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Smoothened signal transduction is promoted by G protein-coupled receptor kinase 2.

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Date
2006-10
Authors
Meloni, AR
Fralish, GB
Kelly, P
Salahpour, A
Chen, JK
Wechsler Reya, RJ
Lefkowitz, RJ
Caron, MG
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Abstract
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 beta-arrestin 2. Indeed, Gli-dependent signaling, mediated by coexpression of Smoothened and GRK2, is diminished by beta-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 beta-arrestin 2 and Smoothened.
Type
Journal article
Subject
Animals
Arrestins
Cattle
Cell Line
Humans
Mice
Oncogene Proteins
Protein Binding
Receptors, G-Protein-Coupled
Signal Transduction
Smoothened Receptor
Trans-Activators
Zinc Finger Protein GLI1
beta-Adrenergic Receptor Kinases
beta-Arrestin 2
beta-Arrestins
Permalink
https://hdl.handle.net/10161/7792
Published Version (Please cite this version)
10.1128/MCB.00546-06
Publication Info
Meloni, AR; Fralish, GB; Kelly, P; Salahpour, A; Chen, JK; Wechsler Reya, RJ; ... Caron, MG (2006). Smoothened signal transduction is promoted by G protein-coupled receptor kinase 2. Mol Cell Biol, 26(20). pp. 7550-7560. 10.1128/MCB.00546-06. Retrieved from https://hdl.handle.net/10161/7792.
This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.
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Scholars@Duke

Caron

Marc G. Caron

James B. Duke Distinguished Professor of Cell Biology
Studies of the mechanisms of action and regulation of hormones and neurotransmitters at the cellular and molecular levels constitute the main goals our of research activities. G protein-coupled receptors (GPCR) mediate the actions of signaling molecules from unicellular organisms to man. We have used adrenergic and dopamine receptors to characterize the structure/function and regulation mechanisms of these prototypes of G protein-coupled receptors. Another approach has been to characterize
This author no longer has a Scholars@Duke profile, so the information shown here reflects their Duke status at the time this item was deposited.
Lefkowitz

Robert J. Lefkowitz

The Chancellor's Distinguished Professor of Medicine
Dr. Lefkowitz’s memoir, A Funny Thing Happened on the Way to Stockholm, recounts his early career as a cardiologist and his transition to biochemistry, which led to his Nobel Prize win. Robert J. Lefkowitz, M.D. is James B. Duke Professor of Medicine and Professor of Biochemistry and Chemistry at the Duke University Medical Center. He has been an Investigator of the
Alphabetical list of authors with Scholars@Duke profiles.
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