Reactome: A Curated Pathway Database

Ligand-receptor interactions

Stable Identifier
R-HSA-5632681
Type
Pathway
Species
Homo sapiens
Locations in the PathwayBrowser
Summation

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
16630821 The ihog cell-surface proteins bind Hedgehog and mediate pathway activation Cell 2006
20519495 All mammalian Hedgehog proteins interact with cell adhesion molecule, down-regulated by oncogenes (CDO) and brother of CDO (BOC) in a conserved manner J. Biol. Chem. 2010
8906794 Biochemical evidence that patched is the Hedgehog receptor Nature 1996
20844013 Interactions between Hedgehog proteins and their binding partners come into view Genes Dev. 2010
23719536 The mechanisms of Hedgehog signalling and its roles in development and disease Nat. Rev. Mol. Cell Biol. 2013
21664576 Overlapping roles and collective requirement for the coreceptors GAS1, CDO, and BOC in SHH pathway function Dev. Cell 2011
17504940 Gas1 extends the range of Hedgehog action by facilitating its signaling Genes Dev. 2007
16136078 Vertebrate Smoothened functions at the primary cilium Nature 2005
8906787 The tumour-suppressor gene patched encodes a candidate receptor for Sonic hedgehog Nature 1996
8898207 Dual roles for patched in sequestering and transducing Hedgehog Cell 1996
17848687 Hedgehog signaling: cooking with Gas1 Sci. STKE 2007
21664577 Boc and Gas1 each form distinct Shh receptor complexes with Ptch1 and are required for Shh-mediated cell proliferation 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 Dev. Cell 2006
17086203 Boc is a receptor for sonic hedgehog in the guidance of commissural axons Nature 2006
22326621 Cdon and Boc: Two transmembrane proteins implicated in cell-cell communication Int. J. Biochem. Cell Biol. 2012
20395968 The primary cilium: a signalling centre during vertebrate development Nat. Rev. Genet. 2010
18794898 The mode of Hedgehog binding to Ihog homologues is not conserved across different phyla Nature 2008
17641202 Patched1 regulates hedgehog signaling at the primary cilium Science 2007
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