Smoothened signal transduction is promoted by G protein-coupled receptor kinase 2.
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 articleSubject
AnimalsArrestins
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
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https://hdl.handle.net/10161/7792Published Version (Please cite this version)
10.1128/MCB.00546-06Publication 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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Show full item recordScholars@Duke
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.
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
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