G-protein-coupled receptor kinase 5 phosphorylates p53 and inhibits DNA damage-induced apoptosis.

G-protein-coupled receptor kinases (GRKs) are an important family of Ser/Thr kinases that specifically phosphorylate and desensitize the activated receptor in response to environmental stimulation. Here we identify p53, a key tumor suppressor, as a novel GRK substrate in vivo, revealing a previously unknown function of GRKs in regulation of genome stability. Knockdown GRK5 in osteosarcoma cells inhibits DNA damage-induced apoptosis via a p53-mediated mechanism. Furthermore, GRK5, but not GRK2 or GRK6, phosphorylates p53 at Thr-55, which promotes the degradation of p53, leading to inhibition of p53-dependent apoptotic response to genotoxic damage. Consistently, the increase of p53 and irradiation-induced apoptosis were observed in GRK5-deficient mice. These results demonstrate GRK5 as a novel kinase of p53, as well as a negative regulator of p53-mediated signal transduction.