Cellular energy stress induces AMPK-mediated regulation of glioblastoma cell proliferation by PIKE-A phosphorylation

• Type of Material: Article
• Authors: Shuai Zhang, Jinan University; Hao Sheng, Jinan University; Xiaoya Zhang, Jinan University; Qi Qi, Emory University; Chi Bun Chan, University of Hong Kong; Leilei Li, Jinan University; Changliang Shan, Jinan University; Keqiang Ye, Emory University
• Language: English
• Date: 2019-03-04
• Publisher: Springer Nature [academic journals on nature.com]: Fully open access journals
• Publication Version: Final Published Version
• Copyright Statement: © 2019, The Author(s).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41419-019-1452-1
• Title of Journal or Parent Work: Cell Death and Disease
• ISSN: 2041-4889
• Volume: 10
• Issue: 3
• Start Page: 222
• End Page: 222
• Grant/Funding Information: The work is supported by a grant from NIH (RO1 DK09092) to C.B.C., NIH (RO1 CA186918) to K.Y., National Natural Science Foundation of China (No. 81672781) and the Fundamental Research Funds for the Central Universities (21616323) to S.Z., National Natural Science Foundation of China (No. 81702746) to L.L., The Fundamental Research Funds for the Central Universities (21617433), the Science and Technology Program of Guangdong (Grant 2017A030313890) and the Science and Technology Program of Guangzhou (Grant 201807010003) to C.S.; This work was also supported by the Program of Introducing Talents of Discipline to Universities (111 Project, No. B16021).
• Keywords: AKT; GTPASE; Cell Biology; 14-3-3 PROTEINS; SURVIVAL; Life Sciences & Biomedicine; Science & Technology; 3-KINASE ENHANCER
• Research Categories: Biology, Cell; Health Sciences, Pharmacology; Chemistry, Biochemistry

Abstract

Phosphoinositide 3-kinase enhancer-activating Akt (PIKE-A), which associates with and potentiates Akt activity, is a pro-oncogenic factor that play vital role in cancer cell survival and growth. However, PIKE-A physiological functions under energy/nutrient deficiency are poorly understood. The AMP-activated protein kinase (AMPK) is an evolutionarily conserved serine/threonine kinase that is a principal regulator of energy homeostasis and has a critical role in metabolic disorders and cancers. In this present study, we show that cellular energy stress induces PIKE-A phosphorylation mediated by AMPK activation, thereby preventing its carcinogenic action. Moreover, AMPK directly phosphorylates PIKE-A Ser-351 and Ser-377, which become accessible for the interaction with 14-3-3β, and in turn stimulates nuclear translocation of PIKE-A. Nuclear PIKE-A associates with CDK4 and then disrupts CDK4-cyclinD1 complex and inhibits the Rb pathway, resulting in cancer cell cycle arrest. Our data uncover a molecular mechanism and functional significance of PIKE-A phosphorylation response to cellular energy status mediated by AMPK.