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J. Biol. Chem., Vol. 279, Issue 8, 7064-7071, February 20, 2004

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The Kinesin-related Protein Costal2 Associates with Membranes in a Hedgehog-sensitive, Smoothened-independent Manner^*

Melanie A. Stegman, John A. Goetz, Manuel Ascano, Jr.¶, Stacey K. Ogden, Kent E. Nybakken||**, and David J. Robbins

From the Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, New Hampshire 03755-3835, the Graduate Program, Department of Molecular Genetics, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, and the ^||G. W. Hooper Foundation and Department of Microbiology and Immunology, University of California, San Francisco, California 94143

In Drosophila, Hedgehog (Hh) signal transduction has been shown to require a multiprotein complex (Hedgehog signaling complex (HSC)), which includes the Kinesin-related protein Costal2 (Cos2), the serine/threonine protein kinase Fused (Fu), and the transcription factor Cubitus interruptus (Ci). We present evidence that a biologically relevant fraction of the HSC is found in association with cellular membranes. We demonstrate that Cos2 is capable of tethering an exogenous protein to vesicular membranes and that Cos2 association with membranes is Hh-sensitive. In addition, we demonstrate that Cos2 associates with membranes in cells that lack the transmembrane protein Smoothened (Smo) through a domain of Cos2 distinct from its recently characterized Smo binding domain. We suggest that an Hh-regulated membrane binding activity of Cos2 is part of the mechanism by which Cos2 contributes to Hh signaling. We propose a model in which there are two distinct HSCs with discrete subcellular localizations and activities: one is endosome-associated and facilitates production of a repressor form of Ci (HSC-R), and one is Smo-associated and promotes Ci activation (HSC-A). In response to Hh and through interaction with Cos2, Smo mediates both inhibition of the endosome-associated HSC-R and activation of HSC-A at the plasma membrane.

Received for publication, October 28, 2003 , and in revised form, November 25, 2003.

^* This work was supported by National Institutes of Health Grant CA82628 (to D. J. R.) and National Institutes of Health Training Grant 5-T32 ES07250 (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.

^¶ An Albert J. Ryan Fellow.

^** Present address: Dept. of Genetics, Howard Hughes Medical Inst., Harvard Medical School, 200 Longwood Ave., Boston, MA 02115.

Recipient of a Burroughs Wellcome Fund Career Award in the Biomedical Sciences. To whom correspondence should be addressed: Dept. of Pharmacology and Toxicology, Dartmouth Medical School, 7650 Remsen Hall, Hanover, NH 03755-3835. Tel.: 603-650-1716; Fax: 603-650-1129; E-mail: david.j.robbins{at}dartmouth.edu.

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