Regulation and function of the proto-oncogene Akt

许多细胞外信号刺激磷脂酰肌醇3-激酶，进而激活Rac1 GTPase、蛋白激酶Akt和Akt T308上游激酶PDK1。活跃的Rac1刺激一系列事件，包括PAK家族激酶亚群的底物磷酸化。Rac1、PDK1和Akt的联合作用对细胞迁移、生长、存活、代谢和肿瘤发生至关重要。在这里，我们发现Rac1刺激PAK1的第二个不依赖激酶的作用。PAK1激酶结构域作为一个支架，促进PDK1刺激Akt，并帮助Akt募集到膜上。PAK不同程度地激活Akt亚群。这些发现揭示了PAK的支架功能调节PDK1-Akt通路的效率、定位和特异性。

Many extracellular signals stimulate phosphatidylinositol 3-kinase, which in turn activates the Rac1 GTPase, the protein kinase Akt and the Akt T308 upstream kinase, PDK1. Active Rac1 stimulates a number of events, including substrate phosphorylation by a subgroup of the PAK family of kinases. The combined effects of Rac1, PDK1 and Akt are critical for cell migration, growth, survival, metabolism and tumorigenesis. Here we show that Rac1 stimulates a second, kinase-independent role of PAK1. The PAK1 kinase domain serves as a scaffold to facilitate Akt stimulation by PDK1 and to aid recruitment of Akt to the membrane. PAK differentially activates sub-populations of Akt. These findings reveal scaffolding functions of PAK that regulate the efficiency, localization and specificity of the PDK1-Akt pathway.