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EMBO J. 2006 Oct 18;25(20):4752-62. Epub 2006 Sep 28.

Mdm2 is involved in the ubiquitination and degradation of G-protein-coupled receptor kinase 2.

Author information

1
Departamento de Biología Molecular and Centro de Biología Molecular 'Severo Ochoa', Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain.

Abstract

G-protein-coupled receptor kinase 2 (GRK2) is a central regulator of G-protein-coupled receptor signaling. We report that Mdm2, an E3-ubiquitin ligase involved in the control of cell growth and apoptosis, plays a key role in GRK2 degradation. Mdm2 and GRK2 association is enhanced by beta(2)-adrenergic receptor stimulation and beta-arrestin. Increased Mdm2 expression accelerates GRK2 proteolysis and promotes kinase ubiquitination at defined residues, whereas GRK2 turnover is markedly impaired in Mdm2-deficient cells. Moreover, we find that activation of the PI3K/Akt pathway by insulin-like growth factor-1 alters Mdm2-mediated GRK2 degradation, leading to enhanced GRK2 stability and increased kinase levels. These data put forward a novel mechanism for controlling GRK2 expression in physiological and pathological conditions.

PMID:
17006543
PMCID:
PMC1618114
DOI:
10.1038/sj.emboj.7601351
[Indexed for MEDLINE]
Free PMC Article

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