Activation of phospholipase Cγ by PI 3-kinase-induced PH domain-mediated membrane targeting
Activation of phospholipase Cγ by PI 3-kinase-induced PH domain-mediated membrane targeting
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DOI：
10.1093/emboj/17.2.414
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发表时间：
1998-01-15
期刊：
影响因子：
11.4
通讯作者：
Schlessinger, J
中科院分区：
文献类型：
--
作者：
Falasca, M;Logan, SK;Schlessinger, J
通过生长因子受体的信号传导经常导致磷脂酶Cy （PLC γ）和磷脂酰肌醇（PI） 3-激酶的同时激活。虽然已经确定PLC γ的酪氨酸磷酸化是其激活所必需的，但我们在这里表明PLC γ还受到PI 3-激酶的脂质产物的调节。我们证明PLC γ的pleckstrin同源（PH）结构域与磷脂酰肌醇3,4,5-三磷酸结合[pdtin (3,4,5)P-3]，并在响应生长因子刺激时靶向膜。而不结合pdtin (3,4,5)P-3的PH结构域的突变版本不是膜靶向的。与这些观察结果一致，PI 3-激酶的激活导致PLC γ PH域介导的膜靶向和PLC γ激活。相比之下，通过过表达一个显性阴性突变体来抑制PI 3-激酶，或者通过过表达PLC γ PH域来防止PLC γ膜靶向，都可以阻止生长因子诱导的PLC γ激活。这些实验揭示了参与控制磷酸肌苷代谢的两种酶之间相互交流和相互调节活性的新机制。
Signaling via growth factor receptors frequently results in the concomitant activation of phospholipase Cy (PLC gamma) and phosphatidylinositol (PI) 3-kinase. While it is well established that tyrosine phosphorylation of PLC gamma is necessary for its activation, we show here that PLC gamma is regulated additionally by the lipid products of PI 3-kinase, We demonstrate that the pleckstrin homology (PH) domain of PLC gamma binds to phosphatidylinositol 3,4,5-trisphosphate [PdtIns(3,4,5)P-3], and is targeted to the membrane in response to growth factor stimulation, while a mutated version of this PH domain that does not bind PdtIns(3,4,5)P-3 is not membrane targeted. Consistent with these observations, activation of PI 3-kinase causes PLC gamma PH domain-mediated membrane targeting and PLC gamma activation. By contrast, either the inhibition of PI 3-kinase by overexpression of a dominant-negative mutant or the prevention of PLC gamma membrane targeting by overexpression of the PLC gamma PH domain prevents growth factor-induced PLC gamma activation. These experiments reveal a novel mechanism for cross-talk and mutual regulation of activity between two enzymes that participate in the control of phosphoinositide metabolism.