RECEPTOR-TYROSINE-KINASE-MEDIATED AND G-BETA-GAMMA-MEDIATED MAP KINASE ACTIVATION BY A COMMON SIGNALING PATHWAY
RECEPTOR-TYROSINE-KINASE-MEDIATED AND G-BETA-GAMMA-MEDIATED MAP KINASE ACTIVATION BY A COMMON SIGNALING PATHWAY
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DOI：
10.1038/376781a0
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发表时间：
1995-08-31
期刊：
影响因子：
64.8
通讯作者：
LEFKOWITZ, RJ
中科院分区：
文献类型：
--
作者：
VANBIESEN, T;HAWES, BE;LEFKOWITZ, RJ
丝裂原活化蛋白（MAP）激酶介导调节细胞生长的核转录因子的磷酸化和激活(1)。MAP激酶激活可能是由酪氨酸激酶（RTK）受体（具有内在酪氨酸激酶活性）或g蛋白偶联受体（GPCR）的刺激引起的（2-4）。rtk介导的有丝分裂信号涉及酪氨酸磷酸化受体、Shc、Grb2和Sos之间一系列依赖SH2和sh3的蛋白相互作用，导致ras依赖的MAP激酶激活（5-7）。异三聚体G蛋白（G β γ）的β γ亚基也介导ras依赖性MAP激酶激活（8-10），其机制尚不清楚。在这里，我们证明了G(i)偶联受体激活MAP激酶之前，G β γ介导的Shc酪氨酸磷酸化，导致Shc、Grb2和Sos之间的功能关联增加。此外，Shc-Grb2-Sos复合物的破坏阻断了G β γ介导的MAP激酶激活，表明G β γ不通过与Sos的直接相互作用介导MAP激酶激活。这些结果表明，G β γ介导的MAP激酶激活是由酪氨酸磷酸化事件启动的，并通过gpcr和rtk共同的途径进行。
MITOGEN-ACTIVATED protein (MAP) kinases mediate the phosphorylation and activation of nuclear transcription factors that regulate cell growth(1). MAP kinase activation may result from stimulation of either tyrosine-kinase (RTK) receptors, which possess intrinsic tyrosine kinase activity, or G-protein-coupled receptors (GPCR)(2-4). RTK-mediated mitogenic signalling involves a series of SH2- and SH3-dependent protein-protein interactions between tyrosine-phosphorylated receptor, Shc, Grb2 and Sos, resulting in Ras-dependent MAP kinase activation(5-7). The beta gamma subunits of heterotrimeric G proteins (G beta gamma) also mediate Ras-dependent MAP kinase activations(8-10) by an as-yet unknown mechanism. Here we demonstrate that activation of MAP kinase by G(i)-coupled receptors is preceded by the G beta gamma-mediated tyrosine phosphorylation of Shc, leading to an increased functional association between Shc, Grb2 and Sos. Moreover, disruption of the Shc-Grb2-Sos complex blocks G beta gamma-mediated MAP kinase activation, indicating that G beta gamma does not mediate MAP kinase activation by a direct interaction with Sos. These results indicate that G beta gamma-mediated MAP kinase activation is initiated by a tyrosine phosphorylation event and proceeds by a pathway common to both GPCRs and RTKs.