Cell Division and Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
Spectroscopy and Nuclear Magnetic Resonance Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
EMBO J. 2023 Jan 16;42(2):e110833. doi: 10.15252/embj.2022110833. Epub 2022 Nov 10.
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.
AKT-mTOR 通路是细胞生长和代谢的中央调节者。在持续的 mTOR 活性下，AKT 活性通过抑制上游信号的反馈环减弱。然而，细胞如何控制限制 AKT 活性的信号尚不完全清楚。在这里，我们表明 MASTL/Greatwall 是一种细胞周期激酶，通过磷酸化 PP2A/B55 抑制剂 ENSA/ARPP19 来支持有丝分裂，通过维持 mTORC1 和 S6K1 依赖性 IRS1 和 GRB10 的磷酸化来抑制 PI3K-AKT 活性。MASTL 的基因缺失导致反馈回路效率低下和 AKT 过度活跃。这些缺陷可以通过表达磷酸模拟 ENSA/ARPP19 或抑制 PP2A/B55 磷酸酶来挽救。MASTL 被 mTORC1 直接磷酸化，从而限制了 mTORC1 下游 IRS1 和 GRB10 的 PP2A/B55 依赖性去磷酸化。MASTL 的下调导致体外葡萄糖摄取增加和成年小鼠葡萄糖耐量增加，表明 MASTL-PP2A/B55 激酶-磷酸酶模块在控制 AKT 和维持代谢稳态方面的相关性。
