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

Jing Wang; Zhengyang An; Zhongsheng Wu; Wei Zhou; Pengyu Sun; Piyu Wu; Song Dang; Rui Xue; Xue Bai; Yongtao Du; Rongmei Chen; Wenxu Wang; Pei Huang; Sin Man Lam; Youwei Ai; Suling Liu; Guanghou Shui; Zhe Zhang; Zheng Liu; Jianyong Huang; Xiaohong Fang; Kangmin He

doi:10.1016/j.molcel.2024.10.010

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

Mol Cell. 2024 Oct 29:S1097-2765(24)00833-5. doi: 10.1016/j.molcel.2024.10.010. Online ahead of print.

Authors

Jing Wang¹, Zhengyang An¹, Zhongsheng Wu¹, Wei Zhou², Pengyu Sun¹, Piyu Wu³, Song Dang⁴, Rui Xue⁵, Xue Bai⁶, Yongtao Du¹, Rongmei Chen¹, Wenxu Wang³, Pei Huang⁷, Sin Man Lam⁸, Youwei Ai⁴, Suling Liu⁹, Guanghou Shui¹, Zhe Zhang¹⁰, Zheng Liu³, Jianyong Huang⁵, Xiaohong Fang¹¹, Kangmin He¹²

Affiliations

¹ 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.
² Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China.
³ The Institute for Advanced Studies, Wuhan University, Wuhan 430072, China.
⁴ State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
⁵ Department of Mechanics and Engineering Science, College of Engineering, Peking University, Beijing 100871, China.
⁶ State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University, Beijing 100871, China.
⁷ School of Life Sciences, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China.
⁸ State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China; Lipidall Technologies Company Limited, Changzhou, Jiangsu 213000, China.
⁹ Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences, State Key Laboratory of Genetic Engineering, Fudan University, Shanghai 200032, China.
¹⁰ State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University, Beijing 100871, China; Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China.
¹¹ Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China. Electronic address: [email protected].
¹² 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. Electronic address: [email protected].

PMID: 39488211
DOI: 10.1016/j.molcel.2024.10.010

Abstract

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)P₃-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)P₃ around FAs. As the effector protein of PI(3,4,5)P₃, AKT1 molecules are dynamically recruited around FAs for activation. The spatial recruitment/activation of the PI3K-PI(3,4,5)P₃-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)P₃-AKT signaling.

Keywords: AKT; FAK; PI(3,4,5)P(3); class I PI3K; focal adhesion; lipid signaling; single-molecule imaging.