Src-mediated tyrosine phosphorylation of dynamin is required for β2-adrenergic receptor internalization and mitogen-activated protein kinase signaling
Src-mediated tyrosine phosphorylation of dynamin is required for β2-adrenergic receptor internalization and mitogen-activated protein kinase signaling
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DOI：
10.1074/jbc.274.3.1185
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发表时间：
1999-01-15
影响因子：
4.8
通讯作者：
Daaka, Y
中科院分区：
文献类型：
--
作者：
Ahn, S;Maudsley, S;Daaka, Y
某些形式的G蛋白偶联受体信号传导，如丝裂原活化蛋白激酶级联的激活以及受体在细胞毒性诱导的脱敏后的再敏化，需要通过动力蛋白依赖的网格蛋白包被的小凹机制的受体内化。在这里，我们证明了β（2）-肾上腺素能受体（β（2）-AR）的激活导致c-Src介导的发动蛋白酪氨酸磷酸化，这是受体内化所必需的。两个酪氨酸残基Tyr（231）和Tyr（597）被鉴定为主要的磷酸化位点。这些残基突变为苯丙氨酸显著降低了β 2-AR刺激后c-Src介导的发动蛋白磷酸化。此外，Y231 F/Y 597 F发动蛋白的表达抑制β（2）-AR内化和异丙肾上腺素刺激的丝裂原活化蛋白激酶活化。因此，激动剂诱导的，c-Src介导的酪氨酸磷酸化的发动蛋白是必不可少的网格蛋白介导的G蛋白偶联受体内吞作用的功能。
Some forms of G protein-coupled receptor signaling, such as activation of mitogen-activated protein kinase cascade as well as resensitization of receptors after hormone-induced desensitization, require receptor internalization via dynamin-dependent clathrin-coated pit mechanisms. Here we demonstrate that activation of beta(2)-adrenergic receptors (beta(2)-ARs) leads to c-Src-mediated tyrosine phosphorylation of dynamin, which is required for receptor internalization. Two tyrosine residues, Tyr(231) and Tyr(597), are identified as the major phosphorylation sites. Mutation of these residues to phenylalanine dramatically decreases the c-Src-mediated phosphorylation of dynamin following beta(2)-AR stimulation. Moreover, expression of Y231F/Y597F dynamin inhibits beta(2)-AR internalization and the isoproterenol-stimulated mitogen-activated protein kinase activation. Thus, agonist-induced, c-Src-mediated tyrosine phosphorylation of dynamin is essential for its function in clathrin mediated G protein-coupled receptor endocytosis.