Phosphorylation of PBX2, a novel downstream target of mTORC1, is determined by GSK3 and PP1
Phosphorylation of PBX2, a novel downstream target of mTORC1, is determined by GSK3 and PP1
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PBX2（mTORC1 的新下游靶标）的磷酸化由 GSK3 和 PP1 决定
DOI：
10.1093/jb/mvac094
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Nakayama Keiichi I
中科院分区：
文献类型：
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作者：
Wada Reona;Fujinuma Shun;Nakatsumi Hirokazu;Matsumoto Masaki;Nakayama Keiichi I
雷帕霉素复合体1 （mTORC1）是一种丝氨酸-苏氨酸激酶，可被细胞外信号激活，如营养物质和生长因子。它通过介导或调节多个靶标分子的磷酸化，在蛋白质合成和能量代谢等多种生物过程的控制中发挥关键作用，其中一些靶标分子仍有待鉴定。我们在这里重新分析了mTORC1靶分子的大规模磷酸化蛋白质组学数据集，并确定了前b细胞白血病转录因子2 （PBX2）是mTORC1下游去磷酸化的新靶标。我们证实PBX2，而不是PBX家族的其他成员，以mTORC1活性依赖的方式去磷酸化。此外，药理学和基因敲除实验表明，糖原合成酶激酶3 （GSK3）和蛋白磷酸酶1 （PP1）分别负责PBX2的磷酸化和去磷酸化。因此，我们的研究结果表明，GSK3和PP1的拮抗作用之间的平衡决定了PBX2的磷酸化状态和mTORC1对其的调节。
Mechanistic target of rapamycin complex 1 (mTORC1) is a serine–threonine kinase that is activated by extracellular signals, such as nutrients and growth factors. It plays a key role in the control of various biological processes, such as protein synthesis and energy metabolism by mediating or regulating the phosphorylation of multiple target molecules, some of which remain to be identified. We have here reanalysed a large-scale phosphoproteomics data set for mTORC1 target molecules and identified pre–B cell leukemia transcription factor 2 (PBX2) as such a novel target that is dephosphorylated downstream of mTORC1. We confirmed that PBX2, but not other members of the PBX family, is dephosphorylated in an mTORC1 activity–dependent manner. Furthermore, pharmacological and gene knockdown experiments revealed that glycogen synthase kinase 3 (GSK3) and protein phosphatase 1 (PP1) are responsible for the phosphorylation and dephosphorylation of PBX2, respectively. Our results thus suggest that the balance between the antagonistic actions of GSK3 and PP1 determines the phosphorylation status of PBX2 and its regulation by mTORC1.