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.
Salcedo
Alicia
A
Departamento de Biología Molecular and Centro de Biología Molecular 'Severo Ochoa', Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain.
Mayor
Federico
F
Penela
Petronila
P
D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D019390:Arrestins / Q000378:metabolism / Q000494:pharmacology; D002460:Cell Line; D054769:G-Protein-Coupled Receptor Kinase 2; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism / Q000494:pharmacology; D051058:Oncogene Protein v-akt / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects / Q000235:genetics; D051736:Proto-Oncogene Proteins c-mdm2 / Q000172:deficiency / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D051552:beta-Adrenergic Receptor Kinases / Q000378:metabolism*; D000071557:beta-Arrestins
D019390:Arrestins; D025801:Ubiquitin; D000071557:beta-Arrestins; D007334:Insulin-Like Growth Factor I; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D044767:Ubiquitin-Protein Ligases; D051058:Oncogene Protein v-akt; C496567:GRK2 protein, human; D051552:beta-Adrenergic Receptor Kinases; D054769:G-Protein-Coupled Receptor Kinase 2