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.

中文翻译：

---

MASTL/PP2A 细胞周期激酶-磷酸酶模块以 mTORC1 依赖性方式抑制 PI3K-Akt 活性

AKT-mTOR 通路是细胞生长和代谢的核心调节因子。当 mTOR 活性持续存在时，AKT 活性会因抑制上游信号传导的反馈回路而减弱。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，我们发现 MASTL/Greatwall 是一种细胞周期激酶，通过磷酸化 PP2A/B55 抑制剂 ENSA/ARPP19 支持有丝分裂，通过维持 IRS1 和 GRB10 的 mTORC1 和 S6K1 依赖性磷酸化来抑制 PI3K-AKT 活性。MASTL的遗传耗竭会导致反馈环路效率低下和 AKT 过度活跃。这些缺陷可以通过表达拟磷酸化 ENSA/ARPP19 或抑制 PP2A/B55 磷酸酶来弥补。MASTL 直接被 mTORC1 磷酸化，从而限制 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的葡萄糖耐量增加，这表明 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。