G protein-coupled receptor kinase 2 (GRK2) modulation and cell cycle progression.
Cell cycle progression requires changes in the activity or levels of a variety of key signaling proteins. G protein-coupled receptor kinase 2 (GRK2) plays a central role in G protein-coupled receptor regulation. Recent research is uncovering its involvement in additional cellular functions, but the potential role of GRK2 in the cell cycle has not been addressed. We report that GRK2 protein levels are transiently down-regulated during the G2/M transition by a mechanism involving CDK2-mediated phosphorylation of GRK2 at Serine670, which triggers binding to the prolyl-isomerase Pin1 and subsequent degradation. Prevention of GRK2 phosphorylation at S670 impedes normal GRK2 down-regulation and markedly delays cell cycle progression. Interestingly, we find that endogenous GRK2 down-regulation is prevented on activation of the G2/M checkpoint by doxorubicin and that stabilized GRK2 levels in such conditions inversely correlate with the p53 response and the induction of apoptosis, suggesting that GRK2 participates in the regulatory network controlling cell cycle arrest and survival in such conditions.
Penela
Petronila
P
Departamento de Biología Molecular and Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Universidad Autónoma, 28049 Madrid, Spain. ppenela@cbm.uam.es
Rivas
Verónica
V
Salcedo
Alicia
A
Mayor
Federico
F
D002453:Cell Cycle; D019925:Cyclin A / Q000378:metabolism*; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism*; D015536:Down-Regulation; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D010766:Phosphorylation; D012694:Serine / Q000378:metabolism
D019925:Cyclin A; D012694:Serine; C496567:GRK2 protein, human; D054769:G-Protein-Coupled Receptor Kinase 2; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2