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Molecular and Cellular Biology, October 2006, p. 7550-7560, Vol. 26, No. 20
0270-7306/06/$08.00+0     doi:10.1128/MCB.00546-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Smoothened Signal Transduction Is Promoted by G Protein-Coupled Receptor Kinase 2{triangledown}

Alison R. Meloni,1 Gregory B. Fralish,1 Patrick Kelly,2 Ali Salahpour,1 James K. Chen,3 Robert J. Wechsler-Reya,2 Robert J. Lefkowitz,4 and Marc G. Caron1*

Department of Cell Biology, Duke University Medical Center, Durham, North Carolina,1 Department of Pharmacology, Duke University Medical Center, Durham, North Carolina,2 Department of Molecular Pharmacology, Stanford University School of Medicine, Stanford, California,3 Departments of Biochemistry and Medicine, Howard Hughes Medical Institute, Duke University Medical Center, Durham, North Carolina4

Received 28 March 2006/ Returned for modification 24 April 2006/ Accepted 2 August 2006

Deregulation of the Sonic hedgehog pathway has been implicated in an increasing number of human cancers. In this pathway, the seven-transmembrane (7TM) signaling protein Smoothened regulates cellular proliferation and differentiation through activation of the transcription factor Gli. The activity of mammalian Smoothened is controlled by three different hedgehog proteins, Indian, Desert, and Sonic hedgehog, through their interaction with the Smoothened inhibitor Patched. However, the mechanisms of signal transduction from Smoothened are poorly understood. We show that a kinase which regulates signaling by many "conventional" 7TM G-protein-coupled receptors, G protein-coupled receptor kinase 2 (GRK2), participates in Smoothened signaling. Expression of GRK2, but not catalytically inactive GRK2, synergizes with active Smoothened to mediate Gli-dependent transcription. Moreover, knockdown of endogenous GRK2 by short hairpin RNA (shRNA) significantly reduces signaling in response to the Smoothened agonist SAG and also inhibits signaling induced by an oncogenic Smoothened mutant, Smo M2. We find that GRK2 promotes the association between active Smoothened and ß-arrestin 2. Indeed, Gli-dependent signaling, mediated by coexpression of Smoothened and GRK2, is diminished by ß-arrestin 2 knockdown with shRNA. Together, these data suggest that GRK2 plays a positive role in Smoothened signaling, at least in part, through the promotion of an association between ß-arrestin 2 and Smoothened.

* Corresponding author. Mailing address: Box 3287, Duke University Medical Center, Durham, NC 27710. Phone: (919) 684-5291. Fax: (919) 681-8641. E-mail: caron002{at}mc.duke.edu.

{triangledown} Published ahead of print on 14 August 2006.

Molecular and Cellular Biology, October 2006, p. 7550-7560, Vol. 26, No. 20
0270-7306/06/$08.00+0     doi:10.1128/MCB.00546-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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