BioPAX pathway converted from "Hedgehog 'on' state" in the Reactome database. Hedgehog 'on' state This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Ligand-receptor interactions This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> LEFT-TO-RIGHT HHIP binds Hedgehog This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome Hh-Npp delipidated Hh-Np Reactome DB_ID: 10453130 F1P3J4 SHH(34-?) Reactome DB_ID: 10453124 extracellular region GENE ONTOLOGY GO:0005576 UniProt:F1P3J4 Gallus gallus NCBI Taxonomy 9031 UniProt F1P3J4 34 EQUAL -1 EQUAL Reactome Database ID Release 78 10453124 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10453124 Reactome R-GGA-5362776 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-5362776.1 Reactome http://www.reactome.org DHH DHH(33-?) A0A1D5PMC9 Reactome DB_ID: 10453128 UniProt:A0A1D5PMC9 DHH UniProt A0A1D5PMC9 33 EQUAL -1 EQUAL Reactome Database ID Release 78 10453128 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10453128 Reactome R-GGA-5362781 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-5362781.1 Reactome Database ID Release 78 10453130 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10453130 Reactome R-GGA-5362783 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-5362783.1 HHIP HHIP A0A1D5PDP9 Reactome DB_ID: 10453120 ciliary membrane GENE ONTOLOGY GO:0060170 UniProt:A0A1D5PDP9 HHIP UniProt A0A1D5PDP9 18 EQUAL 700 EQUAL Reactome Database ID Release 78 10453120 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10453120 Reactome R-GGA-445449 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-445449.1 Hh-Npp:HHIP Reactome DB_ID: 10453132 1 1 Reactome Database ID Release 78 10453132 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10453132 Reactome R-GGA-445447 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-445447.1 Reactome Database ID Release 78 10453134 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10453134 Reactome R-GGA-445448 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-445448.1 HHIP is a Hh-binding transmembrane protein that antagonizes Hh signaling by sequestering the ligand away from PTCH. HHIP is also a downstream target gene of Hh signaling, establishing a negative feedback loop that limits the extent of signaling (Chuang et al, 1999; Chuang et al, 2003; Bosanac et al, 2009; Bishop et al, 2009: Holtz et al, 2013). HHIP binds to all three Hh ligands, and also exists in a secreted form, which also sequesters ligand (Chuang et al, 1999; Coulombe et al, 2004). HHIP expression is altered in some cancers that show upregulated Hh signaling (Olsen et al, 2004; Tada et al, 2008; Tojo et al, 2002). 19561611 Pubmed 2009 Structural insights into hedgehog ligand sequestration by the human hedgehog-interacting protein HHIP Bishop, Benjamin Aricescu, A Radu Harlos, Karl O'Callaghan, Chris A Jones, E Yvonne Siebold, Christian Nat. Struct. Mol. Biol. 16:698-703 15019948 Pubmed 2004 Hedgehog interacting protein in the mature brain: membrane-associated and soluble forms Coulombe, J Traiffort, E Loulier, K Faure, H Ruat, M Mol. Cell. Neurosci. 25:323-33 15294024 Pubmed 2004 Hedgehog-interacting protein is highly expressed in endothelial cells but down-regulated during angiogenesis and in several human tumors Olsen, Catherine L Hsu, Pin-Pin Glienke, Jens Rubanyi, Gabor M Brooks, Alan R BMC Cancer 4:43 12569124 Pubmed 2003 Feedback control of mammalian Hedgehog signaling by the Hedgehog-binding protein, Hip1, modulates Fgf signaling during branching morphogenesis of the lung Chuang, Pao-Tien Kawcak, T'Nay McMahon, Andrew P Genes Dev. 17:342-7 10050855 Pubmed 1999 Vertebrate Hedgehog signalling modulated by induction of a Hedgehog-binding protein Chuang, Pao Tien McMahon, Andrew P Nature 397:617-21 11841368 Pubmed 2002 Expression of a sonic hedgehog signal transducer, hedgehog-interacting protein, by human basal cell carcinoma Tojo, M Kiyosawa, H Iwatsuki, K Kaneko, F Br. J. Dermatol. 146:69-73 23900540 Pubmed 2013 Essential role for ligand-dependent feedback antagonism of vertebrate hedgehog signaling by PTCH1, PTCH2 and HHIP1 during neural patterning Holtz, Alexander M Peterson, Kevin A Nishi, Yuichi Morin, Steves Song, Jane Y Charron, Frédéric McMahon, Andrew P Allen, Benjamin L Development 140:3423-34 18559595 Pubmed 2008 Down-regulation of hedgehog-interacting protein through genetic and epigenetic alterations in human hepatocellular carcinoma Tada, Motohisa Kanai, F Tanaka, Yasuo Tateishi, Keisuke Ohta, Miki Asaoka, Yoshinari Seto, Motoko Muroyama, Ryosuke Fukai, Kenichi Imazeki, Fumio Kawabe, Takao Yokosuka, Osamu Omata, Masao Clin. Cancer Res. 14:3768-76 19561609 Pubmed 2009 The structure of SHH in complex with HHIP reveals a recognition role for the Shh pseudo active site in signaling Bosanac, Ivan Maun, Henry R Scales, Suzie J Wen, Xiaohui Lingel, Andreas Bazan, J Fernando de Sauvage, Frederic J Hymowitz, Sarah G Lazarus, Robert A Nat. Struct. Mol. Biol. 16:691-7 inferred from electronic annotation EVIDENCE CODE ECO:0000203 Reactome Database ID Release 78 10510354 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10510354 Reactome R-GGA-5632681 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-5632681.1 Repression of Hh signaling in the absence of ligand depends on the transmembrane receptor protein Patched (PTCH), which inhibits Smoothened (SMO) activity by an unknown mechanism. This promotes the proteolytic processing and/or degradation of the GLI family of transcription factors and maintains the pathway in a transcriptionally repressed state (reviewed in Briscoe and Therond, 2013). In the absence of ligand, PTCH is localized in the cilium, while SMO is largely concentrated in intracellular compartments. Upon binding of Hh to the PTCH receptor, PTCH is endocytosed, relieving SMO inhibition and allowing it to accumulate in the primary cilium (Marigo et al, 1996; Chen and Struhl, 1996; Stone et al, 1996; Rohatgi et al, 2007; Corbit et al, 2005; reviewed in Goetz and Anderson, 2010). In the cilium, SMO is activated by an unknown mechanism, allowing the full length transcriptional activator forms of the GLI proteins to accumulate and translocate to the nucleus, where they bind to the promoters of Hh-responsive genes (reviewed in Briscoe and Therond, 2013). <br>In addition to PTCH, three additional membrane proteins have been shown to bind Hh and to be required for Hh-dependent signaling in vertebrates: CDON (CAM-related/downregulated by oncogenes), BOC (brother of CDO) and GAS1 (growth arrest specific 1) (Yao et al, 2006; Okada et al, 2006; Tenzen et al, 2006; McLellan et al, 2008; reviewed in Kang et al, 2007; Beachy et al, 2010; Sanchez-Arrones et al, 2012). CDON and BOC, homologues of Drosophila Ihog and Boi respectively, are evolutionarily conserved transmembrane glycoproteins that have been shown to bind both to Hh ligand and to the canonical receptor PTCH to promote Hh signaling (Okada et al, 2006; Yao et al, 2006; Tenzen et al, 2006, McLellan et al, 2008; Izzi et al, 2011; reviewed in Sanchez-Arrones et al, 2012). Despite the evolutionary conservation, the mode of ligand binding by CDON/Ihog and BOC/Boi is distinct in vertebrates and invertebrates. High affinity ligand-binding by CDON and BOC requires Ca2+, while invertebrate ligand-binding is heparin-dependent (Okada et al, 2006; Tenzen et al, 2006; McLellan et al, 2008; Yao et al, 2006; Kavran et al, 2010). GAS1 is a vertebrate-specific GPI-anchored protein that similarly binds both to Hh ligand and to the PTCH receptor to promote Hh signaling (Martinelli and Fan, 2007; Izzi et al, 2011; reviewed in Kang et al, 2007). CDON, BOC and GAS1 have partially overlapping but not totally redundant roles, and knock-out of all three is required to abrogate Hh signaling in mice (Allen et al, 2011; Izzi et al, 2011; reviewed in Briscoe and Therond, 2013). 16136078 Pubmed 2005 Vertebrate Smoothened functions at the primary cilium Corbit, Kevin C Aanstad, Pia Singla, Veena Norman, Andrew R Stainier, Didier Y R Reiter, Jeremy F Nature 437:1018-21 23719536 Pubmed 2013 The mechanisms of Hedgehog signalling and its roles in development and disease Briscoe, James Thérond, Pascal P Nat. Rev. Mol. Cell Biol. 14:416-29 18794898 Pubmed 2008 The mode of Hedgehog binding to Ihog homologues is not conserved across different phyla McLellan, Jason S Zheng, Xiaoyan Hauk, Glenn Ghirlando, Rodolfo Beachy, Philip A Leahy, Daniel J Nature 455:979-83 17641202 Pubmed 2007 Patched1 regulates hedgehog signaling at the primary cilium Rohatgi, Rajat Milenkovic, Ljiljana Scott, Matthew P Science 317:372-6 21664577 Pubmed 2011 Boc and Gas1 each form distinct Shh receptor complexes with Ptch1 and are required for Shh-mediated cell proliferation Izzi, Luisa Lévesque, Martin Morin, Steves Laniel, Dominique Wilkes, Brian C Mille, Frédéric Krauss, Robert S McMahon, Andrew P Allen, Benjamin L Charron, Frédéric Dev. Cell 20:788-801 20519495 Pubmed 2010 All mammalian Hedgehog proteins interact with cell adhesion molecule, down-regulated by oncogenes (CDO) and brother of CDO (BOC) in a conserved manner Kavran, Jennifer M Ward, Matthew D Oladosu, Oyindamola O Mulepati, Sabin Leahy, Daniel J J. Biol. Chem. 285:24584-90 8906794 Pubmed 1996 Biochemical evidence that patched is the Hedgehog receptor Marigo, V Davey, RA Zuo, Y Cunningham, JM Tabin, CJ Nature 384:176-9 20395968 Pubmed 2010 The primary cilium: a signalling centre during vertebrate development Goetz, Sarah C Anderson, Kathryn V Nat. Rev. Genet. 11:331-44 16647304 Pubmed 2006 The cell surface membrane proteins Cdo and Boc are components and targets of the Hedgehog signaling pathway and feedback network in mice Tenzen, Toyoaki Allen, Benjamin L Cole, Francesca Kang, Jong-Sun Krauss, Robert S McMahon, Andrew P Dev. Cell 10:647-56 17504940 Pubmed 2007 Gas1 extends the range of Hedgehog action by facilitating its signaling Martinelli, David C Fan, Chen-Ming Genes Dev. 21:1231-43 17848687 Pubmed 2007 Hedgehog signaling: cooking with Gas1 Kang, Jong-Sun Zhang, W Krauss, Robert S Sci. STKE 2007:pe50 16630821 Pubmed 2006 The ihog cell-surface proteins bind Hedgehog and mediate pathway activation Yao, S Lum, L Beachy, P Cell 125:343-57 17086203 Pubmed 2006 Boc is a receptor for sonic hedgehog in the guidance of commissural axons Okada, Ami Charron, Frédéric Morin, Steves Shin, David S Wong, Karen Fabre, Pierre J Tessier-Lavigne, Marc McConnell, Susan K Nature 444:369-73 8898207 Pubmed 1996 Dual roles for patched in sequestering and transducing Hedgehog Chen, Y Struhl, G Cell 87:553-63 22326621 Pubmed 2012 Cdon and Boc: Two transmembrane proteins implicated in cell-cell communication Sanchez-Arrones, Luisa Cardozo, Marcos Nieto-Lopez, Francisco Bovolenta, Paola Int. J. Biochem. Cell Biol. 44:698-702 8906787 Pubmed 1996 The tumour-suppressor gene patched encodes a candidate receptor for Sonic hedgehog Stone, DM Hynes, M Armanini, M Swanson, TA Gu, Q Johnson, RL Scott, MP Pennica, D Goddard, A Phillips, H Noll, M Hooper, JE de Sauvage, F Rosenthal, A Nature 384:129-34 20844013 Pubmed 2010 Interactions between Hedgehog proteins and their binding partners come into view Beachy, Philip A Hymowitz, Sarah G Lazarus, Robert A Leahy, Daniel J Siebold, Christian Genes Dev. 24:2001-12 21664576 Pubmed 2011 Overlapping roles and collective requirement for the coreceptors GAS1, CDO, and BOC in SHH pathway function Allen, Benjamin L Song, Jane Y Izzi, Luisa Althaus, Irene W Kang, Jong-Sun Charron, Frédéric Krauss, Robert S McMahon, Andrew P Dev. Cell 20:775-87 LEFT-TO-RIGHT GPR161 is internalized This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> GPR161 GPR161 E1C367 Reactome DB_ID: 10481442 UniProt:E1C367 GPR161 UniProt E1C367 1 EQUAL 529 EQUAL Reactome Database ID Release 78 10481442 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10481442 Reactome R-GGA-5610373 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-5610373.1 GPR161 GPR161 E1C367 Reactome DB_ID: 10482743 endocytic vesicle membrane GENE ONTOLOGY GO:0030666 1 EQUAL 529 EQUAL Reactome Database ID Release 78 10482743 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10482743 Reactome R-GGA-5635021 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-5635021.1 Reactome Database ID Release 78 10482745 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10482745 Reactome R-GGA-5635102 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-5635102.1 Hh signaling promotes the removal of the orphan G protein coupled receptor GPR161 from the cilium (Rohatgi et al, 2007). GPR161 is a negative regulator of Hh signaling that is recruited to the cilium through interaction with TULP3 (Mukhopadhyay et al, 2010; Mukhopadhyay et al, 2013). GPR161 thought to act by locally increasing the cAMP levels, promoting PKA activity and thereby favouring the production of the repressor form of the GLI proteins in the absence of Hh ligand. Consistent with this, deletion of GPR161 results in ectopic pathway activation (Mukhopadhyay et al, 2013). The decrease in PKA activity in the cilium after clearance of GPR161 from the ciliary membrane may contribute to the dissociation of the GLI:SUFU complex upon pathway activation, although this remains to formally demonstrated (Humke et al, 2010; Tukachinsky et al, 2010; reviewed in Mukhopadhyay et al, 2014). 23332756 Pubmed 2013 The ciliary G-protein-coupled receptor Gpr161 negatively regulates the Sonic hedgehog pathway via cAMP signaling Mukhopadhyay, Saikat Wen, Xiaohui Ratti, Navneet Loktev, Alexander Rangell, Linda Scales, Suzie J Jackson, Peter K Cell 152:210-23 20360384 Pubmed 2010 The output of Hedgehog signaling is controlled by the dynamic association between Suppressor of Fused and the Gli proteins Humke, Eric W Dorn, Karolin V Milenkovic, Ljiljana Scott, Matthew P Rohatgi, Rajat Genes Dev. 24:670-82 20956384 Pubmed 2010 A mechanism for vertebrate Hedgehog signaling: recruitment to cilia and dissociation of SuFu-Gli protein complexes Tukachinsky, Hanna Lopez, Lyle V Salic, Adrian J. Cell Biol. 191:415-28 20889716 Pubmed 2010 TULP3 bridges the IFT-A complex and membrane phosphoinositides to promote trafficking of G protein-coupled receptors into primary cilia Mukhopadhyay, Saikat Wen, Xiaohui Chih, Ben Nelson, Christopher D Lane, William S Scales, Suzie J Jackson, Peter K Genes Dev. 24:2180-93 24845016 Pubmed 2014 G-protein-coupled receptors, Hedgehog signaling and primary cilia Mukhopadhyay, Saikat Rohatgi, Rajat Semin. Cell Dev. Biol. LEFT-TO-RIGHT SPOP:CUL3:RBX1 ubiquitinates GLI2,3 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome Ub Ubiquitin UBIQ_HUMAN Reactome DB_ID: 10427836 ubiquitin (RPS27A) Reactome DB_ID: 939902 nucleoplasm GENE ONTOLOGY GO:0005654 UniProt:P79781 RPS27A RPS27A UBA80 FUNCTION Ubiquitin exists either covalently attached to another protein, or free (unanchored). When covalently bound, it is conjugated to target proteins via an isopeptide bond either as a monomer (monoubiquitin), a polymer linked via different Lys residues of the ubiquitin (polyubiquitin chains) or a linear polymer linked via the initiator Met of the ubiquitin (linear polyubiquitin chains). Polyubiquitin chains, when attached to a target protein, have different functions depending on the Lys residue of the ubiquitin that is linked: Lys-6-linked may be involved in DNA repair; Lys-11-linked is involved in ERAD (endoplasmic reticulum-associated degradation) and in cell-cycle regulation; Lys-29-linked is involved in lysosomal degradation; Lys-33-linked is involved in kinase modification; Lys-48-linked is involved in protein degradation via the proteasome; Lys-63-linked is involved in endocytosis, DNA-damage responses as well as in signaling processes leading to activation of the transcription factor NF-kappa-B. Linear polymer chains formed via attachment by the initiator Met lead to cell signaling. Ubiquitin is usually conjugated to Lys residues of target proteins, however, in rare cases, conjugation to Cys or Ser residues has been observed. When polyubiquitin is free (unanchored-polyubiquitin), it also has distinct roles, such as in activation of protein kinases, and in signaling (By similarity).FUNCTION Ribosomal protein S27a is a component of the 40S subunit of the ribosome.SUBUNIT Ribosomal protein S27a is part of the 40S ribosomal subunit.MISCELLANEOUS Ubiquitin is encoded by 4 different genes. Uba52 and Rps27a genes code for a single copy of ubiquitin fused to the ribosomal proteins L40 and S27a, respectively. UBB and UBC genes code for a polyubiquitin precursor with exact head to tail repeats, the number of repeats differ between species and strains.SIMILARITY In the N-terminal section; belongs to the ubiquitin family.SIMILARITY In the C-terminal section; belongs to the eukaryotic ribosomal protein eS31 family. UniProt P79781 1 EQUAL 76 EQUAL Reactome Database ID Release 78 939902 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=939902 Reactome R-GGA-939902 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-939902.1 A0A1D5P546 UBA52(1-76) Reactome DB_ID: 10427820 UniProt:A0A1D5P546 UniProt A0A1D5P546 1 EQUAL 76 EQUAL Reactome Database ID Release 78 10427820 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10427820 Reactome R-GGA-939844 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-939844.1 RPS27A UBB(77-152) P79781 Reactome DB_ID: 10427822 77 EQUAL 152 EQUAL Reactome Database ID Release 78 10427822 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10427822 Reactome R-GGA-939870 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-939870.1 ubiquitin (UBB 1) Reactome DB_ID: 939895 UniProt:P0CG62 UBB UBB FUNCTION Ubiquitin exists either covalently attached to another protein, or free (unanchored). When covalently bound, it is conjugated to target proteins via an isopeptide bond either as a monomer (monoubiquitin), a polymer linked via different Lys residues of the ubiquitin (polyubiquitin chains) or a linear polymer linked via the initiator Met of the ubiquitin (linear polyubiquitin chains). Polyubiquitin chains, when attached to a target protein, have different functions depending on the Lys residue of the ubiquitin that is linked: Lys-6-linked may be involved in DNA repair; Lys-11-linked is involved in ERAD (endoplasmic reticulum-associated degradation) and in cell-cycle regulation; Lys-29-linked is involved in lysosomal degradation; Lys-33-linked is involved in kinase modification; Lys-48-linked is involved in protein degradation via the proteasome; Lys-63-linked is involved in endocytosis, DNA-damage responses as well as in signaling processes leading to activation of the transcription factor NF-kappa-B. Linear polymer chains formed via attachment by the initiator Met lead to cell signaling. Ubiquitin is usually conjugated to Lys residues of target proteins, however, in rare cases, conjugation to Cys or Ser residues has been observed. When polyubiquitin is free (unanchored-polyubiquitin), it also has distinct roles, such as in activation of protein kinases, and in signaling (By similarity).MISCELLANEOUS Ubiquitin is encoded by 4 different genes. Uba52 and Rps27a genes code for a single copy of ubiquitin fused to the ribosomal proteins L40 and S27a, respectively. UBB and UBC genes code for a polyubiquitin precursor with exact head to tail repeats, the number of repeats differ between species and strains.MISCELLANEOUS For the sake of clarity sequence features are annotated only for the first chain, and are not repeated for each of the following chains.SIMILARITY Belongs to the ubiquitin family. UniProt P0CG62 1 EQUAL 76 EQUAL Reactome Database ID Release 78 939895 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=939895 Reactome R-GGA-939895 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-939895.1 ubiquitin (UBB 2) Reactome DB_ID: 939893 77 EQUAL 152 EQUAL Reactome Database ID Release 78 939893 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=939893 Reactome R-GGA-939893 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-939893.1 ubiquitin (UBB 3) Reactome DB_ID: 939884 153 EQUAL 228 EQUAL Reactome Database ID Release 78 939884 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=939884 Reactome R-GGA-939884 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-939884.1 ubiquitin (UBB 4) Reactome DB_ID: 939882 229 EQUAL 304 EQUAL Reactome Database ID Release 78 939882 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=939882 Reactome R-GGA-939882 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-939882.1 P0CG62 UBC(305-380) Reactome DB_ID: 10427826 305 EQUAL 380 EQUAL Reactome Database ID Release 78 10427826 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10427826 Reactome R-GGA-939863 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-939863.1 P0CG62 UBC(381-456) Reactome DB_ID: 10427828 381 EQUAL 456 EQUAL Reactome Database ID Release 78 10427828 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10427828 Reactome R-GGA-939856 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-939856.1 P0CG62 UBC(457-532) Reactome DB_ID: 10427830 457 EQUAL 532 EQUAL Reactome Database ID Release 78 10427830 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10427830 Reactome R-GGA-939862 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-939862.1 P0CG62 UBC(533-608) Reactome DB_ID: 10427832 533 EQUAL 608 EQUAL Reactome Database ID Release 78 10427832 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10427832 Reactome R-GGA-939866 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-939866.1 P0CG62 UBC(609-684) Reactome DB_ID: 10427834 609 EQUAL 684 EQUAL Reactome Database ID Release 78 10427834 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10427834 Reactome R-GGA-939868 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-939868.1 Reactome Database ID Release 78 10427836 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10427836 Reactome R-GGA-68524 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-68524.1 2p-GLI:SPOP:CUL3:RBX1 Reactome DB_ID: 10482781 SPOP:CUL3:RBX1 Reactome DB_ID: 10482775 Converted from EntitySet in Reactome SPOP dimer Reactome DB_ID: 10482771 SPOP dimer Reactome DB_ID: 10482763 SPOP E1C049 Reactome DB_ID: 10482761 UniProt:E1C049 UniProt E1C049 1 EQUAL 374 EQUAL Reactome Database ID Release 78 10482761 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10482761 Reactome R-GGA-5635035 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-5635035.1 2 Reactome Database ID Release 78 10482763 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10482763 Reactome R-GGA-5635066 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-5635066.1 SPOP:SPOPL Reactome DB_ID: 10482769 1 SPOPL A0A3Q3AA02 Reactome DB_ID: 10482767 UniProt:A0A3Q3AA02 UniProt A0A3Q3AA02 1 EQUAL 392 EQUAL Reactome Database ID Release 78 10482767 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10482767 Reactome R-GGA-5635036 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-5635036.1 1 Reactome Database ID Release 78 10482769 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10482769 Reactome R-GGA-5635068 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-5635068.1 Reactome Database ID Release 78 10482771 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10482771 Reactome R-GGA-5635065 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-5635065.1 1 RBX1 RBX1 E1BSR9 Reactome DB_ID: 10427855 UniProt:E1BSR9 RBX1 UniProt E1BSR9 2 EQUAL 108 EQUAL Reactome Database ID Release 78 10427855 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10427855 Reactome R-GGA-1234142 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-1234142.1 2 CUL3 CUL3 E1BYQ3 Reactome DB_ID: 10482773 UniProt:E1BYQ3 CUL3 UniProt E1BYQ3 1 EQUAL 768 EQUAL Reactome Database ID Release 78 10482773 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10482773 Reactome R-GGA-5635033 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-5635033.1 2 Reactome Database ID Release 78 10482775 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10482775 Reactome R-GGA-5635071 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-5635071.1 1 Ghost homologue of 2p-GLI2,3 Reactome DB_ID: 10482779 Reactome Database ID Release 78 10482779 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10482779 Reactome R-GGA-5635080 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-5635080.1 1 Reactome Database ID Release 78 10482781 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10482781 Reactome R-GGA-5635087 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-5635087.1 ub-2p-GLI2,3:SPOP:CUL3:RBX1 Reactome DB_ID: 10482777 Ghost homologue of ub-2p-GLI2,3 Reactome DB_ID: 10482757 Reactome Database ID Release 78 10482757 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10482757 Reactome R-GGA-5635092 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-5635092.1 1 1 Reactome Database ID Release 78 10482777 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10482777 Reactome R-GGA-5635095 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-5635095.1 ACTIVATION activeUnit: #Protein22 GENE ONTOLOGY GO:0061630 gene ontology term for cellular function MI MI:0355 Same Catalyst Activity Reactome Database ID Release 78 10482782 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10482782 Reactome Database ID Release 78 10482784 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10482784 Reactome R-GGA-5635856 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-5635856.1 The transcriptional activity of full-length activated Ci/GLI proteins is restricted by their rapid ubiquitin-mediated degradation after initiation of Hh signaling (Ohlmeyer et al, 1998; Humke et al, 2010; Tukachinsky et al, 2010; Wen et al, 2010). Ubiquitination of Ci, GLI2 and GLI3 is mediated by the E3 ligase complex SPOP:CUL3:RBX1, which ubiquitinates the transcription factors in a Hh-dependent manner (Zhang et al, 2006; Kent et al, 2006; Zhang et al, 2009; Chen et al, 2009). 9874371 Pubmed 1998 Hedgehog stimulates maturation of Cubitus interruptus into a labile transcriptional activator Ohlmeyer, Johanna Talavera Kalderon, Daniel Nature 396:749-53 20154143 Pubmed 2010 Kinetics of hedgehog-dependent full-length Gli3 accumulation in primary cilia and subsequent degradation Wen, Xiaohui Lai, Cary K Evangelista, Marie Hongo, Jo-Anne de Sauvage, Frederic J Scales, Suzie J Mol. Cell. Biol. 30:1910-22 16651542 Pubmed 2006 Roadkill attenuates Hedgehog responses through degradation of Cubitus interruptus Kent, D Bush, EW Hooper, JE Development 133:2001-10 19684112 Pubmed 2009 Cilium-independent regulation of Gli protein function by Sufu in Hedgehog signaling is evolutionarily conserved Chen, Miao-Hsueh Wilson, Christopher W Li, Ya-Jun Law, Kelvin King Lo Lu, Chi-Sheng Gacayan, Rhodora Zhang, Xiaoyun Hui, Chi-Chung Chuang, Pao-Tien Genes Dev. 23:1910-28 19955409 Pubmed 2009 Multiple Ser/Thr-rich degrons mediate the degradation of Ci/Gli by the Cul3-HIB/SPOP E3 ubiquitin ligase Zhang, Qing Shi, Qing Chen, Yongbin Yue, Tao Li, Shuang Wang, Bing Jiang, Jin Proc. Natl. Acad. Sci. U.S.A. 106:21191-6 16740475 Pubmed 2006 A hedgehog-induced BTB protein modulates hedgehog signaling by degrading Ci/Gli transcription factor Zhang, Q Zhang, Lei Wang, B Ou, CY Chien, CT Jiang, J Dev Cell 10:719-29 LEFT-TO-RIGHT NUMB binds ITCH This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> NUMB NUMB A0A1D5NU12 Reactome DB_ID: 10452750 plasma membrane GENE ONTOLOGY GO:0005886 UniProt:A0A1D5NU12 NUMB UniProt A0A1D5NU12 1 EQUAL 651 EQUAL Reactome Database ID Release 78 10452750 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10452750 Reactome R-GGA-443595 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-443595.1 ITCH ITCH A0A1D5PQP3 Reactome DB_ID: 10458555 cytosol GENE ONTOLOGY GO:0005829 UniProt:A0A1D5PQP3 ITCH ITCH CATALYTIC ACTIVITY: S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin- conjugating enzyme]-L-cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine. {ECO:0000256|PIRNR:PIRNR001569, ECO:0000256|SAAS:SAAS00628607}. UniProt A0A1D5PQP3 1 EQUAL 903 EQUAL Reactome Database ID Release 78 10458555 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10458555 Reactome R-GGA-975995 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-975995.1 NUMB:ITCH Reactome DB_ID: 10481488 1 1 Reactome Database ID Release 78 10481488 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10481488 Reactome R-GGA-5610562 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-5610562.1 Reactome Database ID Release 78 10481490 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10481490 Reactome R-GGA-5610735 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-5610735.1 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). 20818436 Pubmed 2011 Numb activates the E3 ligase Itch to control Gli1 function through a novel degradation signal Di Marcotullio, L Greco, A Mazzà, D Canettieri, G Pietrosanti, L Infante, P Coni, S Moretti, M De Smaele, E Ferretti, E Screpanti, I Gulino, A Oncogene 30:65-76 17115028 Pubmed 2006 Numb is a suppressor of Hedgehog signalling and targets Gli1 for Itch-dependent ubiquitination Di Marcotullio, L Ferretti, Elisabetta Greco, Azzura De Smaele, Enrico Po, Agnese Sico, Maria Anna Alimandi, M Giannini, Giuseppe Maroder, Marella Screpanti, I Gulino, Alberto Nat. Cell Biol. 8:1415-23 Reactome Database ID Release 78 10510356 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10510356 Reactome R-GGA-5632684 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-GGA-5632684.1 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). <br>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).<br> 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). 21502959 Pubmed 2011 Mechanisms and functions of Hedgehog signalling across the metazoa Ingham, Philip W Nakano, Yoshiro Seger, Claudia Nat. Rev. Genet. 12:393-406 21801010 Pubmed 2011 Gli proteins in development and disease Hui, Chi-Chung Angers, S Annu. Rev. Cell Dev. Biol. 27:513-37