Date of Graduation
Doctor of Philosophy (PhD)
Gordon B. Mills, M.D., Ph.D.
Oliver Bogler, Ph.D.
Ruth Heidelberger, M.D., Ph.D.
Dennis P. Hughes, M.D., Ph.D.
Faye Johnson, M.D., Ph.D.
The phosphatidylinositide 3 kinase (PI3K)/Akt signaling network plays a pivotal role in multiple cellular functions. PI3K links the extracellular growth factor receptors to the serine-threonine kinase Akt which, through phosphorylation of numerous intracellular proteins, mediates increased cell growth, survival, motility and proliferation. The significance of the PI3K/Akt signaling network to human malignancy is demonstrated by cancer-associated genetic aberrations at multiple levels in the PI3K/Akt pathway in many tumor lineages. These aberrations include mutation or amplification of Akt, catalytic and regulatory subunits of PI3K, and growth factor receptors upstream of PI3K. Inactivating mutations and decreased expression of the PTEN, a major antagonist of PI3K signaling, also lead to constitutive hyperactivity of Akt.
Multiple small molecule inhibitors targeting components of the PI3K/Akt signaling pathway including Akt catalytic domain inhibitors, significantly slow tumor growth in preclinical models. Strikingly, these Akt kinase inhibitors induce a paradoxical increase in phosphorylation of Akt activation sites. As Akt catalytic domain inhibitors are entering clinical trials, elucidation of the mechanism(s) underlying Akt inhibitor-induced Akt phosphorylation is needed to understand and anticipate drug effects.
In this study, we demonstrate an unexpected requirement of Glycogen Synthase Kinase 3 (GSK3), a serine-threonine kinase that participates in multiple cell signaling pathways downstream of Akt, for Akt inhibitor-induced Akt phosphorylation. siRNA-mediated knockdown of GSK3 in MDAMB231 breast cancer cells and in mouse embryonic fibroblasts (MEFs) abrogated induction of Akt phosphorylation by the Akt catalytic domain inhibitor A674563. Our discovery that GSK3 can function upstream of Akt led us to explore the role of GSK3 in mediating signaling from growth factors to Akt. Knockdown of GSK3 expression in MDAMB231 cells and in MEFs blocked stimulation of Akt phosphorylation by epidermal growth factor (EGF) and insulin-like growth factor (IGF1).
The results, taken together, demonstrate a novel signaling role for GSK3 upstream of Akt.
GSK3, Akt, PI3K, cancer cell signaling, signal transduction