Wada Reona, Fujinuma Shun, Nakatsumi Hirokazu, Matsumoto Masaki, Nakayama Keiichi I
Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan.
Department of Omics and Systems Biology, Graduate School of Medical and Dental Sciences, Niigata University, 757 Ichibancho, Asahimachi-dori, Chuo-ku, Niigata City, Niigata 951-8510, Japan.
J Biochem. 2023 Feb 3;173(2):129-138. doi: 10.1093/jb/mvac094.
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.
雷帕霉素复合物1的机制性靶点（mTORC1）是一种丝氨酸 - 苏氨酸激酶，可被细胞外信号（如营养物质和生长因子）激活。它通过介导或调节多个靶分子的磷酸化，在控制各种生物学过程（如蛋白质合成和能量代谢）中发挥关键作用，其中一些靶分子仍有待确定。我们在此重新分析了一个关于mTORC1靶分子的大规模磷酸化蛋白质组学数据集，并确定前B细胞白血病转录因子2（PBX2）是这样一个在mTORC1下游去磷酸化的新靶点。我们证实，PBX2而非PBX家族的其他成员，以mTORC1活性依赖的方式去磷酸化。此外，药理学和基因敲低实验表明，糖原合酶激酶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的磷酸化状态及其受mTORC1的调控。
