Skip to main content

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

Publication ,  Journal Article
Meloni, AR; Fralish, GB; Kelly, P; Salahpour, A; Chen, JK; Wechsler-Reya, RJ; Lefkowitz, RJ; Caron, MG
Published in: Mol Cell Biol
October 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 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.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

Mol Cell Biol

DOI

ISSN

0270-7306

Publication Date

October 2006

Volume

26

Issue

20

Start / End Page

7550 / 7560

Location

United States

Related Subject Headings

  • beta-Arrestins
  • beta-Arrestin 2
  • beta-Adrenergic Receptor Kinases
  • Zinc Finger Protein GLI1
  • Trans-Activators
  • Smoothened Receptor
  • Signal Transduction
  • Receptors, G-Protein-Coupled
  • Protein Binding
  • Oncogene Proteins
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Meloni, A. R., Fralish, G. B., Kelly, P., Salahpour, A., Chen, J. K., Wechsler-Reya, R. J., … Caron, M. G. (2006). Smoothened signal transduction is promoted by G protein-coupled receptor kinase 2. Mol Cell Biol, 26(20), 7550–7560. https://doi.org/10.1128/MCB.00546-06
Meloni, Alison R., Gregory B. Fralish, Patrick Kelly, Ali Salahpour, James K. Chen, Robert J. Wechsler-Reya, Robert J. Lefkowitz, and Marc G. Caron. “Smoothened signal transduction is promoted by G protein-coupled receptor kinase 2.Mol Cell Biol 26, no. 20 (October 2006): 7550–60. https://doi.org/10.1128/MCB.00546-06.
Meloni AR, Fralish GB, Kelly P, Salahpour A, Chen JK, Wechsler-Reya RJ, et al. Smoothened signal transduction is promoted by G protein-coupled receptor kinase 2. Mol Cell Biol. 2006 Oct;26(20):7550–60.
Meloni, Alison R., et al. “Smoothened signal transduction is promoted by G protein-coupled receptor kinase 2.Mol Cell Biol, vol. 26, no. 20, Oct. 2006, pp. 7550–60. Pubmed, doi:10.1128/MCB.00546-06.
Meloni AR, Fralish GB, Kelly P, Salahpour A, Chen JK, Wechsler-Reya RJ, Lefkowitz RJ, Caron MG. Smoothened signal transduction is promoted by G protein-coupled receptor kinase 2. Mol Cell Biol. 2006 Oct;26(20):7550–7560.

Published In

Mol Cell Biol

DOI

ISSN

0270-7306

Publication Date

October 2006

Volume

26

Issue

20

Start / End Page

7550 / 7560

Location

United States

Related Subject Headings

  • beta-Arrestins
  • beta-Arrestin 2
  • beta-Adrenergic Receptor Kinases
  • Zinc Finger Protein GLI1
  • Trans-Activators
  • Smoothened Receptor
  • Signal Transduction
  • Receptors, G-Protein-Coupled
  • Protein Binding
  • Oncogene Proteins