HEDGEHOG AND ITS PATCHED-SMOOTHENED RECEPTOR COMPLEX - A NOVEL SIGNALING MECHANISM AT THE CELL-SURFACE

Pattern formation and morphogenesis depend on the careful execution of complex genetic programs, which are conserved in multicellular organi sms. An important signal in some of these programs in Drosophila and v ertebrates is the secreted Hedgehog (Hh) protein, which primarily func tions as an inducer of morphogenetic signals. The Hh signal plays a de cisive role in such critical developmental processes as neurulation an d somite and limb formation, The Hh signalling pathway exhibits a nove l mechanism of signal reception and transduction. In the absence of th e Hh signal, the membrane protein Patched (Ptc) represses the constitu tive signalling activity of a second membrane protein, Smoothened (Smo ), by virtue of its ability to form a Ptc-Smo complex. Hence, mutation s within the ptc gene that result in the failure of Ptc to inhibit Smo lead to constitutive activity of the Hh signalling pathway and to can cer, such as basal cell carcinoma. For activation of Hh-target genes, the N-terminal signalling domain of Hh binds to the Ptc-Smo receptor c omplex to activate two parallel signalling pathways. Furthermore, Hh l imits its own range of action by impeding its diffusion through (i) co valent linkage of its N-terminal signalling moiety to cholesterol, med iated by the cholesterol transferase activity of its C-terminal moiety , and (ii) induction of, and sequestration by, its antagonist, Ptc.