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Published Online May 22, 2008
Science DOI: 10.1126/science.1157983

Reports

Submitted on March 18, 2008
Accepted on May 7, 2008

{beta}-Arrestin–Mediated Localization of Smoothened to the Primary Cilium

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

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

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

{beta}-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. {beta}-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 demonstrate that {beta}-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 {beta}-arrestin siRNA. {beta}-arrestin 1 or {beta}-arrestin 2 depletion prevented localization of Smo to primary cilia and Smo-dependent activation of Gli. These results support roles for {beta}-arrestins in mediating the intracellular transport of a 7TMR to its obligate subcellular location for signaling.


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