Src-mediated tyrosine phosphorylation of dynamin is required for beta(2)-adrenergic receptor internalization and mitogen-activated protein kinase signaling

Some forms of G protein-coupled receptor signaling, such as activation of m itogen-activated protein kinase cascade as well as resensitization of recep tors after hormone-induced desensitization, require receptor internalizatio n via dynamin-dependent clathrin-coated pit mechanisms. Here we demonstrate that activation of beta(2)-adrenergic receptors (beta(2)-ARs) leads to c-S rc-mediated tyrosine phosphorylation of dynamin, which is required for rece ptor internalization. Two tyrosine residues, Tyr(231) and Tyr(597), are ide ntified as the major phosphorylation sites. Mutation of these residues to p henylalanine dramatically decreases the c-Src-mediated phosphorylation of d ynamin following beta(2)-AR stimulation. Moreover, expression of Y231F/Y597 F dynamin inhibits beta(2)-AR internalization and the isoproterenol-stimula ted mitogen-activated protein kinase activation. Thus, agonist-induced, c-S rc-mediated tyrosine phosphorylation of dynamin is essential for its functi on in clathrin mediated G protein-coupled receptor endocytosis.