Cellular energy stress induces AMPK-mediated regulation of glioblastoma cell proliferation by PIKE-A phosphorylation.
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 14-3-3?, 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.
Mesh Terms:
14-3-3 Proteins, AMP-Activated Protein Kinases, Cell Nucleus, Cell Proliferation, Cyclin-Dependent Kinase 4, Energy Metabolism, Enzyme Activation, Feedback, Physiological, GTP-Binding Proteins, GTPase-Activating Proteins, Glioblastoma, Phosphorylation, Signal Transduction, Stress, Physiological
14-3-3 Proteins, AMP-Activated Protein Kinases, Cell Nucleus, Cell Proliferation, Cyclin-Dependent Kinase 4, Energy Metabolism, Enzyme Activation, Feedback, Physiological, GTP-Binding Proteins, GTPase-Activating Proteins, Glioblastoma, Phosphorylation, Signal Transduction, Stress, Physiological
Cell Death Dis
Date: Dec. 04, 2018
PubMed ID: 30833542
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