UMX1" /> </DataNode> <DataNode TextLabel="KIF3A " GraphId="c3067" Type="Protein" GroupRef="dfb9d"> <Attribute Key="cellular_location" Value="cilium" /> <Attribute Key="complex_id" Value="R-HSA-5610625" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="800.0" CenterY="2045.0" Width="100.0" Height="20.0" ZOrder="32768" 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Type="Complex"> <BiopaxRef>ac2</BiopaxRef> <BiopaxRef>c44</BiopaxRef> <Attribute Key="cellular_location" Value="ciliary base" /> <Graphics CenterX="2153.5" CenterY="708.0" Width="111.0" Height="36.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-5610526" /> </DataNode> <DataNode TextLabel="IFT122 " GraphId="ff668" Type="Protein" GroupRef="dadb0"> <Attribute Key="cellular_location" Value="cilium" /> <Attribute Key="complex_id" Value="R-HSA-5610556" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="940.0" CenterY="1785.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9HBG6" /> </DataNode> <Interaction GraphId="a076d"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1564.0" Y="1004.0" GraphRef="ad708" RelX="0.7100000000000364" RelY="0.009999999999990905" /> <Point X="1567.0" Y="1005.0" GraphRef="f6367" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610742" /> </Interaction> <Interaction GraphId="a0cfa"> <Comment Source="Reactome">cAMP is a known regulator of PKA activity and works by binding to the regulatory subunits and promoting dissociation of the tetramer, freeing the active catalytic subunits (reviewed in Sassone-Corsi, 2012). In the Hh pathway in the absence of ligand, cAMP levels increase in response to the recruitment of GPR161 to the ciliary base by TULP3 and the IFT-A retrograde complex (Mukhopadhyay et al, 2010; Mukhopadhyay et al, 2013). Activated PKA then initiates the phosphorylation cascade that regulates processing and/or degradation of the GLI proteins (reviewed in Briscoe and Therond, 2013; Mukhopadhyay and Rohatgi, 2014).</Comment> <BiopaxRef>b4f</BiopaxRef> <BiopaxRef>f9b</BiopaxRef> <BiopaxRef>fd9</BiopaxRef> <BiopaxRef>ff4</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1334.0" Y="557.0" /> <Point X="1261.0" Y="556.0" /> <Anchor Position="0.0" Shape="None" GraphId="c8f27" /> <Anchor Position="0.99" Shape="None" GraphId="bf601" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610749" /> </Interaction> <Interaction GraphId="a0f98"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="826.0" Y="857.0" GraphRef="c9b11" RelX="0.0" RelY="-1.1200000000000045" /> <Point X="827.0" Y="853.0" GraphRef="c266e" RelX="-0.011764705882352941" RelY="0.9047619047619048" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610723" /> </Interaction> <Interaction GraphId="a1fb0"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="827.0" Y="833.0" GraphRef="c266e" RelX="-0.011764705882352941" RelY="-1.0" /> <Point X="826.0" Y="830.0" GraphRef="fcf42" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610767" /> </Interaction> <Interaction GraphId="a24af"> <Comment Source="Reactome">In the absence of Hh ligand, the Hh receptor PTCH inhibits signaling by negatively regulating the activity of SMO, a candidate member of the GPCR superfamily that transduces the Hh signal to downstream pathway components (reviewed in Ayers and Therond, 2010; Briscoe and Therond, 2013). Neither the mechanism by which SMO activates Hh signaling nor the manner in which PTCH represses this activty are fully elucidated, but these may involve regulation of putative SMO ligand(s) or changes in cellular localization, protein conformation and phosphorylation status, among other possibilities (reviewed in Briscoe and Therond, 2013; Ayers and Therond; 2010). &lt;br&gt;PTCH is a 7 transmembrane protein that is localized to the primary cilium in the absence of Hh ligand (Rohatgi et al, 2007). PTCH regulates SMO in a non-stoichiometric manner and there is little evidence that endogenous PTCH and SMO interact directly (Taipale et al, 2002; reviewed in Huangfu and Anderson, 2006). PTCH has a sterol sensing domain (SSD) and structural similarity to bacterial RND transporters. Mutation in conserved motifs in the RND domain abrogate the ability of PTCH to negatively regulate SMO activity (Taipale et al, 2002). The transmembrane heptahelical domain of SMO has been shown to bind to a number of natural and synthetic molecules, many of which are structurally related to sterols, and this binding can activate or repress SMO activity (Mas et al, 2010; Dwyer et al, 2007; Nachtergaele et al, 2012; Corcoran et al, 2006). Together, these data suggest a speculative model where PTCH regulates SMO activity by controlling the flux of sterol-related SMO agonists and/or antagonists, although this has not been fully substantiated (Khaliullina et al, 2009; reviewed in Rohatgi and Scott, 2007; Briscoe and Therond, 2013).&lt;br&gt;In the absence of Hh signal, SMO is largely found in intracellular vesicles, with a fraction localized to the plasma membrane (Milenkovic et al, 2009; Huangfu et al, 2006; Corbit et al, 2005; Rohatgi et al, 2007; Wang et al, 2009; Wilson et al, 2009). Like GLI2, 3 and SUFU, however, SMO may traffic through the cilium in the absence of ligand (Wilson et al, 2009; Kim et al, 2009). SMO and PTCH appear to have opposing localizations in both the 'off' and 'on' state, with PTCH exiting and SMO entering the cilium upon Hh pathway activation (Denef et al, 2000; Rohatgi et al, 2007; reviewed in Goetz and Anderson, 2010; Hui and Angers, 2011). Clearance of PTCH from the ciliary membrane in the presence of Hh is promoted by its ubiquitination by the E3 ligase SMURF (Huang et al, 2013; Yue et al, 2014)&lt;br&gt;Like the Drosophila homologue, vertebrate SMO appears to exists as a constitutive dimer. Dimerization is mediated by the N-terminal Cys-rich domain (CRD) and is required for function (Zhao et al, 2007). The C-terminal tail of SMO has arginine-rich clusters that appear to regulate the conformation of the tails in the dimer, maintaining the SMO dimer in an inactive state. In Drosophila, the inhibitory effect of the arginine-rich region is counteracted upon Hh pathway activation by PKA-mediated phosphorylation of adjacent serine residues. This promotes an open tail conformation that is required for cell surface accumulation and signaling (Zhao et al, 2007; Chen et al, 2010). These consensus PKA motifs are not conserved in the vertebrate SMO C-terminal tail, and a role for PKA-mediated phosphorylation and direct activation of SMO appears not to hold true in mammalian cells (Zhao et al, 2007; Tuson et al, 2011). A similar activating phosphorylation of vertebrate SMO may be CK1 or GRK2-dependent (Chen et al, 2011).</Comment> <BiopaxRef>fff</BiopaxRef> <BiopaxRef>bc2</BiopaxRef> <BiopaxRef>e12</BiopaxRef> <BiopaxRef>c94</BiopaxRef> <BiopaxRef>d82</BiopaxRef> <BiopaxRef>c34</BiopaxRef> <BiopaxRef>d28</BiopaxRef> <BiopaxRef>a9b</BiopaxRef> <BiopaxRef>b9e</BiopaxRef> <BiopaxRef>f7e</BiopaxRef> <BiopaxRef>d8f</BiopaxRef> <BiopaxRef>b45</BiopaxRef> <BiopaxRef>b61</BiopaxRef> <BiopaxRef>a0f</BiopaxRef> <BiopaxRef>e0b</BiopaxRef> <BiopaxRef>c5d</BiopaxRef> <BiopaxRef>ce8</BiopaxRef> <BiopaxRef>e53</BiopaxRef> <BiopaxRef>c19</BiopaxRef> <BiopaxRef>e21</BiopaxRef> <BiopaxRef>fee</BiopaxRef> <BiopaxRef>dcf</BiopaxRef> <BiopaxRef>b94</BiopaxRef> <BiopaxRef>c04</BiopaxRef> <BiopaxRef>a8f</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="309.0" Y="623.0" /> <Point X="704.0" Y="319.0" /> <Anchor Position="0.0" Shape="None" GraphId="e4ca6" /> <Anchor Position="0.99" Shape="None" GraphId="f5433" /> <Anchor Position="0.5" Shape="None" GraphId="bb5ab" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610763" /> </Interaction> <Interaction GraphId="a3466"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2208.0" Y="708.0" GraphRef="fe00b" RelX="0.9819819819819819" RelY="0.0" /> <Point X="2212.0" Y="710.0" GraphRef="b33c5" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610754" /> </Interaction> <Interaction GraphId="a3731"> <Comment Source="Reactome">Like GLI3, GLI2 has putative GSK3 sites that contribute to the proteasome-dependent degradation of the protein in the absence of Hh signal. Deletion of the GSK3 phosphorylation sites abrogates the interaction with beta-TrCP, stabilizes GLI2 protein and increases the expression of a GLI-dependent reporter, consistent with a role for GSK3 in promoting GLI2 degradation (Pan et al, 2006).</Comment> <BiopaxRef>e5a</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1900.0" Y="874.0" /> <Point X="1943.0" Y="874.0" /> <Anchor Position="0.0" Shape="None" GraphId="be509" /> <Anchor Position="0.99" Shape="None" GraphId="e4d5b" /> <Anchor Position="0.5" Shape="None" GraphId="b6de2" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610730" /> </Interaction> <Interaction GraphId="a3bfb"> <Comment Source="Reactome">Vertebrate hedgehog signaling depends on the passage and/or localization of many of the pathway components through the primary cilium (reviewed in Goetz and Anderson, 2010). Although GLI and SUFU proteins are not concentrated in the cilium in the absence of Hh signaling, processing and/or degradation of the transcription factors requires transit through the cilium and basal levels of these proteins can be detected there (Wen et al, 2010; Tukachinsky et al, 2010; Kim et al, 2006; Liu et al, 2005; Haycraft et 2005). Consistent with this, members of both the IFT-B and IFT-A complex, as well as components of the ciliary basal body and the kinesin-2 and dynein motor proteins have been identified as regulators of Hh signaling (Huangfu et al, 2003; Tran et al, 2008; Liu et al, 2005; Houde et al, 2006; Huangfu et al, 2005; May et al, 2005; Cortellino et al, 2009; Vierkotten et al, 2007; Ferrante et al, 2006; Weatherbee et al, 2009; Liem et al, 2012; Qin et al 2011). KIF7, a microtubule-associated kinesin-type motor that negatively regulates the length of axonemal microtubules, is also required for correct localization of GLI:SUFU (He et al, 2014). Finally, a number of PCP pathway effectors have recently been shown to be required for ciliogenesis, and mutations in these genes disrupt GLI processing (Zeng et al, 2010; Gray et al, 2009; Heydeck et al, 2009; Park et al, 2006).</Comment> <BiopaxRef>e53</BiopaxRef> <BiopaxRef>d37</BiopaxRef> <BiopaxRef>a15</BiopaxRef> <BiopaxRef>c5d</BiopaxRef> <BiopaxRef>cc6</BiopaxRef> <BiopaxRef>aa7</BiopaxRef> <BiopaxRef>c25</BiopaxRef> <BiopaxRef>b66</BiopaxRef> <BiopaxRef>e06</BiopaxRef> <BiopaxRef>fe7</BiopaxRef> <BiopaxRef>b83</BiopaxRef> <BiopaxRef>d78</BiopaxRef> <BiopaxRef>d31</BiopaxRef> <BiopaxRef>e89</BiopaxRef> <BiopaxRef>b8d</BiopaxRef> <BiopaxRef>da6</BiopaxRef> <BiopaxRef>b37</BiopaxRef> <BiopaxRef>fec</BiopaxRef> <BiopaxRef>a2f</BiopaxRef> <BiopaxRef>a06</BiopaxRef> <BiopaxRef>f9e</BiopaxRef> <BiopaxRef>bbf</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1009.0" Y="278.0" /> <Point X="1045.0" Y="507.0" /> <Anchor Position="0.0" Shape="None" GraphId="ef049" /> <Anchor Position="0.99" Shape="None" GraphId="c5d17" /> <Anchor Position="0.5" Shape="None" GraphId="daa67" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610766" /> </Interaction> <Interaction GraphId="a3f77"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1371.0" Y="221.0" GraphRef="f2fd6" RelX="0.9622641509433962" RelY="0.0" /> <Point X="1400.0" Y="236.0" GraphRef="d2008" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610726" /> </Interaction> <Interaction GraphId="a4872"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2685.0" Y="824.0" GraphRef="b69cc" RelX="0.9534883720930233" RelY="0.0" /> <Point X="2825.0" Y="749.0" GraphRef="d9d6a" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5617408" /> </Interaction> <Interaction GraphId="a50d0"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2009.0" Y="702.0" GraphRef="de2ad" RelX="1.0" RelY="-0.034482758620689655" /> <Point X="2030.0" Y="708.0" GraphRef="a646a" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610746" /> </Interaction> <Interaction GraphId="a5773"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2424.0" Y="711.0" GraphRef="a3a25" RelX="0.9534883720930233" RelY="0.0" /> <Point X="2428.0" Y="719.0" GraphRef="f47cd" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610752" /> </Interaction> <Interaction GraphId="a590f"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2685.0" Y="824.0" GraphRef="b69cc" RelX="0.9534883720930233" RelY="0.0" /> <Point X="2799.0" Y="666.0" GraphRef="aefed" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5612508" /> </Interaction> <Interaction GraphId="a5c56"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="818.0" Y="260.0" GraphRef="c0ece" RelX="0.0" RelY="0.9512195121951219" /> <Point X="822.0" Y="393.0" GraphRef="d36c7" RelX="-72.5" RelY="-161.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610767" /> </Interaction> <Interaction GraphId="a5e4e"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1502.0" Y="881.0" GraphRef="e28ce" RelX="0.4700000000000273" RelY="0.03999999999996362" /> <Point X="1535.0" Y="876.0" GraphRef="b27c6" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610717" /> </Interaction> <Interaction GraphId="a73b3"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1139.0" Y="205.0" GraphRef="c487d" RelX="-1.0" RelY="-0.023255813953488372" /> <Point X="1058.0" Y="311.0" GraphRef="daa67" RelX="31.0" RelY="-81.5" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610766" /> </Interaction> <Interaction GraphId="a756a"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2758.0" Y="646.0" GraphRef="e42a1" RelX="1.0" RelY="-0.0196078431372549" /> <Point X="2799.0" Y="666.0" GraphRef="aefed" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5612508" /> </Interaction> <Interaction GraphId="a9a40"> <Comment Source="Reactome">Vertebrate SUFU plays a critical role in the negative regulation of Hh signaling in the absence of ligand. Disruption of SUFU causes constitutive activation of the pathway, and is associated with the development of medulloblastoma in humans (Cooper et al, 2005; Svard et al, 2006; Taylor et al, 2002; Pastorino et al, 2009). SUFU binds directly to all three GLI proteins (Pearse et al, 1999; Stone et al, 1999; Jia et al, 2009; Svard et al, 2006). Formation of a SUFU:GLI complex is required for the processing of GLI3 to the GLI3R repressor form, and the processing depends on transit through the primary cilia (Kise et al, 2009; Humke et al, 2010; Huangfu and Anderson, 2005). Despite this, primary cilia are not required for SUFU to inhibit GLI activity; SUFU may also serve in a cilia-independent manner to sequester the full-length protein in the cytoplasm in the absence of Hh signal (Chen et al, 2009; Humke et al, 2010; Jia et al, 2009; Tukachinsky et al, 2010). After processing, GLI3R dissociates from SUFU and its activity is SUFU-independent (Humke et al, 2010; Tukachinsky et al, 2010). Nuclear SUFU may also play a direct role as a transcriptional co-repressor through interaction with the N-terminal DNA-binding domain of GLI proteins, though this remains to be fully elaborated (Monnier et al, 1998; Pearse et al, 1999; Cheng and Bishop, 2002; Paces-Fessy et al, 2004; Dunaeva et al, 2003; Szczepny et al, 2014).</Comment> <BiopaxRef>c65</BiopaxRef> <BiopaxRef>a14</BiopaxRef> <BiopaxRef>a2c</BiopaxRef> <BiopaxRef>b0e</BiopaxRef> <BiopaxRef>d34</BiopaxRef> <BiopaxRef>dff</BiopaxRef> <BiopaxRef>c10</BiopaxRef> <BiopaxRef>cca</BiopaxRef> <BiopaxRef>fe7</BiopaxRef> <BiopaxRef>a4a</BiopaxRef> <BiopaxRef>c99</BiopaxRef> <BiopaxRef>e71</BiopaxRef> <BiopaxRef>a15</BiopaxRef> <BiopaxRef>f52</BiopaxRef> <BiopaxRef>adb</BiopaxRef> <BiopaxRef>b86</BiopaxRef> <BiopaxRef>aa1</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="826.0" Y="969.0" /> <Point X="826.0" Y="857.0" /> <Anchor Position="0.0" Shape="None" GraphId="c592d" /> <Anchor Position="0.99" Shape="None" GraphId="c9b11" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610723" /> </Interaction> <Interaction GraphId="a9bcd"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1261.0" Y="556.0" GraphRef="bf601" RelX="-0.7300000000000182" RelY="-0.009999999999990905" /> <Point X="1337.0" Y="767.0" GraphRef="bcdcd" RelX="0.0" RelY="-1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610749" /> </Interaction> <Interaction GraphId="aa172"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1270.0" Y="1180.0" GraphRef="b72ef" RelX="0.9672131147540983" RelY="0.0" /> <Point X="1315.0" Y="1144.0" GraphRef="c517c" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610735" /> </Interaction> <Interaction GraphId="aadec"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="818.0" Y="260.0" GraphRef="e1ea9" RelX="-4.3076923076923075" RelY="12.066666666666666" /> <Point X="822.0" Y="393.0" GraphRef="d36c7" RelX="-72.5" RelY="-161.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610767" /> </Interaction> <Interaction GraphId="abd2e"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2758.0" Y="646.0" GraphRef="e42a1" RelX="1.0" RelY="-0.0196078431372549" /> <Point X="2767.0" Y="623.0" GraphRef="bca5e" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5612510" /> </Interaction> <Interaction GraphId="ac18a"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1045.0" Y="507.0" GraphRef="c5d17" RelX="0.35999999999989996" RelY="2.2899999999999636" /> <Point X="1045.0" Y="510.0" GraphRef="bfc5c" RelX="-0.014925373134328358" RelY="-1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610766" /> </Interaction> <Interaction GraphId="adde1"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2685.0" Y="824.0" GraphRef="b69cc" RelX="0.9534883720930233" RelY="0.0" /> <Point X="2720.0" Y="883.0" GraphRef="fc343" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5617410" /> </Interaction> <Interaction GraphId="ae988"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1365.0" Y="997.0" GraphRef="f2bd0" RelX="0.9100000000000819" RelY="-0.009999999999990905" /> <Point X="1388.0" Y="998.0" GraphRef="c0afa" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610741" /> </Interaction> <Interaction GraphId="af0e0"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1246.0" Y="1030.0" GraphRef="cf66b" RelX="0.0" RelY="-1.0" /> <Point X="1274.0" Y="998.0" GraphRef="cca14" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610741" /> </Interaction> <Interaction GraphId="affd0"> <Comment Source="Reactome">In the absence of Hh signal, GLI1 is degraded by the proteasome. Degradation depends on GLI1 ubiquitination by SCF(beta-TrCP) and by the E3 ligase ITCH (Huntzicker et al, 2006; di Marcotullio et al, 2006, 2011).</Comment> <BiopaxRef>e63</BiopaxRef> <BiopaxRef>de3</BiopaxRef> <BiopaxRef>bf2</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1693.0" Y="1009.0" /> <Point X="877.0" Y="1097.0" /> <Anchor Position="0.0" Shape="None" GraphId="f09a2" /> <Anchor Position="0.99" Shape="None" GraphId="ab0a6" /> <Anchor Position="0.5" Shape="None" GraphId="ef274" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610758" /> </Interaction> <Interaction GraphId="b1110"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1943.0" Y="874.0" GraphRef="e4d5b" RelX="0.43000000000006366" RelY="0.0" /> <Point X="1957.0" Y="909.0" GraphRef="e7364" RelX="-0.02564102564102564" RelY="-1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610730" /> </Interaction> <Interaction GraphId="b26e8"> <Comment Source="Reactome">TULP3 and the retrograde complex IFT-A are required to recruit GPR161 to the cilium in the absence of Hh ligand (Mukhopadhyay et al, 2010; Mukhopadhyay et al, 2013; reviewed in Mukhopadhyay and Rohtagi, 2014). TULP3 is a negative regulator of Hh signaling and siRNA depletion of TULP3 reduces the ciliary accumulation of GPR161 (Norman et al, 2009; Patterson et al, 2009; Mukhopadhyay et al, 2010; Mukhopadhyay et al, 2013).</Comment> <BiopaxRef>f9b</BiopaxRef> <BiopaxRef>fd9</BiopaxRef> <BiopaxRef>ff4</BiopaxRef> <BiopaxRef>fe4</BiopaxRef> <BiopaxRef>cbf</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1519.0" Y="329.0" /> <Point X="1525.0" Y="398.0" /> <Anchor Position="0.0" Shape="None" GraphId="ba0bd" /> <Anchor Position="0.99" Shape="None" GraphId="e1220" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610725" /> </Interaction> <Interaction GraphId="b2ecd"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1393.0" Y="786.0" GraphRef="bcdcd" RelX="1.0" RelY="0.0" /> <Point X="1423.0" Y="717.0" GraphRef="b5207" RelX="0.5" RelY="2.0" ArrowHead="mim-catalysis" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610720" /> </Interaction> <Interaction GraphId="b31e0"> <Comment Source="Reactome">GLI3R is a DNA-binding transcriptional repressor that recognizes consensus GLI sites 5'-GACCACCC-3' in the promoters of target genes (Kinzler and Vogelstein, 1990). DNA-binding is mediated through 5 C2H2 Kruppel zinc fingers in the N-terminal region of the protein, which remains intact after proteasome-mediated processing (reviewed in Hui and Angers, 2011). In the absence of Hh signaling, GLI3R has been shown to bind to the promoters of the GLI1 and GLI2 genes as assesed by ChIP and to repress gene expression (Hu et al, 2006).</Comment> <BiopaxRef>cf6</BiopaxRef> <BiopaxRef>c19</BiopaxRef> <BiopaxRef>d07</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2825.0" Y="749.0" /> <Point X="2950.0" Y="732.0" /> <Anchor Position="0.0" Shape="None" GraphId="d9d6a" /> <Anchor Position="0.99" Shape="None" GraphId="a97e6" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5617408" /> </Interaction> <Interaction GraphId="b3f7e"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2800.0" Y="882.0" GraphRef="b7b5e" RelX="0.8000000000001819" RelY="-0.009999999999990905" /> <Point X="2803.0" Y="885.0" GraphRef="f4c00" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5617410" /> </Interaction> <Interaction GraphId="b42c7"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2950.0" Y="732.0" GraphRef="a97e6" RelX="1.25" RelY="-0.16999999999995907" /> <Point X="2953.0" Y="732.0" GraphRef="fd633" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5617408" /> </Interaction> <Interaction GraphId="b4b8b"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1502.0" Y="881.0" GraphRef="e28ce" RelX="0.4700000000000273" RelY="0.03999999999996362" /> <Point X="1530.0" Y="910.0" GraphRef="c00f7" RelX="-0.024390243902439025" RelY="-1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610717" /> </Interaction> <Interaction GraphId="b4f88"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="704.0" Y="319.0" GraphRef="f5433" RelX="3.9500000000000455" RelY="-3.0400000000000205" /> <Point X="730.0" Y="316.0" GraphRef="cfb57" RelX="-0.008264462809917356" RelY="1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610763" /> </Interaction> <Interaction GraphId="b552f"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1591.0" Y="461.0" GraphRef="e2141" RelX="-1.0" RelY="0.0" /> <Point X="1511.0" Y="561.0" GraphRef="f15c1" RelX="-23.0" RelY="2.5" ArrowHead="mim-catalysis" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610727" /> </Interaction> <Interaction GraphId="b8532"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1497.0" Y="1151.0" GraphRef="d135d" RelX="0.9789473684210527" RelY="0.0" /> <Point X="1537.0" Y="1147.0" GraphRef="fb15c" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610737" /> </Interaction> <Interaction GraphId="b8795"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2640.0" Y="814.0" GraphRef="e1356" RelX="2.119999999999891" RelY="0.9500000000000455" /> <Point X="2643.0" Y="824.0" GraphRef="b69cc" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610752" /> </Interaction> <Interaction GraphId="b9a88"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2056.0" Y="804.0" GraphRef="a12b3" RelX="-0.010752688172043012" RelY="1.0" /> <Point X="2131.0" Y="881.0" GraphRef="d6ed2" RelX="-0.5" RelY="0.5" ArrowHead="mim-catalysis" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610745" /> </Interaction> <Interaction GraphId="baac8"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1511.0" Y="1074.0" GraphRef="b5031" RelX="-1.0" RelY="0.0" /> <Point X="1516.0" Y="1004.0" GraphRef="ee97f" RelX="-12.5" RelY="0.5" ArrowHead="mim-catalysis" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610742" /> </Interaction> <Interaction GraphId="bb068"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1497.0" Y="1151.0" GraphRef="d135d" RelX="0.9789473684210527" RelY="0.0" /> <Point X="1571.0" Y="1145.0" GraphRef="bbccb" RelX="-4.5" RelY="-2.0" ArrowHead="mim-catalysis" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610737" /> </Interaction> <Interaction GraphId="bb0b9"> <Comment Source="Reactome">Phosphorylation by PKA primes GLI3 for subsequent phosphorylation by CK1 at four or more sites. These serial phosphorylations are required for the recruitment of beta-TrCP and subsequent ubiquitination and processing of GLI3 (Tempe et al, 2006; Wang and Li, 2006; Wen et al, 2010; Schrader et al, 2011)</Comment> <BiopaxRef>ac2</BiopaxRef> <BiopaxRef>c44</BiopaxRef> <BiopaxRef>ac1</BiopaxRef> <BiopaxRef>d37</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1618.0" Y="707.0" /> <Point X="1680.0" Y="708.0" /> <Anchor Position="0.0" Shape="None" GraphId="d8d81" /> <Anchor Position="0.99" Shape="None" GraphId="c442a" /> <Anchor Position="0.5" Shape="None" GraphId="a2ee0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610722" /> </Interaction> <Interaction GraphId="bb1e2"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2803.0" Y="885.0" GraphRef="f4c00" RelX="-1.0" RelY="0.0" /> <Point X="2760.0" Y="987.0" GraphRef="fab96" RelX="-6.5" RelY="-4.5" ArrowHead="TBar" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5617413" /> </Interaction> <Interaction GraphId="bb58d"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1586.0" Y="557.0" GraphRef="c9597" RelX="-1.0" RelY="0.0" /> <Point X="1583.0" Y="557.0" GraphRef="c73f8" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610727" /> </Interaction> <Interaction GraphId="bbc35"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1689.0" Y="1005.0" GraphRef="f6367" RelX="0.983739837398374" RelY="0.0" /> <Point X="1693.0" Y="1009.0" GraphRef="f09a2" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610758" /> </Interaction> <Interaction GraphId="bbca5"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1583.0" Y="705.0" GraphRef="e969a" RelX="1.0" RelY="0.0" /> <Point X="1618.0" Y="707.0" GraphRef="d8d81" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610722" /> </Interaction> <Interaction GraphId="bc0fc"> <Comment Source="Reactome">After phosphorylation and ubiquitination, GLI3 is processed by the proteasome to an 83-kDa repressor form that lacks the C-terminal activation domain (Wang et al, 2000; Tempe et al, 2006; Wang and Li, 2006). Partial processing appears to rely on at least three features of the GLI3 protein: the folded N-terminal zinc finger domain, an adjacent simple linker sequence, and the degron in the C-terminus that contains the phosphorylation and ubiquitination target residues (Pan and Wang, 2007; Schrader et al, 2011). The C-terminal end of the processed repressor form is not precisely defined.</Comment> <BiopaxRef>cc4</BiopaxRef> <BiopaxRef>c44</BiopaxRef> <BiopaxRef>ac2</BiopaxRef> <BiopaxRef>f22</BiopaxRef> <BiopaxRef>ac1</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2212.0" Y="710.0" /> <Point X="2339.0" Y="712.0" /> <Anchor Position="0.0" Shape="None" GraphId="b33c5" /> <Anchor Position="0.99" Shape="None" GraphId="e60d4" /> <Anchor Position="0.5" Shape="None" GraphId="a5942" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610754" /> </Interaction> <Interaction GraphId="bcbcc"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1820.0" Y="668.0" GraphRef="bb670" RelX="0.0" RelY="1.0" /> <Point X="1841.0" Y="707.0" GraphRef="ca79d" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610732" /> </Interaction> <Interaction GraphId="bd3ed"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="963.0" Y="278.0" GraphRef="dee39" RelX="1.3700000000000045" RelY="-5.519999999999982" /> <Point X="985.0" Y="275.0" GraphRef="aba36" RelX="-0.012987012987012988" RelY="1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610767" /> </Interaction> <Interaction GraphId="bef2d"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="791.0" Y="1063.0" GraphRef="a3de6" RelX="0.9805825242718447" RelY="-0.02857142857142857" /> <Point X="826.0" Y="969.0" GraphRef="c592d" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610723" /> </Interaction> <Interaction GraphId="c065b"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1030.0" Y="78.0" GraphRef="a284e" RelX="0.7599999999999909" RelY="-0.030000000000001137" /> <Point X="1033.0" Y="79.0" GraphRef="e1ea9" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610733" /> </Interaction> <Interaction GraphId="c099d"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1874.0" Y="905.0" GraphRef="a5a0f" RelX="0.0" RelY="-1.0" /> <Point X="1900.0" Y="874.0" GraphRef="be509" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610730" /> </Interaction> <Interaction GraphId="c0f31"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1261.0" Y="556.0" GraphRef="bf601" RelX="-0.7300000000000182" RelY="-0.009999999999990905" /> <Point X="1221.0" Y="517.0" GraphRef="d9c15" RelX="1.0" RelY="-0.02564102564102564" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610749" /> </Interaction> <Interaction GraphId="c2acb"> <Comment Source="Reactome">GLI2 interacts directly with beta-TrCP and is polyubiquitinated in a phosphorylation-dependent manner. Binding and ubiquitination by beta-TrCP depends on 2 motifs located in the region of GLI2 phosphorylated by PKA, CK1 and GSK3 (Pan et al, 2006).</Comment> <BiopaxRef>e5a</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2102.0" Y="880.0" /> <Point X="2161.0" Y="881.0" /> <Anchor Position="0.0" Shape="None" GraphId="eb793" /> <Anchor Position="0.99" Shape="None" GraphId="eaaea" /> <Anchor Position="0.5" Shape="None" GraphId="d6ed2" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610745" /> </Interaction> <Interaction GraphId="c3719"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1373.0" Y="563.0" GraphRef="b887f" RelX="-1.0" RelY="0.0" /> <Point X="1334.0" Y="557.0" GraphRef="c8f27" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610749" /> </Interaction> <Interaction GraphId="c5af9"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2161.0" Y="881.0" GraphRef="eaaea" RelX="0.5900000000001455" RelY="0.009999999999990905" /> <Point X="2164.0" Y="882.0" GraphRef="d263b" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610745" /> </Interaction> <Interaction GraphId="c6d1a"> <Comment Source="Reactome">Although direct phosphorylation of GLI1 by PKA has not been demonstrated, deletion of the putative PKA sites abrogates the interaction of GLI1 with beta-TrCP and stabilizes GLI1 protein levels; similarly, treatment of GLI1-expressing cells with PKA inhibitors delays the kinetics of GLI1 degradation (Huntzicker et al, 2006). These data are consistent with a role for PKA-mediated phosphorylation in promoting the proteasome-dependent degradation of GLI1 in the absence of Hh signal, as is the case for GLI2 and GLI3 (Huntzicker et al, 2006; Tempe et al, 2006; Pan and Wang, 2007; Pan et al, 2009). Potential roles for CK2 and GSK3 in promoting the phosphorylation-dependent degradation of GLI1 have not been investigated.</Comment> <BiopaxRef>e63</BiopaxRef> <BiopaxRef>c44</BiopaxRef> <BiopaxRef>f22</BiopaxRef> <BiopaxRef>e09</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1274.0" Y="998.0" /> <Point X="1365.0" Y="997.0" /> <Anchor Position="0.0" Shape="None" GraphId="cca14" /> <Anchor Position="0.99" Shape="None" GraphId="f2bd0" /> <Anchor Position="0.5" Shape="None" GraphId="ab989" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610741" /> </Interaction> <Interaction GraphId="c783a"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2339.0" Y="712.0" GraphRef="e60d4" RelX="1.2699999999999818" RelY="0.01999999999998181" /> <Point X="888.0" Y="1082.0" GraphRef="dbd91" RelX="0.9636363636363636" RelY="-0.043478260869565216" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610754" /> </Interaction> <Interaction GraphId="c7e97"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="711.0" Y="421.0" GraphRef="e513f" RelX="-20.559999999999945" RelY="-2.019999999999982" /> <Point X="712.0" Y="417.0" GraphRef="bdf33" RelX="0.0" RelY="0.92" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5612510" /> </Interaction> <Interaction GraphId="c85fc"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1360.0" Y="704.0" GraphRef="c9a66" RelX="0.9753086419753086" RelY="-0.034482758620689655" /> <Point X="1398.0" Y="715.0" GraphRef="c38b8" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610720" /> </Interaction> <Interaction GraphId="c87fa"> <Comment Source="Reactome">GLI1 protein is degraded by the proteasome in the absence of Hh signal. GLI1 levels are stabilized by treatment of cells with the proteasome inhibitor MG312, and GLI1 and beta-TrCP1 co-precipitate when expressed in NIH 3T3 cells. &lt;br&gt;Two SCF(beta-TrCP)-dependent degradation sites, Dn and Dc, have been identified in human GLI1. Removal of these sites abrogates the interaction with beta-TrCP, reduces the beta-TrCP-dependent ubiquitination of GLI1 and stabilizes the GLI1 protein levels. As is the case for GLI2 and GLI3, ubiquitination of GLI1 depends on the its prior phosphorylation by PKA, as GLI1 degradation is sensitive to PKA inhibitors and removal of the putative PKA sites abrogates the interaction with beta-TrCP and delays the kinetics of degradation (Huntzicker et al, 2006).</Comment> <BiopaxRef>e63</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1493.0" Y="1003.0" /> <Point X="1564.0" Y="1004.0" /> <Anchor Position="0.0" Shape="None" GraphId="f1d90" /> <Anchor Position="0.99" Shape="None" GraphId="ad708" /> <Anchor Position="0.5" Shape="None" GraphId="ee97f" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610742" /> </Interaction> <Interaction GraphId="c8b55"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2007.0" Y="665.0" GraphRef="b1465" RelX="-0.015873015873015872" RelY="1.0" /> <Point X="2030.0" Y="708.0" GraphRef="a646a" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610746" /> </Interaction> <Interaction GraphId="c94f5"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1404.0" Y="183.0" GraphRef="c0972" RelX="0.0" RelY="0.9259259259259259" /> <Point X="1400.0" Y="236.0" GraphRef="d2008" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610726" /> </Interaction> <Interaction GraphId="c9d03"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1796.0" Y="1151.0" GraphRef="a7f65" RelX="0.8299999999999272" RelY="0.009999999999990905" /> <Point X="888.0" Y="1082.0" GraphRef="dbd91" RelX="0.9636363636363636" RelY="-0.043478260869565216" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610760" /> </Interaction> <Interaction GraphId="c9f75"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1614.0" Y="1147.0" GraphRef="e9c4f" RelX="0.7699999999999818" RelY="0.0" /> <Point X="1617.0" Y="1150.0" GraphRef="ab05c" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610737" /> </Interaction> <Interaction GraphId="c9ffb"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1943.0" Y="874.0" GraphRef="e4d5b" RelX="0.43000000000006366" RelY="0.0" /> <Point X="1972.0" Y="878.0" GraphRef="a880d" RelX="-1.0" RelY="-0.02127659574468085" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610730" /> </Interaction> <Interaction GraphId="ca6d6"> <Comment Source="Reactome">Expression of the PTCH1 gene is repressed in the absence of Hh signaling by GLI3R (Agren et al, 2004; Lee et al, 2010; Vokes et al, 2007; Vokes et al, 2008). GLI3R may exert its repression activity through the SKI-dependent recruitment of HDACs (Dai et al, 2002).</Comment> <BiopaxRef>ec7</BiopaxRef> <BiopaxRef>fdb</BiopaxRef> <BiopaxRef>f7a</BiopaxRef> <BiopaxRef>f1a</BiopaxRef> <BiopaxRef>f79</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2767.0" Y="623.0" /> <Point X="711.0" Y="421.0" /> <Anchor Position="0.0" Shape="None" GraphId="bca5e" /> <Anchor Position="0.99" Shape="None" GraphId="e513f" /> <Anchor Position="0.5" Shape="None" GraphId="d797b" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5612510" /> </Interaction> <Interaction GraphId="ca96a"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1598.0" Y="774.0" GraphRef="a8adf" RelX="0.0" RelY="-1.0" /> <Point X="1647.0" Y="708.0" GraphRef="a2ee0" RelX="-2.0" RelY="0.5" ArrowHead="mim-catalysis" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610722" /> </Interaction> <Interaction GraphId="cccf9"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1447.0" Y="715.0" GraphRef="c5fdf" RelX="0.4900000000000091" RelY="0.0" /> <Point X="1483.0" Y="705.0" GraphRef="e969a" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610720" /> </Interaction> <Interaction GraphId="ce352"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2253.0" Y="808.0" GraphRef="e67e7" RelX="-0.009708737864077669" RelY="1.0" /> <Point X="2395.0" Y="1295.0" GraphRef="c1b94" RelX="825.0" RelY="310.0" ArrowHead="mim-catalysis" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610757" /> </Interaction> <Interaction GraphId="cea38"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="966.0" Y="124.0" GraphRef="dc679" RelX="1.0" RelY="0.0" /> <Point X="954.0" Y="81.0" GraphRef="ce804" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610733" /> </Interaction> <Interaction GraphId="cead2"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1337.0" Y="805.0" GraphRef="bcdcd" RelX="0.0" RelY="1.0" /> <Point X="1312.0" Y="998.0" GraphRef="ab989" RelX="-7.5" RelY="0.5" ArrowHead="mim-catalysis" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610741" /> </Interaction> <Interaction GraphId="ceecb"> <Comment Source="Reactome">Vertebrate hedgehog signaling depends on the passage and/or localization of many of the pathway components through the primary cilium (reviewed in Goetz and Anderson, 2010). Although GLI and SUFU proteins are not concentrated in the cilium in the absence of Hh signaling, processing and/or degradation of the transcription factors requires transit through the cilium and basal levels of these proteins can be detected there (Wen et al, 2010; Tukachinsky et al, 2010; Kim et al, 2006; Liu et al, 2005; Haycraft et 2005). Consistent with this, members of both the IFT-B and IFT-A complex, as well as components of the ciliary basal body and the kinesin-2 and dynein motor proteins have been identified as regulators of Hh signaling (Huangfu et al, 2003; Tran et al, 2008; Liu et al, 2005; Houde et al, 2006; Huangfu et al, 2005; May et al, 2005; Cortellino et al, 2009; Vierkotten et al, 2007; Ferrante et al, 2006; Weatherbee et al, 2009; Liem et al, 2012; Qin et al 2011). KIF7, a microtubule-associated kinesin-type motor that negatively regulates the length of axonemal microtubules, is also required for correct localization of GLI:SUFU (He et al, 2014). Finally, a number of PCP pathway effectors have recently been shown to be required for ciliogenesis, and mutations in these genes disrupt GLI processing (Zeng et al, 2010; Gray et al, 2009; Heydeck et al, 2009; Park et al, 2006).</Comment> <BiopaxRef>e53</BiopaxRef> <BiopaxRef>d37</BiopaxRef> <BiopaxRef>a15</BiopaxRef> <BiopaxRef>c5d</BiopaxRef> <BiopaxRef>b66</BiopaxRef> <BiopaxRef>cc6</BiopaxRef> <BiopaxRef>aa7</BiopaxRef> <BiopaxRef>c25</BiopaxRef> <BiopaxRef>e06</BiopaxRef> <BiopaxRef>fe7</BiopaxRef> <BiopaxRef>b83</BiopaxRef> <BiopaxRef>d78</BiopaxRef> <BiopaxRef>d31</BiopaxRef> <BiopaxRef>e89</BiopaxRef> <BiopaxRef>b8d</BiopaxRef> <BiopaxRef>b37</BiopaxRef> <BiopaxRef>fec</BiopaxRef> <BiopaxRef>da6</BiopaxRef> <BiopaxRef>bbf</BiopaxRef> <BiopaxRef>a2f</BiopaxRef> <BiopaxRef>a06</BiopaxRef> <BiopaxRef>f9e</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="826.0" Y="830.0" /> <Point X="963.0" Y="278.0" /> <Anchor Position="0.0" Shape="None" GraphId="fcf42" /> <Anchor Position="0.99" Shape="None" GraphId="dee39" /> <Anchor Position="0.5" Shape="None" GraphId="d36c7" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610767" /> </Interaction> <Interaction GraphId="d018c"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1266.0" Y="1121.0" GraphRef="a0c44" RelX="1.0" RelY="-0.030303030303030304" /> <Point X="1315.0" Y="1144.0" GraphRef="c517c" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610735" /> </Interaction> <Interaction GraphId="d1cac"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1464.0" Y="327.0" GraphRef="cf9f6" RelX="1.0" RelY="0.0" /> <Point X="1519.0" Y="329.0" GraphRef="ba0bd" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610725" /> </Interaction> <Interaction GraphId="d1f14"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1380.0" Y="674.0" GraphRef="ec46d" RelX="0.0" RelY="1.0" /> <Point X="1398.0" Y="715.0" GraphRef="c38b8" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610720" /> </Interaction> <Interaction GraphId="d2984"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1447.0" Y="715.0" GraphRef="c5fdf" RelX="0.4900000000000091" RelY="0.0" /> <Point X="1470.0" Y="679.0" GraphRef="bcd9f" RelX="-0.01639344262295082" RelY="1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610720" /> </Interaction> <Interaction GraphId="d313b"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1525.0" Y="398.0" GraphRef="e1220" RelX="0.05999999999994543" RelY="0.6899999999999977" /> <Point X="1527.0" Y="401.0" GraphRef="eb303" RelX="-0.010752688172043012" RelY="-1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610725" /> </Interaction> <Interaction GraphId="d346b"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1401.0" Y="305.0" GraphRef="ffc0a" RelX="0.009999999999990905" RelY="0.6899999999999977" /> <Point X="1402.0" Y="308.0" GraphRef="cf9f6" RelX="0.0" RelY="-1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610726" /> </Interaction> <Interaction GraphId="d4479"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1637.0" Y="876.0" GraphRef="b27c6" RelX="0.9805825242718447" RelY="0.0" /> <Point X="1672.0" Y="875.0" GraphRef="b0d61" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610718" /> </Interaction> <Interaction GraphId="d485d"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2783.0" Y="782.0" GraphRef="fc152" RelX="-0.010309278350515464" RelY="-1.0" /> <Point X="2825.0" Y="749.0" GraphRef="d9d6a" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5617408" /> </Interaction> <Interaction GraphId="d4c18"> <Comment Source="Reactome">GLI3R is a DNA-binding transcriptional repressor that recognizes consensus GLI sites 5'-GACCACCC-3' in the promoters of target genes (Kinzler and Vogelstein, 1990). DNA-binding is mediated through 5 C2H2 Kruppel zinc fingers in the N-terminal region of the protein, which remains intact after proteasome-mediated processing (reviewed in Hui and Angers, 2011). In the absence of Hh signaling, GLI3R has been shown to bind to the promoters of the GLI1 and GLI2 genes as assesed by ChIP and to repress gene expression (Hu et al, 2006).</Comment> <BiopaxRef>cf6</BiopaxRef> <BiopaxRef>c19</BiopaxRef> <BiopaxRef>d07</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2720.0" Y="883.0" /> <Point X="2800.0" Y="882.0" /> <Anchor Position="0.0" Shape="None" GraphId="fc343" /> <Anchor Position="0.99" Shape="None" GraphId="b7b5e" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5617410" /> </Interaction> <Interaction GraphId="d60d2"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1591.0" Y="674.0" GraphRef="dbf74" RelX="0.0" RelY="1.0" /> <Point X="1618.0" Y="707.0" GraphRef="d8d81" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610722" /> </Interaction> <Interaction GraphId="d6f27"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1348.0" Y="533.0" GraphRef="aea6d" RelX="0.0" RelY="0.9130434782608695" /> <Point X="1334.0" Y="557.0" GraphRef="c8f27" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610749" /> </Interaction> <Interaction GraphId="d777f"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="861.0" Y="1071.0" GraphRef="dbd91" RelX="-0.01818181818181818" RelY="-1.0" /> <Point X="826.0" Y="969.0" GraphRef="c592d" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610723" /> </Interaction> <Interaction GraphId="d77bc"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1527.0" Y="437.0" GraphRef="eb303" RelX="-0.010752688172043012" RelY="1.0" /> <Point X="1511.0" Y="561.0" GraphRef="edda7" RelX="-23.0" RelY="2.5" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610727" /> </Interaction> <Interaction GraphId="d7f33"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1852.0" Y="773.0" GraphRef="a68f8" RelX="-0.02127659574468085" RelY="-1.0" /> <Point X="1859.0" Y="706.0" GraphRef="a4b01" RelX="-0.5" RelY="-0.5" ArrowHead="mim-catalysis" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610732" /> </Interaction> <Interaction GraphId="d93f4"> <Comment Source="Reactome">After processing by the proteasome, the truncated GLI3 translocates into the nucleus where it acts as the primary repressor for Hh-responsive genes (reviewed in Briscoe and Therond, 2013). Based on sequence comparisons with Ci and GLI1, GLI3 is predicted to have a bipartite NLS signal near the zinc finger domain, and import to the nucleus may be mediated by Importin alpha3, although the details remain to be worked out (reviewed in Hatayama and Aruga, 2012).</Comment> <BiopaxRef>fff</BiopaxRef> <BiopaxRef>f0c</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2428.0" Y="719.0" /> <Point X="2640.0" Y="814.0" /> <Anchor Position="0.0" Shape="None" GraphId="f47cd" /> <Anchor Position="0.99" Shape="None" GraphId="e1356" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610752" /> </Interaction> <Interaction GraphId="d9ec8"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1878.0" Y="706.0" GraphRef="e97bf" RelX="0.36999999999989086" RelY="-0.009999999999990905" /> <Point X="1901.0" Y="702.0" GraphRef="de2ad" RelX="-1.0" RelY="-0.034482758620689655" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610732" /> </Interaction> <Interaction GraphId="d9f7a"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2953.0" Y="732.0" GraphRef="fd633" RelX="-1.0" RelY="0.0" /> <Point X="3010.0" Y="894.0" GraphRef="d227c" RelX="83.0" RelY="-23.5" ArrowHead="TBar" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5617412" /> </Interaction> <Interaction GraphId="da975"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1852.0" Y="795.0" GraphRef="a68f8" RelX="-0.02127659574468085" RelY="1.0" /> <Point X="1921.0" Y="875.0" GraphRef="b6de2" RelX="-0.5" RelY="1.0" ArrowHead="mim-catalysis" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610730" /> </Interaction> <Interaction GraphId="dabb2"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="877.0" Y="1097.0" GraphRef="ab0a6" RelX="-8.159999999999968" RelY="0.8800000000001091" /> <Point X="861.0" Y="1093.0" GraphRef="dbd91" RelX="-0.01818181818181818" RelY="0.9130434782608695" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610758" /> </Interaction> <Interaction GraphId="db6b0"> <Comment Source="Reactome">Hyperphosphorylated GLI3 binds directly with beta-TrCP though at least three independent domains and is polyubiquitinated at lysines 773, 778, 784 and 800 (Tempe et al, 2006). 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GPR161 is an orphan GPCR that has recently been identified as a negative regulator of Hh signaling that acts by increasing cellular cAMP levels in the absence of ligand. Overexpression of GPR161 increases cellular cAMP levels in a manner that depends on the G alpha s subunit, and depletion of GPR161 results in aberrant Hh signaling and a decrease in the ratio of processed GLI3R (Mukhopadhyay et al, 2013). These data suggest that GPR161 negatively regulates GLI processing in the absence of Hh signal by modulating PKA activity through cAMP levels (Mukhopadhyay et al, 2013; reviewed in Mukhopadhyay and Rohatgi, 2014).</Comment> <BiopaxRef>b4f</BiopaxRef> <BiopaxRef>ff4</BiopaxRef> <BiopaxRef>f9b</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1583.0" Y="557.0" /> <Point X="1485.0" Y="560.0" /> <Anchor Position="0.0" Shape="None" GraphId="c73f8" /> <Anchor Position="0.99" Shape="None" GraphId="cbf6d" /> <Anchor Position="0.5" Shape="None" GraphId="f15c1" /> <Anchor Position="0.5" Shape="None" GraphId="edda7" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610727" /> </Interaction> <Interaction GraphId="e2c36"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2840.0" Y="1069.0" GraphRef="caf7d" RelX="1.4699999999998" RelY="1.5499999999999545" /> <Point X="2851.0" Y="1072.0" GraphRef="d0fa9" RelX="0.0" RelY="-1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5617413" /> </Interaction> <Interaction GraphId="e2c47"> <Comment Source="Reactome">Despite sharing 44% amino acid identity with GLI3, only a small fraction of GLI2 appears to be processed to a repressor form in the absence of Hh signaling; the bulk of the protein is completely degraded in a phosphorylation- and proteasome-dependent manner (Pan et al, 2007; Pan et al, 2009; Pan and Wang, 2007). Degradation of GLI2 depends on phosphorylation of four consensus PKA sites in the C-terminal region. This phosphorylation primes GLI2 for subsequent phosphorylation by CK1 and GSK3, creating a binding site for betaTrCP and promoting its subsequent ubiquitination and degradation (Pan et al, 2006; Pan and Wang, 2007; Pan et al, 2009).</Comment> <BiopaxRef>e5a</BiopaxRef> <BiopaxRef>f22</BiopaxRef> <BiopaxRef>e09</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1455.0" Y="877.0" /> <Point X="1502.0" Y="881.0" /> <Anchor Position="0.0" Shape="None" GraphId="dde0b" /> <Anchor Position="0.99" Shape="None" GraphId="e28ce" /> <Anchor Position="0.5" Shape="None" GraphId="ed7ea" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610717" /> </Interaction> <Interaction GraphId="e3a50"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1680.0" Y="708.0" GraphRef="c442a" RelX="0.6199999999998909" RelY="0.009999999999990905" /> <Point X="1712.0" Y="703.0" GraphRef="ebe02" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610722" /> </Interaction> <Interaction GraphId="e4002"> <Comment Source="Reactome">GLI1 is recruited to the NUMB:ITCH complex through a direct interaction with both proteins. Once recruited, GLI1 is ubiquitinated by ITCH and subsequently degraded by the proteasome. ITCH-mediated degradation of GLI1 does not depend on the Dc or Dn degrons required for interaction with beta-TrCP, but instead relies on a novel PPXYs/pSP degron of GLI1 (di Marcotullio et al, 2006, 2011; Huntzicker et al, 2006). How these two apparently parallel systems of GLI1 ubiquitination and degradation are coordinated is not yet clear.</Comment> <BiopaxRef>bf2</BiopaxRef> <BiopaxRef>de3</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1537.0" Y="1147.0" /> <Point X="1614.0" Y="1147.0" /> <Anchor Position="0.0" Shape="None" GraphId="fb15c" /> <Anchor Position="0.99" Shape="None" GraphId="e9c4f" /> <Anchor Position="0.5" Shape="None" GraphId="bbccb" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610737" /> </Interaction> <Interaction GraphId="e480d"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1478.0" Y="998.0" GraphRef="c0afa" RelX="1.0" RelY="0.0" /> <Point X="1537.0" Y="1147.0" GraphRef="fb15c" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610737" /> </Interaction> <Interaction GraphId="e4cad"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2100.0" Y="914.0" GraphRef="a8814" RelX="-0.015873015873015872" RelY="-1.0" /> <Point X="2102.0" Y="880.0" GraphRef="eb793" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610745" /> </Interaction> <Interaction GraphId="e4fd2"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2062.0" Y="878.0" GraphRef="a880d" RelX="0.978021978021978" RelY="-0.02127659574468085" /> <Point X="2102.0" Y="880.0" GraphRef="eb793" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610745" /> </Interaction> <Interaction GraphId="e5f3d"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1709.0" Y="1150.0" GraphRef="ab05c" RelX="0.978494623655914" RelY="0.0" /> <Point X="1713.0" Y="1150.0" GraphRef="b9b4c" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610760" /> </Interaction> <Interaction GraphId="e618d"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1478.0" Y="998.0" GraphRef="c0afa" RelX="1.0" RelY="0.0" /> <Point X="1493.0" Y="1003.0" GraphRef="f1d90" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610742" /> </Interaction> <Interaction GraphId="e6348"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1869.0" Y="877.0" GraphRef="f1951" RelX="0.9759036144578314" RelY="0.0" /> <Point X="1900.0" Y="874.0" GraphRef="be509" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610730" /> </Interaction> <Interaction GraphId="e6e79"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="901.0" Y="75.0" GraphRef="e2812" RelX="1.0" RelY="0.0" /> <Point X="954.0" Y="81.0" GraphRef="ce804" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610733" /> </Interaction> <Interaction GraphId="e791a"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2253.0" Y="786.0" GraphRef="e67e7" RelX="-0.009708737864077669" RelY="-1.0" /> <Point X="2278.0" Y="714.0" GraphRef="a5942" RelX="2.5" RelY="3.0" ArrowHead="mim-catalysis" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610754" /> </Interaction> <Interaction GraphId="e8120"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1816.0" Y="703.0" GraphRef="ebe02" RelX="0.9809523809523809" RelY="0.0" /> <Point X="1841.0" Y="707.0" GraphRef="ca79d" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610732" /> </Interaction> <Interaction GraphId="e8420"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2683.0" Y="937.0" GraphRef="f3cba" RelX="0.9733333333333334" RelY="-0.0196078431372549" /> <Point X="2720.0" Y="883.0" GraphRef="fc343" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5617410" /> </Interaction> <Interaction GraphId="e8e02"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1527.0" Y="437.0" GraphRef="ed59d" RelX="-4.483870967741935" RelY="-1.7222222222222223" /> <Point X="1511.0" Y="561.0" GraphRef="edda7" RelX="-23.0" RelY="2.5" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610727" /> </Interaction> <Interaction GraphId="e93e5"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1728.0" Y="874.0" GraphRef="d4555" RelX="0.5599999999999454" RelY="-0.009999999999990905" /> <Point X="1787.0" Y="877.0" GraphRef="f1951" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610718" /> </Interaction> <Interaction GraphId="e96ec"> <Comment Source="Reactome">TULP3 is recruited to the primary cilium through a direct interaction with the retrograde transport IFT-A complex and with membrane phosphoinositides (Santagata et al, 2001; Mukhopadhyay et al, 2010; Qin et al, 2011; reviewed in Mukhopadhyay and Rohatgi, 2014). TULP3 facilitates GLI processing by recruiting the GPCR GPR161, which in turn activates PKA by increasing cAMP levels in a G alpha s-dependent manner (Mukhopadhyay et al, 2013, reviewed in Hwang and Mukhopadhyay, 2014; Pal and Mukhopadhyay, 2014).</Comment> <BiopaxRef>fd9</BiopaxRef> <BiopaxRef>fec</BiopaxRef> <BiopaxRef>cd3</BiopaxRef> <BiopaxRef>f9b</BiopaxRef> <BiopaxRef>ff4</BiopaxRef> <BiopaxRef>ae0</BiopaxRef> <BiopaxRef>b2c</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1400.0" Y="236.0" /> <Point X="1401.0" Y="305.0" /> <Anchor Position="0.0" Shape="None" GraphId="d2008" /> <Anchor Position="0.99" Shape="None" GraphId="ffc0a" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610726" /> </Interaction> <Interaction GraphId="e9a0a"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1485.0" Y="560.0" GraphRef="cbf6d" RelX="-0.9800000000000182" RelY="0.029999999999972715" /> <Point X="1421.0" Y="563.0" GraphRef="b887f" RelX="1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610727" /> </Interaction> <Interaction GraphId="eb26d"> <Comment Source="Reactome">Expression of the GLI2 gene is repressed in the absence of Hh signaling by GLI3R (Hu et al, 2006). GLI3R may exert its repression activity through the SKI-dependent recruitment of HDACs (Dai et al, 2002).</Comment> <BiopaxRef>d07</BiopaxRef> <BiopaxRef>f79</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2693.0" Y="914.0" /> <Point X="2840.0" Y="1069.0" /> <Anchor Position="0.0" Shape="None" GraphId="c21fd" /> <Anchor Position="0.99" Shape="None" GraphId="caf7d" /> <Anchor Position="0.5" Shape="None" GraphId="fab96" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5617413" /> </Interaction> <Interaction GraphId="eb4c5"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="818.0" Y="260.0" GraphRef="d5085" RelX="-1.9821428571428572" RelY="-7.848484848484849" /> <Point X="822.0" Y="393.0" GraphRef="d36c7" RelX="-72.5" RelY="-161.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610767" /> </Interaction> <Interaction GraphId="ec4e8"> <Comment Source="Reactome">Phosphorylation of GLI3 by PKA on up to six sites in the C-terminal region primes the protein for subsequent phosphorylation by CK1 and GSK3 and is required for the ubiquitin-mediated processing by the proteasome to yield the truncated repressor form (Tempe et al, 2006; Pan et al, 2006; Pan and Wang, 2007; Wang and Li, 2006). Processing of GLI3 is regulated in part by movement through the primary cilia, and disruption of intraflagellar transport abrogates processing (Wen et al, 2010)</Comment> <BiopaxRef>ac2</BiopaxRef> <BiopaxRef>c44</BiopaxRef> <BiopaxRef>e5a</BiopaxRef> <BiopaxRef>f22</BiopaxRef> <BiopaxRef>d37</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1398.0" Y="715.0" /> <Point X="1447.0" Y="715.0" /> <Anchor Position="0.0" Shape="None" GraphId="c38b8" /> <Anchor Position="0.99" Shape="None" GraphId="c5fdf" /> <Anchor Position="0.5" Shape="None" GraphId="b5207" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610720" /> </Interaction> <Interaction GraphId="ed3fd"> <Comment Source="Reactome">NUMB is a negative regulator of Hh signaling that acts by promoting the ITCH-dependent ubiquitination of GLI1. ITCH is an E3 ligase that is kept in an inactive conformation by an intramolecular interaction between the HECT domain and a WW motif. Binding of the adaptor protein NUMB to the WW region of ITCH displaces the HECT domain and promotes the catalytic activity of the E3 ligase (di Marcotullio et al, 2006; 2011).</Comment> <BiopaxRef>bf2</BiopaxRef> <BiopaxRef>de3</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1315.0" Y="1144.0" /> <Point X="1400.0" Y="1148.0" /> <Anchor Position="0.0" Shape="None" GraphId="c517c" /> <Anchor Position="0.99" Shape="None" GraphId="cbfd4" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610735" /> </Interaction> <Interaction GraphId="f0001"> <Comment Source="Reactome">GLI3R is a DNA-binding transcriptional repressor that recognizes consensus GLI sites 5'-GACCACCC-3' in the promoters of target genes (Kinzler and Vogelstein, 1990). DNA-binding is mediated through 5 C2H2 Kruppel zinc fingers in the N-terminal region of the protein, which remains intact after proteasome-mediated processing (reviewed in Hui and Angers, 2011). GLI-dependent target genes have been identified by a number of ChIP based screens, and one well established target of GLI3R is the Hh receptor, PTCH1 (Lee et al, 2010; Vokes et al, 2007; Vokes et al, 2008). GLI3R has been shown to bind to a GLI-consensus sequence in the PTCH1 promoter as assesed by electrophoretic mobility shift assay and the protein is able to repress expression of a reporter gene driven by this element (Agren et al, 2004). GLI3R may promote repressive complexes at the PTCH1 promoter by the SKI1-dependent recruitment of HDAC complexes (Dai et al, 2002). Other GLI3R transcriptional targets include GLI1 and GLI2 (Hu et al, 2006).</Comment> <BiopaxRef>cf6</BiopaxRef> <BiopaxRef>c19</BiopaxRef> <BiopaxRef>fdb</BiopaxRef> <BiopaxRef>f7a</BiopaxRef> <BiopaxRef>f1a</BiopaxRef> <BiopaxRef>ec7</BiopaxRef> <BiopaxRef>f79</BiopaxRef> <BiopaxRef>d07</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2799.0" Y="666.0" /> <Point X="2900.0" Y="662.0" /> <Anchor Position="0.0" Shape="None" GraphId="aefed" /> <Anchor Position="0.99" Shape="None" GraphId="eef2d" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5612508" /> </Interaction> <Interaction GraphId="f0311"> <Comment Source="Reactome">After being ubiquitinated, the bulk of GLI2 is fully degraded by the proteasome; a small fraction of GLI2 may be converted to the repressor form after ubiquitination (Pan et al, 2006; Pan and Wang, 2007). </Comment> <BiopaxRef>e5a</BiopaxRef> <BiopaxRef>f22</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2267.0" Y="873.0" /> <Point X="873.0" Y="1097.0" /> <Anchor Position="0.0" Shape="None" GraphId="b14e7" /> <Anchor Position="0.99" Shape="None" GraphId="dedd6" /> <Anchor Position="0.5" Shape="None" GraphId="c1b94" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610757" /> </Interaction> <Interaction GraphId="f19bd"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2056.0" Y="768.0" GraphRef="a12b3" RelX="-0.010752688172043012" RelY="-1.0" /> <Point X="2052.0" Y="708.0" GraphRef="dae95" RelX="-10.5" RelY="0.0" ArrowHead="mim-catalysis" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610746" /> </Interaction> <Interaction GraphId="f2542"> <Comment Source="Reactome">GSK3-mediated phosphorylation of GLI3 is primed by earlier phosphorylations by PKA and CK1 and is required for the subsequent recruitment of beta-TrCP (Tempe et al, 2006; Wang and Li, 2006).</Comment> <BiopaxRef>ac2</BiopaxRef> <BiopaxRef>c44</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1841.0" Y="707.0" /> <Point X="1878.0" Y="706.0" /> <Anchor Position="0.0" Shape="None" GraphId="ca79d" /> <Anchor Position="0.99" Shape="None" GraphId="e97bf" /> <Anchor Position="0.5" Shape="None" GraphId="a4b01" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610732" /> </Interaction> <Interaction GraphId="f46f6"> <Comment Source="Reactome">Phosphorylation by PKA primes GLI2 for subsequent phosphorylation at adjacent CK sites (Pan et al, 2006; Pan and Wang, 2007).</Comment> <BiopaxRef>e5a</BiopaxRef> <BiopaxRef>f22</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1672.0" Y="875.0" /> <Point X="1728.0" Y="874.0" /> <Anchor Position="0.0" Shape="None" GraphId="b0d61" /> <Anchor Position="0.99" Shape="None" GraphId="d4555" /> <Anchor Position="0.5" Shape="None" GraphId="e6111" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610718" /> </Interaction> <Interaction GraphId="f4728"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2095.0" Y="708.0" GraphRef="f8740" RelX="0.650000000000091" RelY="0.0" /> <Point X="2098.0" Y="708.0" GraphRef="fe00b" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610746" /> </Interaction> <Interaction GraphId="f4905"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1139.0" Y="205.0" GraphRef="ccb9c" RelX="4.108910891089109" RelY="-18.473684210526315" /> <Point X="1058.0" Y="311.0" GraphRef="daa67" RelX="31.0" RelY="-81.5" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610766" /> </Interaction> <Interaction GraphId="f49ed"> <Comment Source="Reactome">Expression of the GLI1 gene is repressed in the absence of Hh signaling by GLI3R (Hu et al, 2006). GLI3R may exert its repression activity through the SKI-dependent recruitment of HDACs (Dai et al, 2002).</Comment> <BiopaxRef>d07</BiopaxRef> <BiopaxRef>f79</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2841.0" Y="784.0" /> <Point X="3013.0" Y="1051.0" /> <Anchor Position="0.0" Shape="None" GraphId="a4842" /> <Anchor Position="0.99" Shape="None" GraphId="cd15d" /> <Anchor Position="0.5" Shape="None" GraphId="d227c" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5617412" /> </Interaction> <Interaction GraphId="f55d7"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1139.0" Y="205.0" GraphRef="d5085" RelX="3.75" RelY="-11.181818181818182" /> <Point X="1058.0" Y="311.0" GraphRef="daa67" RelX="31.0" RelY="-81.5" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610766" /> </Interaction> <Interaction GraphId="f683a"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1728.0" Y="874.0" GraphRef="d4555" RelX="0.5599999999999454" RelY="-0.009999999999990905" /> <Point X="1759.0" Y="904.0" GraphRef="a7501" RelX="-0.02564102564102564" RelY="-1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610718" /> </Interaction> <Interaction GraphId="f6cf9"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1711.0" Y="1092.0" GraphRef="bf812" RelX="-0.009708737864077669" RelY="1.0" /> <Point X="1759.0" Y="1151.0" GraphRef="e6b7b" RelX="4.5" RelY="0.5" ArrowHead="mim-catalysis" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610760" /> </Interaction> <Interaction GraphId="f6d76"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2339.0" Y="712.0" GraphRef="e60d4" RelX="1.2699999999999818" RelY="0.01999999999998181" /> <Point X="2382.0" Y="711.0" GraphRef="a3a25" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610754" /> </Interaction> <Interaction GraphId="f7b00"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1485.0" Y="560.0" GraphRef="cbf6d" RelX="-0.9800000000000182" RelY="0.029999999999972715" /> <Point X="1452.0" Y="514.0" GraphRef="d71ed" RelX="1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610727" /> </Interaction> <Interaction GraphId="f7c61"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="3013.0" Y="1051.0" GraphRef="cd15d" RelX="1.7199999999998" RelY="2.6700000000000728" /> <Point X="3014.0" Y="1054.0" GraphRef="c7dec" RelX="0.0" RelY="-1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5617412" /> </Interaction> <Interaction GraphId="f7fac"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1524.0" Y="259.0" GraphRef="f8109" RelX="-0.01694915254237288" RelY="1.0" /> <Point X="1519.0" Y="329.0" GraphRef="ba0bd" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610725" /> </Interaction> <Interaction GraphId="f8171"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1393.0" Y="786.0" GraphRef="bcdcd" RelX="1.0" RelY="0.0" /> <Point X="1475.0" Y="880.0" GraphRef="ed7ea" RelX="-3.5" RelY="1.0" ArrowHead="mim-catalysis" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610717" /> </Interaction> <Interaction GraphId="f8add"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1249.0" Y="1006.0" GraphRef="d0164" RelX="0.9770114942528736" RelY="0.0" /> <Point X="1274.0" Y="998.0" GraphRef="cca14" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610741" /> </Interaction> <Interaction GraphId="f8dac"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1630.0" Y="785.0" GraphRef="a8adf" RelX="1.0" RelY="0.0" /> <Point X="1705.0" Y="874.0" GraphRef="e6111" RelX="5.0" RelY="-0.5" ArrowHead="mim-catalysis" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610718" /> </Interaction> <Interaction GraphId="f9a79"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="2903.0" Y="662.0" GraphRef="e7c6b" RelX="-1.0" RelY="-0.024390243902439025" /> <Point X="3133.0" Y="1417.0" GraphRef="d797b" RelX="1394.0" RelY="895.0" ArrowHead="TBar" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5612510" /> </Interaction> <Interaction GraphId="fa127"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="670.0" Y="405.0" GraphRef="bdf33" RelX="-1.0" RelY="-0.04" /> <Point X="425.0" Y="513.0" GraphRef="bb5ab" RelX="-81.5" RelY="42.0" ArrowHead="TBar" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5610763" /> </Interaction> <Interaction GraphId="fa22f"> <Comment Source="Reactome">KIF7, the human ortholog of Drosophila COS2, is a kinesin-4 motor protein that binds directly to the plus ends of axonemal microtubules and inhibits their growth in an ATP-dependent manner (He et al, 2014). KIF7 is required for the processing and activity of GLI in the absence of Hh signal, and KIF7 function depends on the primary cilium (Liem et al, 2009; Cheung et al, 2009; Endoh-Yamagami et al, 2009). KIF7 has been shown to bind to GLI3 and to SUFU and may act in part by promoting the transit of the GLI:SUFU complex through the primary cilium, which is required for GLI processing (Endoh-Yamagami et al, 2009; Maurya et al, 2013). How KIF7 itself is localized to the cilia tip is unknown, although localization depends on the KIF7 motor domain (Liem et al, 2009; He et al, 2014). 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