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Science 320 (5884): 1777-1781

Copyright © 2008 by the American Association for the Advancement of Science

β-Arrestin–Mediated Localization of Smoothened to the Primary Cilium

Jeffrey J. Kovacs,1,2 Erin J. Whalen,1 Renshui Liu,1 Kunhong Xiao,3 Jihee Kim,1 Minyong Chen,1 Jiangbo Wang,1 Wei Chen,1 Robert J. Lefkowitz1,2,3,4*

Abstract: β-Arrestins have important roles in the regulation of seven-transmembrane receptors (7TMRs). Smoothened (Smo) is a 7TMR that mediates effects of Hedgehog on developmental processes and whose dysregulation may cause tumorigenesis. β-Arrestins are required for endocytosis of Smo and signaling to Gli transcription factors. In mammalian cells, Smo-dependent signaling requires translocation to primary cilia. We demonstrated that β-arrestins mediate the activity-dependent interaction of Smo and the kinesin motor protein Kif3A. This multimeric complex localized to primary cilia and was disrupted in cells transfected with β-arrestin small interfering RNA. β-Arrestin 1 or β-arrestin 2 depletion prevented the localization of Smo to primary cilia and the Smo-dependent activation of Gli. These results suggest roles for β-arrestins in mediating the intracellular transport of a 7TMR to its obligate subcellular location for signaling.

1 Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
2 Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA.
3 Department of Biochemistry, Duke University Medical Center, Durham, NC 27710, USA.
4 Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710, USA.

* To whom correspondence should be addressed. E-mail: lefko001{at}receptor-biol.duke.edu

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