A cell cycle kinase-phosphatase module restrains PI3K-Akt activity in an mTORC1-dependent manner

Abstract

The AKT-mTOR pathway is a central regulator of cell growth and metabolism. Upon sustained mTOR activity, AKT activity is attenuated by a feedback loop that restrains upstream signaling. However, how cells control the signals that limit AKT activity is not fully understood. Here we show that MASTL/Greatwall, a cell-cycle kinase that supports mitosis by phosphorylating the PP2A/B55 inhibitors ENSA/ARPP19, inhibits PI3K-AKT activity by sustaining mTORC1- and S6K1-dependent phosphorylation of IRS1 and GRB10. Genetic depletion of MASTL results in an inefficient feedback loop and AKT hyperactivity. These defects are rescued by expression of phospho-mimetic ENSA/ARPP19 or inhibition of PP2A/B55 phosphatases. MASTL is directly phosphorylated by mTORC1, thereby limiting the PP2A/B55-dependent dephosphorylation of IRS1 and GRB10 downstream of mTORC1. Downregulation of MASTL results in increased glucose uptake in vitro and increased glucose tolerance in adult mice, suggesting the relevance of the MASTL-PP2A/B55 kinase-phosphatase module in controlling AKT and maintaining metabolic homeostasis.

Flavonoid combination therapy regulating immune system's homeostasis via activation the FOXO3 signaling pathway for the cure of Propionibacterium acnes infection

“…The functions of FOXO3 were to maintain blood vessel homeostasis, regulating the activity of mammalian target of rapamycin complex 1 (mTORC1), and related to human lifespan [7]. FOXO3, phosphorylated by the PI3K/Akt cascade, induces mTORC1 activation by downregulating adenosine monophosphate activated protein kinase (AMPK) [8]. Activated mTORC1 leads to the formation of acne and acne scars.…”