Transducing the Hedgehog Signal

ates Ptc from Smo (Figure 1B) is also generally enter-Daniel Kalderon* tained (Chen and Struhl, 1996) because it is countered Department of Biological Sciences only by a single observation of Ptc-mediated binding of Columbia University Hh to Smo in tissue culture cells that expressed high New York, New York 10027 levels of both vertebrate Ptc and Smo (Stone et al., 1996). Some new data support the idea that active Smo protein is not in a complex with Ptc following Hh stimula-Members of the Hedgehog (Hh) family of secreted sig-tion (Figure 1B) and can even be interpreted to suggest naling molecules direct an enormous variety of develop-that Ptc can repress Smo activity without directly con-mental events in vertebrates and in Drosophila. To fulfill tacting Smo (Figure 1C). The first new observation is these roles, both the distribution of Hh molecules and that antibodies directed either to amino-or carboxy-the response of cells to Hh must be tightly regulated. A terminal regions of the Smo protein show dramatically good deal is known about the mechanisms that deter-enhanced staining in cells that either lack Ptc activity mine which cells make Hh in Drosophila, and some fasci-or are exposed to Hh, while smo RNA levels remain nating observations are prompting ideas about how Hh unchanged (Alcedo et al., 2000; Denef et al., 2000; Ing-is transported between cells (McMahon, 2000). Our un-ham et al., 2000). There is, however, some disagreement derstanding of the mechanism of Hh signal transduction about what the newly reported Smo staining pattern is more fragmentary (Ingham, 1998). Patched (Ptc) is the represents. All three groups constructed a smo trans-direct receptor for Hh, but Ptc actively silences intracel-gene with a carboxy-terminal epitope tag and examined lular signaling in the absence of Hh. A second transmem-whether Hh modifies the epitope tag staining pattern brane protein, Smoothened (Smo), can bind to Ptc but posttranscriptionally. In two studies, epitope tag stain-not to Hh, and is essential for signal transduction elicited ing mirrored Smo antibody staining, supporting the hy-either by Hh or by mutational inactivation of Ptc. Thus, pothesis that Hh signaling increases Smo protein levels. Hh binding to Ptc is thought to activate Smo by abrogat-This was the first indication that Smo might accumulate ing an otherwise repressive influence of Ptc (Figure 1). in excess of Ptc, and therefore free of Ptc, during Hh Hh signaling regulates the transcription of several tis-signaling. However, Ingham et al. …