The critical role of AMPK in driving Akt activation under stress, tumorigenesis and drug resistance

• Published in: Nature communications Vol. 9; no. 1; pp. 4728 - 16
• Main Authors: Han, Fei, Li, Chien-Feng, Cai, Zhen, Zhang, Xian, Jin, Guoxiang, Zhang, Wei-Na, Xu, Chuan, Wang, Chi-Yun, Morrow, John, Zhang, Shuxing, Xu, Dazhi, Wang, Guihua, Lin, Hui-Kuan
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 09.11.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 1-Phosphatidylinositol 3-kinase; 13; 631/337/458/1733; 631/67/395; 96; Activation; Adenylate Kinase - metabolism; AKT protein; Animal models; Animals; Breast cancer; Calcium - metabolism; Calcium ions; Calcium-binding protein; Calcium-Calmodulin-Dependent Protein Kinase Kinase - metabolism; Calmodulin; Cancer; Carcinogenesis - drug effects; Carcinogenesis - metabolism; Carcinogenesis - pathology; Cell Line, Tumor; Cell Movement - drug effects; Cell Survival - drug effects; Disease Progression; Drug resistance; Drug Resistance, Neoplasm - drug effects; Enzyme Activation - drug effects; Epidermal Growth Factor - pharmacology; ErbB Receptors - metabolism; Fibroblasts - drug effects; Fibroblasts - metabolism; Glucose; Glycolysis - drug effects; Growth factors; Human Umbilical Vein Endothelial Cells - metabolism; Humanities and Social Sciences; Humans; Mice; multidisciplinary; Neovascularization, Pathologic - pathology; Phosphorylation; Phosphorylation - drug effects; Phosphoserine - metabolism; Proto-Oncogene Proteins c-akt - metabolism; S-Phase Kinase-Associated Proteins - metabolism; Science; Science (multidisciplinary); Signal Transduction - drug effects; Skp2 protein; Stress, Physiological - drug effects; Stresses; Tumorigenesis; Tumors; Ubiquitin-protein ligase; Ubiquitination; Ubiquitination - drug effects
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-07188-9

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.