Essential role for G protein-coupled receptor endocytosis in the activation of mitogen-activated protein kinase
Essential role for G protein-coupled receptor endocytosis in the activation of mitogen-activated protein kinase
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DOI：
10.1074/jbc.273.2.685
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发表时间：
1998-01-09
影响因子：
4.8
通讯作者：
Lefkowitz, RJ
中科院分区：
文献类型：
--
作者：
Daaka, Y;Luttrell, LM;Lefkowitz, RJ
G蛋白偶联受体（GPCR）信号转导的经典范例涉及GPCR与异源三聚体G蛋白在质膜上的激动剂依赖性相互作用以及随后通过膜定位效应物产生可溶性第二信使或离子电流。GPCR信号的终止遵循G蛋白偶联受体激酶（GRK）和β-抑制蛋白介导的受体解偶联和内化。在此我们发现，这些范例不足以解释GPCR介导的、Ras依赖的有丝分裂原活化蛋白（MAP）激酶Erk 1和Erk-2的激活。在表达β-抑制蛋白或发动蛋白显性抑制突变体的HEK 293细胞中，β（2）-肾上腺素能受体介导的MAP激酶激活被抑制。受体内化抑制剂特异性阻断Raf-mediated MEK激活。GPCR介导的MAP激酶途径活化中的质膜界定步骤，如Pas对Shc和Raf激酶的酪氨酸磷酸化活化，不受受体内化抑制剂的影响。因此，GRKs和β-抑制蛋白，其解偶联GPCR并靶向它们用于内化，在GPCR介导的MAP激酶信号级联中作为必需元件起作用。
The classical paradigm for G protein-coupled receptor (GPCR) signal transduction involves the agonist dependent interaction of GPCRs with heterotrimeric G proteins at the plasma membrane and the subsequent generation, by membrane-localized effecters, of soluble second messengers or ion currents, Termination of GPCR signals follows G protein-coupled receptor kinase (GRK)- and beta-arrestin-mediated receptor uncoupling and internalization. Here we show that these paradigms are inadequate to account for GPCR-mediated, Ras-dependent activation of the mitogen-activated protein (MAP) kinases Erk1 and -2, In HEK293 cells expressing dominant suppressor mutants of beta-arrestin or dynamin, beta(2)-adrenergic receptor-mediated activation of MAP kinase is inhibited, The inhibitors of receptor internalization specifically blocked Raf-mediated activation of MEK. Plasma membrane-delimited steps in the GPCR-mediated activation of the MAP kinase pathway, such as tyrosine phosphorylation of Shc and Raf kinase activation by Pas, are unaffected by inhibitors of receptor internalization. Thus, GRKs and beta-arrestins, which uncouple GPCRs and target them for internalization, function as essential elements in the GPCR-mediated MAP kinase signaling cascade.