Reactome | Ligand-receptor interactions

Ligand-receptor interactions

Stable Identifier

R-HSA-5632681

Type

Pathway

Species

Homo sapiens

ReviewStatus

5/5

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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).
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).

Literature References

PubMed ID	Title	Journal	Year
20519495	All mammalian Hedgehog proteins interact with cell adhesion molecule, down-regulated by oncogenes (CDO) and brother of CDO (BOC) in a conserved manner Kavran, JM, Oladosu, OO, Leahy, DJ, Mulepati, S, Ward, MD	J. Biol. Chem.	2010
16630821	The ihog cell-surface proteins bind Hedgehog and mediate pathway activation Beachy, P, Lum, L, Yao, S	Cell	2006
8906794	Biochemical evidence that patched is the Hedgehog receptor Davey, RA, Cunningham, JM, Marigo, V, Zuo, Y, Tabin, CJ	Nature	1996
20844013	Interactions between Hedgehog proteins and their binding partners come into view Hymowitz, SG, Beachy, PA, Leahy, DJ, Lazarus, RA, Siebold, C	Genes Dev.	2010
23719536	The mechanisms of Hedgehog signalling and its roles in development and disease Thérond, PP, Briscoe, J	Nat. Rev. Mol. Cell Biol.	2013
21664576	Overlapping roles and collective requirement for the coreceptors GAS1, CDO, and BOC in SHH pathway function Charron, F, Song, JY, Krauss, RS, Allen, BL, McMahon, AP, Althaus, IW, Kang, JS, Izzi, L	Dev. Cell	2011
17504940	Gas1 extends the range of Hedgehog action by facilitating its signaling Fan, CM, Martinelli, DC	Genes Dev.	2007
16136078	Vertebrate Smoothened functions at the primary cilium Stainier, DY, Singla, V, Norman, AR, Reiter, JF, Aanstad, P, Corbit, KC	Nature	2005
8906787	The tumour-suppressor gene patched encodes a candidate receptor for Sonic hedgehog Stone, DM, de Sauvage, F, Hooper, JE, Gu, Q, Pennica, D, Goddard, A, Rosenthal, A, Phillips, H, Noll, M, Swanson, TA, Johnson, RL, Armanini, M, Hynes, M, Scott, MP	Nature	1996
8898207	Dual roles for patched in sequestering and transducing Hedgehog Chen, Y, Struhl, G	Cell	1996
17848687	Hedgehog signaling: cooking with Gas1 Krauss, RS, Kang, JS, Zhang, W	Sci. STKE	2007
21664577	Boc and Gas1 each form distinct Shh receptor complexes with Ptch1 and are required for Shh-mediated cell proliferation Charron, F, Morin, S, Krauss, RS, Allen, BL, Laniel, D, Lévesque, M, McMahon, AP, Mille, F, Wilkes, BC, Izzi, L	Dev. Cell	2011
16647304	The cell surface membrane proteins Cdo and Boc are components and targets of the Hedgehog signaling pathway and feedback network in mice Krauss, RS, Allen, BL, McMahon, AP, Cole, F, Tenzen, T, Kang, JS	Dev. Cell	2006
17086203	Boc is a receptor for sonic hedgehog in the guidance of commissural axons Charron, F, Fabre, PJ, Morin, S, Okada, A, Wong, K, McConnell, SK, Tessier-Lavigne, M, Shin, DS	Nature	2006
22326621	Cdon and Boc: Two transmembrane proteins implicated in cell-cell communication Nieto-Lopez, F, Cardozo, M, Bovolenta, P, Sanchez-Arrones, L	Int. J. Biochem. Cell Biol.	2012
20395968	The primary cilium: a signalling centre during vertebrate development Anderson, KV, Goetz, SC	Nat. Rev. Genet.	2010
18794898	The mode of Hedgehog binding to Ihog homologues is not conserved across different phyla Ghirlando, R, Beachy, PA, Zheng, X, Leahy, DJ, Hauk, G, McLellan, JS	Nature	2008
17641202	Patched1 regulates hedgehog signaling at the primary cilium Milenkovic, L, Rohatgi, R, Scott, MP	Science	2007