State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China.
Mol Cell. 2024 Nov 21;84(22):4401-4418.e9. doi: 10.1016/j.molcel.2024.10.010. Epub 2024 Nov 1.
The class I phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway is a key regulator of cell survival, growth, and proliferation and is among the most frequently mutated pathways in cancer. However, where and how PI3K-AKT signaling is spatially activated and organized in mammalian cells remains poorly understood. Here, we identify focal adhesions (FAs) as subcellular signaling hubs organizing the activation of PI3K-PI(3,4,5)P-AKT signaling in human cancer cells containing p110α mutations under basal conditions. We find that class IA PI3Ks are preferentially recruited to FAs for activation, resulting in localized production of PI(3,4,5)P around FAs. As the effector protein of PI(3,4,5)P, AKT1 molecules are dynamically recruited around FAs for activation. The spatial recruitment/activation of the PI3K-PI(3,4,5)P-AKT cascade is regulated by activated FA kinase (FAK). Furthermore, combined inhibition of p110α 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-AKT signaling.
该级别的磷脂酰肌醇 3-激酶 (PI3K)-AKT 信号通路是细胞存活、生长和增殖的关键调节剂，也是癌症中最常发生突变的途径之一。然而，PI3K-AKT 信号在哺乳动物细胞中的空间激活和组织方式仍知之甚少。在这里，我们确定黏着斑（FA）是细胞内信号枢纽，在含有 p110α 突变的人类癌细胞中，在基础条件下组织 PI3K-PI(3,4,5)P-AKT 信号的激活。我们发现，IA 类 PI3Ks 优先被募集到 FA 以被激活，导致 FA 周围局部产生 PI(3,4,5)P。作为 PI(3,4,5)P 的效应蛋白，AKT1 分子在 FA 周围被动态募集以被激活。PI3K-PI(3,4,5)P-AKT 级联的空间募集/激活受到激活的 FA 激酶（FAK）的调节。此外，联合抑制 p110α 和 FAK 对癌细胞产生更有效的抑制作用。因此，我们的研究结果揭示了一种生长因子非依赖性、分隔组织的 PI3K-PI(3,4,5)P-AKT 信号通路的机制。
