The critical role of AMPK in driving Akt activation under stress, tumorigenesis and drug resistance.
The critical role of AMPK in driving Akt activation under stress, tumorigenesis and drug resistance.
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DOI：
10.1038/s41467-018-07188-9
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发表时间：
2018-11-09
影响因子：
16.6
通讯作者：
Lin HK
中科院分区：
文献类型：
--
作者：
Han F;Li CF;Cai Z;Zhang X;Jin G;Zhang WN;Xu C;Wang CY;Morrow J;Zhang S;Xu D;Wang G;Lin HK
PI 3 K/Akt信号在癌症中被激活，并控制肿瘤的发生和发展，但Akt在不同应激下如何被激活还知之甚少。在这里，我们确定AMPK作为Akt激活各种压力的重要调节因子。令人惊讶的是，AMPK也被生长因子EGF通过Ca 2 +/钙调蛋白依赖性激酶激活，并且对于EGF介导的Akt激活和生物学功能是必需的。AMPK在S256处磷酸化Skp 2并促进Skp 2 SCF复合物的完整性和E3连接酶活性，导致K63连接的泛素化和Akt的活化以及随后的致癌过程。重要的是，AMPK介导的Skp 2 S256磷酸化促进小鼠肿瘤模型中的乳腺癌进展，与乳腺癌患者中的Akt和AMPK激活相关，并预测不良的生存结局。最后，靶向AMPK介导的Skp 2 S256磷酸化使细胞对抗EGF受体靶向治疗敏感。我们的研究揭示了压力和EGF如何诱导Akt激活以及AMPK介导的肿瘤发生和耐药性的新机制。Akt通路在应激下如何被激活还知之甚少。在这里，作者证明了AMPK通过涉及E3泛素连接酶Skp 2和Cullin-1的机制对细胞应激和生长因子介导的Akt激活的关键作用。
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. How Akt pathway is activated under stress is poorly understood. Here, the authors demonstrate the crucial role of AMPK for cellular stresses and growth factors- mediated Akt activation through a mechanism involving the E3 ubiquitin ligase Skp2 and Cullin-1.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
8.8
作者：
通讯作者：
--
影响因子：
21.3
作者：
通讯作者：
--
DOI：
10.1073/pnas.95.13.7451
发表时间：
1998-06-23
影响因子：
11.1
作者：
Lyapina, SA;Correll, CC;Deshaies, RJ
通讯作者：
Deshaies, RJ
影响因子：
5.3
作者：
Cen, Bo;Xiong, Ying;Kraft, Andrew S.
通讯作者：
Kraft, Andrew S.