BioPAX pathway converted from "Ligand-receptor interactions" in the Reactome database. Ligand-receptor interactions 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> HHIP binds Hedgehog 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> Reactome DB_ID: 10453120 1 ciliary membrane GO 0060170 UniProt:A0A1D5PDP9 HHIP Reactome http://www.reactome.org Gallus gallus NCBI Taxonomy 9031 UniProt A0A1D5PDP9 Chain Coordinates 18 EQUAL 700 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 10453130 1 extracellular region GO 0005576 Hh-Npp [extracellular region] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity SHH(34-?) [extracellular region] UniProt F1P3J4 Reactome DB_ID: 10453132 1 Hh-Npp:HHIP [ciliary membrane] Hh-Npp:HHIP Reactome DB_ID: 10453120 1 18 EQUAL 700 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 10453130 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 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 10050855 Pubmed 1999 Vertebrate Hedgehog signalling modulated by induction of a Hedgehog-binding protein Chuang, Pao Tien McMahon, Andrew P Nature 397:617-21 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 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 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 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 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 inferred by electronic annotation IEA GO IEA 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). 20395968 Pubmed 2010 The primary cilium: a signalling centre during vertebrate development Goetz, Sarah C Anderson, Kathryn V Nat. Rev. Genet. 11:331-44 17848687 Pubmed 2007 Hedgehog signaling: cooking with Gas1 Kang, Jong-Sun Zhang, W Krauss, Robert S Sci. STKE 2007:pe50 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 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 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 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 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 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 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 16630821 Pubmed 2006 The ihog cell-surface proteins bind Hedgehog and mediate pathway activation Yao, S Lum, L Beachy, P Cell 125:343-57 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 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 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 8898207 Pubmed 1996 Dual roles for patched in sequestering and transducing Hedgehog Chen, Y Struhl, G Cell 87:553-63 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 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 17641202 Pubmed 2007 Patched1 regulates hedgehog signaling at the primary cilium Rohatgi, Rajat Milenkovic, Ljiljana Scott, Matthew P Science 317:372-6 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 inferred by electronic annotation IEA GO IEA