Spatial organization of PI3K-PI(3,4,5)P3-AKT signaling by focal adhesions

The class I PI3K-AKT signaling pathway is the master regulator of cell survival, growth, and proliferation, and is among the most frequently mutated pathways in cancer. However, where and how the PI3K-AKT signaling is spatially activated and organized in mammalian cells remains poorly understood. Here, we identified focal adhesions (FAs) as subcellular signaling hubs organizing the activation of PI3K-PI(3,4,5)P3-AKT signaling in human cancer cells containing p110α mutations under basal conditions. We found that class IA PI3Ks are preferentially recruited to FAs for activation, resulting in localized production of PI(3,4,5)P3 around FAs. As the effector protein of PI(3,4,5)P3, AKT molecules are dynamically recruited around FAs for activation. The spatial recruitment/activation of PI3K-PI(3,4,5)P3-AKT cascade is regulated by the activated FAK. Furthermore, combined inhibition of class I PI3K and FAK results in a more potent inhibitory effect on cancer cells. Thus, our results unveil a growth-factor independent, compartmentalized organization mechanism for PI3K-PI(3,4,5)P3-AKT signaling.

PI3K-AKT信号通路作为细胞存活、生长和增殖的主导调控者，在癌症中是最常发生突变的信号通路之一。然而，PI3K-AKT信号在哺乳细胞中的空间激活和组织方式尚不清楚。本研究中，我们鉴定出焦点粘附（FAs）作为亚细胞信号枢纽，在人类癌细胞中组织PI3K-PI(3,4,5)P3-AKT信号激活，这些癌细胞在基础条件下含有p110α突变。我们发现，Ia类PI3Ks优先被招募到FAs以实现激活，从而在FAs周围产生局部的PI(3,4,5)P3。作为PI(3,4,5)P3的效应蛋白，AKT分子在FAs周围动态招募以实现激活。PI3K-PI(3,4,5)P3-AKT级联反应的空间招募/激活受到激活的FAK的调节。此外，I类PI3K和FAK的联合抑制对癌细胞产生了更强的抑制作用。因此，我们的研究结果揭示了PI3K-PI(3,4,5)P3-AKT信号的空间化、独立于生长因子的组织机制。