GRK2 is a member of the G protein-coupled receptor kinase (GRK) family,which serine/threonine phosphorylates and desensitizes agonist-occupied G protein-coupled receptors (GPCR).It has been recently reported that GRK2 is able to serine phophorylate epidermal growth factor receptor (EGFR) in vitro and in vivo,and EGF induces translocation of GRK2 to the plasma membrane and the GRK2-EGFR complex formation.However,whether the function of GRK2 itself can be regulated by EGFR and further effect the GPCR signaling is unclear.Here we demonstrated that EGF stimulation could induce the tyrosyl phosphorylation of GRK2,and this required EGFR kinase activity.Mutational analysis suggested that EGFR phosphorylated the same N-terminal tyrosyl residues as c-Src,whereas we found that Src contributed little in EGF induced GRK2 phosphorylation.The peptide encoding the catalytic domain of GRK2,which we demonstrated is responsible for the interaction of GRK2 with EGFR,greatly inhibited EGF-induced tyrosyl phosphorylation of GRK2.It suggests that activated EGFR first recruits GRK2 by binding its catalytic domain and then tyrosyl phosphorylates the N-terminal tyrosine residues of GRK2.Thus we conclude that the activated EGFR recruits GRK2,and then phosphorylates and activates GRK2 on the membrane.Our study may present a novel mechanism for regulation of the GPCR signaling by the receptor tyrosyl kinase.