Mutations in the sterol sensing domain of patched suggest a role for vesicular trafficking in smoothened regulation (vol 11, pg 608, 2001)

The tumor suppressor gene patched (ptc) encodes an similar to 140 kDa polyt opic transmembrane protein [1-3] that binds members of the Hedgehog (Hh) fa mily of signaling proteins [4-6] and regulates the activity of Smoothened ( Smo), a G protein-coupled receptor-like protein essential for Hh signal tra nsduction [7-9]. Ptc contains a sterol-sensing domain (SSD) [10, 11], a mot if found in proteins implicated in the intracellular trafficking of cholest erol [12] and/or other cargoes [13-15]. Cholesterol plays a critical role i n Hedgehog (Hh) signaling by facilitating the regulated secretion and seque stration of the Hh protein [16], to which it is covalently coupled [17]. In addition, cholesterol synthesis inhibitors block the ability of cells to r espond to Hh [18, 19], and this finding points to an additional requirement for the lipid in regulating downstream components of the Hh signaling path way. Although the SSD of Ptc has been linked to both the sequestration of, and the cellular response to Hh [16, 20, 21], definitive evidence for its f unction has so far been lacking. Here we describe the identification and ch aracterization of two missense mutations in the SSD of Drosophila Ptc; stri kingly, while both mutations abolish Smo repression, neither affects the ab ility of Ptc to interact with Hh. We speculate that Ptc may control Smo act ivity by regulating an intracellular trafficking process dependent upon the integrity of the SSD.