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Pi3k/Akt Signaling Activates Hsf1 To Preserve Proteostasis And Sustain Growth, Zijian Tang

Electronic Theses and Dissertations

Signaling through oncogenic PI3K/AKT kinase pathway is crucial to cell and organ growth. Phosphorylation by AKT has long been perceived as a key factor to enhance protein biosynthesis that enables cell growth and survival. Here, we report that HSF1, the master regulator of the proteotoxic stress response (PSR), is a new AKT substrate. Beyond mobilizing the PSR under heat shock, the AKT-mediated HSF1 activation supports robust growth. In a mouse model of human megalencephaly, expression of a constitutively active PI3KCAsuffices to drive brain overgrowth, and strikingly, it also provokes proteomic chaos including protein aggregation and amyloidogenesis. Deletion of Hsf1 …