蛋白激酶B
安普克
PI3K/AKT/mTOR通路
磷酸化
癌症研究
AMP活化蛋白激酶
mTORC1型
泛素连接酶
癌变
信号转导
细胞生物学
蛋白激酶A
化学
生物
癌症
泛素
生物化学
基因
遗传学
作者
Fei Han,Chien‐Feng Li,Zhen Cai,Xian Zhang,Guoxiang Jin,Wei Na Zhang,Chuan Xu,Chi-Yun Wang,John Kenneth Morrow,Shuxing Zhang,Dazhi Xu,Guihua Wang,Hui Kuan Lin
标识
DOI:10.1038/s41467-018-07188-9
摘要
PI3K/Akt signaling is activated in cancers and governs tumor initiation and progression, but how Akt is activated under diverse stresses is poorly understood. Here we identify AMPK as an essential regulator for Akt activation by various stresses. Surprisingly, AMPK is also activated by growth factor EGF through Ca2+/Calmodulin-dependent kinase and is essential for EGF-mediated Akt activation and biological functions. AMPK phosphorylates Skp2 at S256 and promotes the integrity and E3 ligase activity of Skp2 SCF complex leading to K63-linked ubiquitination and activation of Akt and subsequent oncogenic processes. Importantly, AMPK-mediated Skp2 S256 phosphorylation promotes breast cancer progression in mouse tumor models, correlates with Akt and AMPK activation in breast cancer patients, and predicts poor survival outcomes. Finally, targeting AMPK-mediated Skp2 S256 phosphorylation sensitizes cells to anti-EGF receptor targeted therapy. Our study sheds light on how stress and EGF induce Akt activation and new mechanisms for AMPK-mediated oncogenesis and drug resistance.
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