蛋白激酶B
PI3K/AKT/mTOR通路
细胞生物学
PTEN公司
磷酸化
核质
生物
磷脂酰肌醇
AKT1型
DNA损伤
信号转导
化学
生物化学
核心
DNA
核仁
作者
Mo Chen,Sungyeol Choi,Tianmu Wen,Changliang Chen,Narendra Thapa,Jeong Hyo Lee,Vincent L. Cryns,Richard A. Anderson
标识
DOI:10.1038/s41556-022-00949-1
摘要
The tumour suppressor p53 and PI3K-AKT pathways have fundamental roles in the regulation of cell growth and apoptosis, and are frequently mutated in cancer. Here, we show that genotoxic stress induces nuclear AKT activation through a p53-dependent mechanism that is distinct from the canonical membrane-localized PI3K-AKT pathway. Following genotoxic stress, a nuclear PI3K binds p53 in the non-membranous nucleoplasm to generate a complex of p53 and phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3), which recruits AKT, PDK1 and mTORC2 to activate AKT and phosphorylate FOXO proteins, thereby inhibiting DNA damage-induced apoptosis. Wild-type p53 activates nuclear AKT in an on/off fashion following stress, whereas mutant p53 dose-dependently stimulates high basal AKT activity. The p53-PtdIns(3,4,5)P3 complex is dephosphorylated to p53-phosphatidylinositol 4,5-bisphosphate by PTEN to inhibit AKT activation. The nuclear p53-phosphoinositide signalosome is distinct from the canonical membrane-localized pathway and insensitive to PI3K inhibitors currently in the clinic, which underscores its therapeutic relevance.
科研通智能强力驱动
Strongly Powered by AbleSci AI