Mdm2 is involved in the ubiquitination and degradation of G-protein-coupled receptor kinase 2.
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.
Mesh Terms:
Apoptosis, Arrestins, Cell Line, G-Protein-Coupled Receptor Kinase 2, Gene Expression Regulation, Enzymologic, Humans, Insulin-Like Growth Factor I, Oncogene Protein v-akt, Protein Processing, Post-Translational, Proto-Oncogene Proteins c-mdm2, Signal Transduction, Ubiquitin, Ubiquitin-Protein Ligases, beta-Adrenergic Receptor Kinases
Apoptosis, Arrestins, Cell Line, G-Protein-Coupled Receptor Kinase 2, Gene Expression Regulation, Enzymologic, Humans, Insulin-Like Growth Factor I, Oncogene Protein v-akt, Protein Processing, Post-Translational, Proto-Oncogene Proteins c-mdm2, Signal Transduction, Ubiquitin, Ubiquitin-Protein Ligases, beta-Adrenergic Receptor Kinases
EMBO J.
Date: Oct. 18, 2006
PubMed ID: 17006543
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