부산대학교 도서관

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 the expression of phosphomimetic 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. Synopsis: In the presence of excessive signaling, the AKT‐mTOR pathway limits its activity by phosphorylating upstream regulators. When phosphorylated by mTOR, the MASTL/Greatwall kinase contributes to this negative feedback loop by inhibiting the phosphatase PP2A to prevent excessive AKT activity. MASTL is a new component of the feedback loop that restricts mTOR activity.MASTL inhibits dephosphorylation of IRS1 and GRB10 by PP2A/B55.mTOR phosphorylates and activates MASTL to inhibit PP2A/B55.MASTL inhibition results in improved glucose homeostasis in vivo. [ABSTRACT FROM AUTHOR]