Jiang Qiwei, Zhang Xiaomei, Dai Xiaoming, Han Shiyao, Wu Xueji, Wang Lei, Wei Wenyi, Zhang Ning, Xie Wei, Guo Jianping
Department of Gastroenterology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
Institute of Precision Medicine, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
Nat Commun. 2022 Mar 22;13(1):1548. doi: 10.1038/s41467-022-28910-8.
Functioning as a master kinase, 3-phosphoinositide-dependent protein kinase 1 (PDK1) plays a fundamental role in phosphorylating and activating protein kinases A, B and C (AGC) family kinases, including AKT. However, upstream regulation of PDK1 remains largely elusive. Here we report that ribosomal protein S6 kinase beta 1 (S6K1), a member of AGC kinases and downstream target of mechanistic target of rapamycin complex 1 (mTORC1), directly phosphorylates PDK1 at its pleckstrin homology (PH) domain, and impairs PDK1 interaction with and activation of AKT. Mechanistically, S6K1-mediated phosphorylation of PDK1 augments its interaction with 14-3-3 adaptor protein and homo-dimerization, subsequently dissociating PDK1 from phosphatidylinositol 3,4,5 triphosphate (PIP) and retarding its interaction with AKT. Pathologically, tumor patient-associated PDK1 mutations, either attenuating S6K1-mediated PDK1 phosphorylation or impairing PDK1 interaction with 14-3-3, result in elevated AKT kinase activity and oncogenic functions. Taken together, our findings not only unravel a delicate feedback regulation of AKT signaling via S6K1-mediated PDK1 phosphorylation, but also highlight the potential strategy to combat mutant PDK1-driven cancers.
作为一种主激酶，3-磷酸肌醇依赖性蛋白激酶1（PDK1）在磷酸化和激活包括AKT在内的蛋白激酶A、B和C（AGC）家族激酶方面发挥着重要作用。然而，PDK1的上游调控在很大程度上仍然不清楚。在此，我们报道核糖体蛋白S6激酶β1（S6K1），AGC激酶家族的成员以及雷帕霉素复合物1（mTORC1）的下游靶点，直接在其普列克底物蛋白同源（PH）结构域磷酸化PDK1，并损害PDK1与AKT的相互作用及对AKT的激活。机制上，S6K1介导的PDK1磷酸化增强了其与14-3-3衔接蛋白的相互作用和同二聚化，随后使PDK1与磷脂酰肌醇3,4,5-三磷酸（PIP）解离，并阻碍其与AKT的相互作用。病理上，肿瘤患者相关的PDK1突变，要么减弱S6K1介导的PDK1磷酸化，要么损害PDK1与14-3-3的相互作用，导致AKT激酶活性升高和致癌功能。综上所述，我们的发现不仅揭示了通过S6K1介导的PDK1磷酸化对AKT信号通路的精细反馈调节，也突出了对抗突变PDK1驱动癌症的潜在策略。
