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

SUMMARY The class I PI3K-AKT signaling pathway is the master regulator of cell survival, growth, and proliferation, and among the most frequently mutated pathways in cancer. However, where and how the PI3K-AKT signaling is spatially activated and organized in mammalian cells remain poorly understood. Here, we identified focal adhesions (FAs) as the subcellular signaling hubs organizing the activation of PI3K-PI(3,4,5)P 3 -AKT signaling in mammalian cells. We found that class IA PI3Ks are preferentially and dynamically recruited to FAs for activation, resulting in localized production of the critical signaling lipid PI(3,4,5)P 3 around FAs. As the effector protein of PI(3,4,5)P 3 , AKT molecules are dynamically recruited around FAs for activation. Mechanistically, the spatial recruitment/activation of PI3K-PI(3,4,5)P 3 -AKT cascade are 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)P 3 -AKT signaling.