Small GTPases and tyrosine kinases coregulate a molecular switch in the phosphoinositide 3-kinase regulatory subunit
Small GTPases and tyrosine kinases coregulate a molecular switch in the phosphoinositide 3-kinase regulatory subunit
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DOI：
10.1016/s1535-6108(02)00033-8
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发表时间：
2002-03-01
期刊：
影响因子：
50.3
通讯作者：
Tsichlis, PN
中科院分区：
文献类型：
--
作者：
Chan, TO;Rodeck, U;Tsichlis, PN
磷酸肌醇3-激酶（PI 3 K）IA型是催化亚基p110和调节亚基p85的异源二聚体。在这里，我们表明，p85包含一个GTP酶反应域和一个抑制域，它们共同形成一个分子开关，调节PI 3 K。H-Ras和Rac 1通过靶向GTP酶应答结构域激活PI 3 K。然而，这些分子的刺激作用被抑制性结构域阻断，抑制性结构域通过结合酪氨酸磷酸化分子起作用并被酪氨酸磷酸化中和。酪氨酸激酶和小GTP酶对p85分子开关的互补作用导致这两类分子之间的协同作用，从而激活PI 3 K/Akt途径。
Phosphoinositide 3-kinase (PI3K) type IA is a heterodimer of a catalytic subunit, p110, and a regulatory subunit, p85. Here we show that p85 contains a GTPase-responsive domain and an inhibitory domain, which together form a molecular switch that regulates PI3K. H-Ras and Rac1 activate PI3K by targeting the GTPase-responsive domain. The stimulatory effect of these molecules, however, is blocked by the inhibitory domain, which functions by binding to tyrosine-phosphorylated molecules and is neutralized by tyrosine phosphorylation. The complementary effects of tyrosine kinases and small GTPases on the p85 molecular switch result in synergy between these two classes of molecules toward the activation of the PI3K/Akt pathway.