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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}

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S. Wang and Z. Dong (2013)
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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T. C. Archer, S. D. Weeraratne, and S. L. Pomeroy (2012)
J. Clin. Oncol. 30, 2154-2156
   Full Text »    PDF »
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K. E. Ryan and C. Chiang (2012)
J. Biol. Chem. 287, 17905-17913
   Abstract »    Full Text »    PDF »
Disruption of Kif3a in osteoblasts results in defective bone formation and osteopenia.
N. Qiu, Z. Xiao, L. Cao, M. M. Buechel, V. David, E. Roan, and L. D. Quarles (2012)
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   Abstract »    Full Text »    PDF »
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S. Shi, Y.-Z. Deng, J.-S. Zhao, X.-D. Ji, J. Shi, Y.-X. Feng, G. Li, J.-J. Li, D. Zhu, H. P. Koeffler, et al. (2012)
J. Biol. Chem. 287, 7845-7858
   Abstract »    Full Text »    PDF »
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A. E. Douglas, J. A. Heim, F. Shen, L. L. Almada, N. A. Riobo, M. E. Fernandez-Zapico, and D. R. Manning (2011)
J. Biol. Chem. 286, 30714-30722
   Abstract »    Full Text »    PDF »
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T. Evron, M. Philipp, J. Lu, A. R. Meloni, M. Burkhalter, W. Chen, and M. G. Caron (2011)
J. Biol. Chem. 286, 27676-27686
   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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S. S. Francis, J. Sfakianos, B. Lo, and I. Mellman (2011)
J. Cell Biol. 193, 219-233
   Abstract »    Full Text »    PDF »
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A. K. Lovgren, J. J. Kovacs, T. Xie, E. N. Potts, Y. Li, W. M. Foster, J. Liang, E. B. Meltzer, D. Jiang, R. J. Lefkowitz, et al. (2011)
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   Abstract »    Full Text »    PDF »
International Union of Basic and Clinical Pharmacology. LXXX. The Class Frizzled Receptors.
G. Schulte (2010)
Pharmacol. Rev. 62, 632-667
   Abstract »    Full Text »    PDF »
Inositol hexakisphosphate kinase-2 acts as an effector of the vertebrate Hedgehog pathway.
B. Sarmah and S. R. Wente (2010)
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   Abstract »    Full Text »    PDF »
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H. Tukachinsky, L. V. Lopez, and A. Salic (2010)
J. Cell Biol. 191, 415-428
   Abstract »    Full Text »    PDF »
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C. W. Wilson and P.-T. Chuang (2010)
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H. Shankar, A. Michal, R. C. Kern, D. S. Kang, V. V. Gurevich, and J. L. Benovic (2010)
J. Biol. Chem. 285, 8316-8329
   Abstract »    Full Text »    PDF »
Sonic-hedgehog-mediated proliferation requires the localization of PKA to the cilium base.
M. Barzi, J. Berenguer, A. Menendez, R. Alvarez-Rodriguez, and S. Pons (2010)
J. Cell Sci. 123, 62-69
   Abstract »    Full Text »    PDF »
Opposite-polarity motors activate one another to trigger cargo transport in live cells.
S. Ally, A. G. Larson, K. Barlan, S. E. Rice, and V. I. Gelfand (2009)
J. Cell Biol. 187, 1071-1082
   Abstract »    Full Text »    PDF »
Lateral transport of Smoothened from the plasma membrane to the membrane of the cilium.
L. Milenkovic, M. P. Scott, and R. Rohatgi (2009)
J. Cell Biol. 187, 365-374
   Abstract »    Full Text »    PDF »
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J. E. Murphy, B. E. Padilla, B. Hasdemir, G. S. Cottrell, and N. W. Bunnett (2009)
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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