Falasca M, Logan S K, Lehto V P, Baccante G, Lemmon M A, Schlessinger J
Department of Pharmacology, NYU Medical Center, New York 10016, USA.
EMBO J. 1998 Jan 15;17(2):414-22. doi: 10.1093/emboj/17.2.414.
Signaling via growth factor receptors frequently results in the concomitant activation of phospholipase C gamma (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)P3], 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)P3 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.
通过生长因子受体发出的信号常常会导致磷脂酶Cγ（PLCγ）和磷脂酰肌醇（PI）3激酶的同时激活。虽然PLCγ的酪氨酸磷酸化对其激活是必需的这一点已得到充分证实，但我们在此表明，PLCγ还受到PI 3激酶脂质产物的调控。我们证明，PLCγ的普列克底物蛋白同源（PH）结构域与磷脂酰肌醇3,4,5 - 三磷酸[PdtIns(3,4,5)P3]结合，并在生长因子刺激下靶向细胞膜，而这个不结合PdtIns(3,4,5)P3的PH结构域突变体则不会靶向细胞膜。与这些观察结果一致，PI 3激酶的激活会导致PLCγ的PH结构域介导的细胞膜靶向和PLCγ的激活。相比之下，通过过表达显性负性突变体抑制PI 3激酶，或通过过表达PLCγ的PH结构域阻止PLCγ的细胞膜靶向，都会阻止生长因子诱导的PLCγ激活。这些实验揭示了参与磷酸肌醇代谢控制的两种酶之间相互作用和相互调节活性的新机制。
