National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA.
J Cell Biol. 2011 Mar 21;192(6):979-92. doi: 10.1083/jcb.201005100. Epub 2011 Mar 14.
Akt activation relies on the binding of Akt to phosphatidylinositol-3,4,5-trisphosphate (PIP(3)) in the membrane. Here, we demonstrate that Akt activation requires not only PIP(3) but also membrane phosphatidylserine (PS). The extent of insulin-like growth factor-induced Akt activation and downstream signaling as well as cell survival under serum starvation conditions positively correlates with plasma membrane PS levels in living cells. PS promotes Akt-PIP(3) binding, participates in PIP(3)-induced Akt interdomain conformational changes for T308 phosphorylation, and causes an open conformation that allows for S473 phosphorylation by mTORC2. PS interacts with specific residues in the pleckstrin homology (PH) and regulatory (RD) domains of Akt. Disruption of PS-Akt interaction by mutation impairs Akt signaling and increases susceptibility to cell death. These data identify a critical function of PS for Akt activation and cell survival, particularly in conditions with limited PIP(3) availability. The novel molecular interaction mechanism for Akt activation suggests potential new targets for controlling Akt-dependent cell survival and proliferation.
Akt 的激活依赖于 Akt 与膜中的磷脂酰肌醇-3,4,5-三磷酸 (PIP(3)) 的结合。在这里，我们证明 Akt 的激活不仅需要 PIP(3)，还需要膜磷脂酰丝氨酸 (PS)。胰岛素样生长因子诱导的 Akt 激活及其下游信号以及在血清饥饿条件下的细胞存活与活细胞中质膜 PS 水平呈正相关。PS 促进 Akt-PIP(3)结合，参与 PIP(3)诱导的 Akt 结构域间构象变化以进行 T308 磷酸化，并导致允许 mTORC2 进行 S473 磷酸化的开放构象。PS 与 Akt 的 Pleckstrin 同源 (PH) 和调节 (RD) 结构域中的特定残基相互作用。通过突变破坏 PS-Akt 相互作用会损害 Akt 信号转导并增加细胞死亡的易感性。这些数据确定了 PS 对于 Akt 激活和细胞存活的关键功能，特别是在 PIP(3) 可用性有限的情况下。Akt 激活的新分子相互作用机制为控制 Akt 依赖性细胞存活和增殖提供了潜在的新靶点。
