Direct regulation of the Akt proto-oncogene product by phosphatidylinositol-3,4-bisphosphate
Direct regulation of the Akt proto-oncogene product by phosphatidylinositol-3,4-bisphosphate
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DOI：
10.1126/science.275.5300.665
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发表时间：
1997-01-31
期刊：
影响因子：
56.9
通讯作者：
Toker, A
中科院分区：
文献类型：
--
作者：
Franke, TF;Kaplan, DR;Toker, A
研究了磷脂酰肌醇3-激酶（PI 3-kinase）脂质产物对丝氨酸-苏氨酸激酶Akt的调节作用。Akt活性被发现与体内磷脂酰肌醇-3，4-二磷酸（PtdIns-3，4-P-2）的量相关，并且合成的PtdIns-3，4-P-2在体外和体内均激活Akt。PtdIns-3，4-P-2的结合发生在Akt普列克底物蛋白同源（PH）结构域内，并促进Akt的二聚化。在PH结构域中突变的Akt在体内不被PI 3-激酶或在体外不被PtdIns-3，4-P-2激活，并且其与PtdIns-3，4-P-2的结合受损。对与其他磷酸肌醇结合的检查显示，它们与Akt PH结构域结合的亲和力比PtdIns-3，4-P-2低得多，并且不能增加Akt活性。因此，Akt显然受到PtdIns-3，4-P-2与Akt PH结构域的直接相互作用的调节。
The regulation of the serine-threonine kinase Akt by lipid products of phosphoinositide 3-kinase (PI 3-kinase) was investigated. Akt activity was found to correlate with the amount of phosphatidylinositol-3,4-bisphosphate (PtdIns-3,4-P-2) in vivo, and synthetic PtdIns-3,4-P-2 activated Akt both in vitro and in vivo. Binding of PtdIns-3,4-P-2 occurred within the Akt pleckstrin homology (PH) domain and facilitated dimerization of Akt. Akt mutated in the PH domain was not activated by PI 3-kinase in vivo or by PtdIns-3,4-P-2 in vitro, and it was impaired in binding to PtdIns-3,4-P-2. Examination of the binding to other phosphoinositides revealed that they bound to the Akt PH domain with much lower affinity than did PtdIns-3,4-P-2 and failed to increase Akt activity. Thus, Akt is apparently regulated by the direct interaction of PtdIns-3,4-P-2 with the Akt PH domain.