beta-arrestin- and c-Src-dependent degradation of G-protein-coupled receptor kinase 2

G-protein-coupled receptor kinase 2 (GRK2) plays a key role in the regulati on of G-protein-coupled receptors (GPCRs). GRK2 expression is altered in se veral pathological conditions, but the molecular mechanisms that modulate G RK2 cellular levels are largely unknown. We recently have described that GR K2 is degraded rapidly by the proteasome pathway. This process is enhanced by GPCR stimulation and is severely impaired in a GRK2 mutant that lacks ki nase activity (GRK2-K220R). In this report, we find that beta -arrestin fun ction and Src-mediated phosphorylation of GRK2 are critically involved in G RK2 proteolysis. Overexpression of beta -arrestin triggers GRK2-K220R degra dation based on its ability to recruit c-Src, since this effect is not obse rved with beta -arrestin mutants that display an impaired c-Src interaction . The presence of an inactive c-Src mutant or of tyrosine kinase inhibitors strongly inhibits co-transfected or endogenous GRK2 turnover, respectively , and a GRK2 mutant with impaired phosphorylation by c-Src shows a markedly retarded degradation. This pathway for the modulation of GRK2 protein stab ility puts forward a new feedback mechanism for regulating GRK2 levels and GPCR signaling.