Signal characteristics of G protein-transactivated EGF receptor
Signal characteristics of G protein-transactivated EGF receptor
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DOI：
10.1093/emboj/16.23.7032
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发表时间：
1997-12-01
期刊：
影响因子：
11.4
通讯作者：
Ullrich, A
中科院分区：
文献类型：
--
作者：
Daub, H;Wallasch, C;Ullrich, A
表皮生长因子受体（EGFR）酪氨酸激酶最近被鉴定为在大鼠-1成纤维细胞中响应于G蛋白偶联受体（GPCR）激动剂而提供与促分裂原活化蛋白激酶（MAPK）的连接。这种串扰途径也在其他细胞类型中建立，例如HaCaT角质形成细胞、原代小鼠星形胶质细胞和COS-7细胞。G（q）或G（i）偶联受体在COS-7细胞中的瞬时表达允许GPCR激动剂诱导的EGFR反式激活，以及溶血磷脂酸（LPA）产生的信号涉及对接蛋白Gab 1，选择性抑制EGFR功能后，通过G（q）-和G（i）-偶联受体的SHC酪氨酸磷酸化和MAPK刺激的增加强烈降低。在用GPCR激动剂和低剂量EGF处理后，磷酸肌醇3-激酶的抑制不影响GPCR诱导的EGFR酪氨酸磷酸化的刺激，但抑制MAPK刺激。此外，Src酪氨酸激酶抑制剂PP 1强烈干扰LPA和EGF诱导的EGFR下游的酪氨酸磷酸化和MAPK活化，我们的研究结果证明了EGFR功能在通过G（q）和G（i）偶联受体的信号传导中的重要作用，并为EGFR下游信号传递提供了新的见解，以有效激活Ras/MAPK通路。
The epidermal growth factor receptor (EGFR) tyrosine kinase recently was identified as providing a link to mitogen-activated protein kinase (MAPK) in response to G protein-coupled receptor (GPCR) agonists in Rat-1 fibroblasts. This cross-talk pathway is also established in other cell types such as HaCaT keratinocytes, primary mouse astrocytes and COS-7 cells, Transient expression of either G(q)- or G(i)-coupled receptors in COS-7 cells allowed GPCR agonist-induced EGFR transactivation, and lysophosphatidic acid (LPA)-generated signals involved the docking protein Gab1, The increase in SHC tyrosine phosphorylation and MAPK stimulation through both G(q)- and G(i)-coupled receptors was reduced strongly upon selective inhibition of EGFR function. Inhibition of phosphoinositide 3-kinase did not affect GPCR-induced stimulation of EGFR tyrosine phosphorylation, but inhibited MAPK stimulation, upon treatment with both GPCR agonists and low doses of EGF Furthermore, the Src tyrosine kinase inhibitor PP1 strongly interfered with LPA- and EGF-induced tyrosine phosphorylation and MAPK activation downstream of EGFR, Our results demonstrate an essential role for EGFR function in signaling through both G(q)- and G(i)-coupled receptors and provide novel insights into signal transmission downstream of EGFR for efficient activation of the Ras/MAPK pathway.