Smoothened Regulates Activator and Repressor Functions of Hedgehog Signaling via Two Distinct Mechanisms^*

Stacey K. Ogden, David J. Casso, Manuel Ascano, Jr.^¶, Mark M. Yore, Thomas B. Kornberg, , and David J. Robbins¹

Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, New Hampshire 03755, the Department of Biochemistry and Biophysics, University of California, San Francisco, California 94143, and the ^¶Department of Molecular Genetics Graduate Program, University of Cincinnati Medical Center, Cincinnati, Ohio 45267

Abstract: The secreted protein Hedgehog (Hh) plays an important role in metazoan development and as a survival factor for many human tumors. In both cases, Hh signaling proceeds through the activation of the seven-transmembrane protein Smoothened (Smo), which is thought to convert the Gli family of transcription factors from transcriptional repressors to transcriptional activators. Here, we provide evidence that Smo signals to the Hh signaling complex, which consists of the kinesin-related protein Costal2 (Cos2), the protein kinase Fused (Fu), and the Drosophila Gli homolog cubitus interruptus (Ci), in two distinct manners. We show that many of the commonly observed molecular events following Hh signaling are not transmitted in a linear fashion but instead are activated through two signals that bifurcate at Smo to independently affect activator and repressor pools of Ci.

Received for publication September 15, 2005. Revision received December 21, 2005.

^* This work was supported by National Institutes of Health Grants CA82628 (to D. J. R.) and T32-ES07250-14 (to S. K. O. and M. A.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Pharmacology and Toxicology, Dartmouth Medical School, HB 7650 Remsen, Hanover, NH, 03755-7650. Tel.: 603-650-1716; Fax: 603-650-1129; E-mail: David.J.Robbins{at}dartmouth.edu.

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