An epidermal growth factor receptor/Gab1 signaling pathway is required for activation of phosphoinositide 3-kinase by lysophosphatidic acid
An epidermal growth factor receptor/Gab1 signaling pathway is required for activation of phosphoinositide 3-kinase by lysophosphatidic acid
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DOI：
10.1074/jbc.274.46.32835
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发表时间：
1999-11-12
影响因子：
4.8
通讯作者：
Chap, H
中科院分区：
文献类型：
--
作者：
Laffargue, M;Raynal, P;Chap, H
磷酸肌醇3-激酶（PI 3 K）已被证明在G蛋白诱导的信号传导中起重要作用，甚至在非髓细胞中，其中已知很少有G蛋白偶联受体的激动剂激活PI 3 K。我们已经鉴定了粘附细胞系，其中溶血磷脂酸（LPA）强烈且快速地激活PI 3 K脂质产物的积累。该过程不受G β γ-响应性PI 3 K p110 γ的激酶死亡突变体表达的影响。相反，它被染料木黄酮或p85的显性负突变体的表达抑制，并通过过度表达野生型p110 α或β而不是γ而增强。通过使用表皮生长因子受体（EGFR）的特异性化学抑制剂和显性负突变体的表达，我们观察到p85/p110 PI 3 Ks的募集通过LPA对EGFR的反式激活和LPA刺激后与p85相关的对接蛋白Gab 1的下游动员而发生。最后，我们表明，LPA不能激活PI 3 K的细胞系缺乏EGFR/Gab 1途径，包括细胞的PDGF受体的反式激活。总之，这些结果表明LPA对PI 3 K的激活是由LPA反式激活EGFR/Gab 1信号通路的能力调节的。
Phosphoinositide 3-kinase (PI3K) has been shown to play an essential role in G protein-induced signaling even in non-myeloid cells where few agonists of G protein-coupled receptors are known to activate PI3K. We have identified adherent cell lines where lysophosphatidic acid (LPA) strongly and rapidly activates the accumulation of PI3K lipid products. The process is not modified by expression of a kinase-dead mutant of the G beta gamma-responsive PI3K p110 gamma. In contrast, it is inhibited by genistein or expression of a dominant negative mutant of p85 and potentiated by overexpressing wild-type p110 alpha or -beta but not -gamma. By using a specific chemical inhibitor of the epidermal growth factor receptor (EGFR) and expression of a dominant negative mutant, we have observed that recruitment of p85/p110 PI3Ks occurs through transactivation of the EGFR by LPA and downstream mobilization of the docking protein Gab1 that associates with p85 upon LPA stimulation. Finally, we show that LPA cannot activate PI3K in cell lines lacking the EGFR/Gab1 pathway, including cells that transactivate the PDGF receptor. Altogether, these results demonstrate that activation of PI3K by LPA is conditioned by the ability of LPA to transactivate an EGFR/Gab1 signaling pathway.