The tumour-suppressor gene patched encodes a candidate receptor for Sonic hedgehog

Abstract

The protein Sonic hedgehog (Shh) controls patterning and growth during vertebrate development. Here we demonstrate that it binds Patched (vPtc), which has been identified as a tumour-suppressor protein in basal cell carcinoma, with high affinity. We show that Ptc can form a physical complex with a newly cloned vertebrate homologue of the Drosophila protein Smoothened (vSmo), and that vSmo is coexpressed with vPtc in many tissues but does not bind Shh directly. These findings, combined with available genetic evidence from Drosophila, support the hypothesis that Ptc is a receptor for Shh, and that vSmo could be a signalling component that is linked to Ptc.

Activation of the hedgehog-signaling pathway in human cancer and the clinical implications

“…Patched (PTC, one PTC in fly and two PTCs in vertebrates-PTCH1 and PTCH2) is the major receptor for Hh proteins (Stone et al, 1996). Several molecules are involved in regulation of Hh reception.…”

Dependence receptors: a new paradigm in cell signaling and cancer therapy

“…Patched is also a known tumor suppressor (Stone et al, 1996). Inactive mutations of Ptc, as well as loss of expression, are found in basal cell carcinoma and medulloblastoma (Wicking and McGlinn, 2001).…”

The hedgehog signalling pathway in tumorigenesis and development

“…While there is only a single Drosophila hedgehog gene, three vertebrate homologues have been identi®ed, Sonic (Shh), Desert (Dhh), and Indian hedgehog (Ihh) (Echelard et al, 1993). In vitro studies suggest that each of these proteins can act through the same signal transduction pathway, and that the di erent hedgehog genes regulate patterning of di erent organ systems by virtue of their unique expression pattern (Echelard et al, 1993;Marigo et al, 1996;Stone et al, 1996). The most extensively studied of the vertebrate hedgehog genes is Shh which is expressed widely throughout the developing CNS, limb, lung, gut, teeth and hair-follicle (Bellusci et al, 1997;Hardcastle et al, 1998;Litingtung et al, 1998;Marigo and Tabin, 1996;Riddle et al, 1993;St-Jacques et al, 1998).…”

“…Both smoothened and patched are putative transmembrane proteins, either of which could potentially act as the hedgehog receptor. It was not until in vitro studies were undertaken using vertebrate patched and smoothened proteins that patched was shown to bind hedgehog directly and hence act as the hedgehog receptor (Stone et al, 1996;Marigo et al, 1996).…”

“…This was determined following the ®nding that patched also interacts with smoothened, and that hedgehog, smoothened and patched can be immunoprecipitated in a single complex (Stone et al, 1996). Smoothened, which is structurally similar to the family of serpentine G-protein coupled receptors, is responsible for triggering intracellular signalling and the subsequent activation of target genes.…”