PPM1K Regulates Hematopoiesis and Leukemogenesis through CDC20-Mediated Ubiquitination of MEIS1 and p21

• DOI: 10.1016/j.celrep.2018.03.140
• Publication Date: 2018-05-02T08:10:48Z
• Authors: Xiaoye Liu; Feifei Zhang; Yaping Zhang; Xie Li; Chiqi Chen; Meiyi Zhou; Zhuo Yu; Yunxia Liu; Yuzheng Zhao; Xiaoxin Hao; Yabin Tang; Liang Zhu; Ligen Liu; Li Xie; Hao Gu; Hongfang Shao; Fangzhen Xia; Chunrong Yin; Minfang Tao; Jingjing Xie; Cheng Cheng Zhang; Yi Yang; Haipeng Sun; Guo-Qiang Chen; Junke Zheng
• Keywords: Cyclin-Dependent Kinase Inhibitor p21; Mice, Knockout; 0301 basic medicine; Leukemia; QH301-705.5; Cdc20 Proteins; Ubiquitination; Hematopoietic Stem Cells; Hematopoiesis; Neoplasm Proteins; Protein Phosphatase 2C; Mice; 03 medical and health sciences; Cell Transformation, Neoplastic; Animals; Biology (General); Myeloid Ecotropic Viral Integration Site 1 Protein; Signal Transduction

In addition to acting as building blocks for biosynthesis, amino acids might serve as signaling regulators in various physiological and pathological processes. However, it remains unknown whether amino acid levels affect the activities of hematopoietic stem cells (HSCs). By using a genetically encoded fluorescent sensor of the intracellular levels of branched-chain amino acids (BCAAs), we could monitor the dynamics of BCAA metabolism in HSCs. A mitochondrial-targeted 2C-type Ser/Thr protein phosphatase (PPM1K) promotes the catabolism of BCAAs to maintain MEIS1 and p21 levels by decreasing the ubiquitination-mediated degradation controlled by the E3 ubiquitin ligase CDC20. PPM1K deficiency led to a notable decrease in MEIS1/p21 signaling to reduce the glycolysis and quiescence of HSCs, followed by a severe impairment in repopulation activities. Moreover, the deletion of Ppm1k dramatically extended survival in a murine leukemia model. These findings will enhance the current understanding of nutrient signaling in metabolism and function of stem cells.