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.