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

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 XieChengcheng Zhang, Yi Yang, Haipeng Sun, Guo Qiang Chen, Junke Zheng

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

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. Liu et al. show that the dynamics of BCAA metabolism in hematopoietic stem cells (HSCs) and leukemia-initiating cells (LICs) can be monitored by a genetically encoded fluorescent sensor. PPM1K promotes BCAA catabolism and maintains the glycolysis and quiescence of HSCs/LICs through the downregulation of CDC20-mediated ubiquitination of MEIS1 and p21.

Original languageEnglish (US)
Pages (from-to)1461-1475
Number of pages15
JournalCell Reports
Volume23
Issue number5
DOIs
StatePublished - May 1 2018

Keywords

  • CDC20
  • MEIS1/p21
  • PPM1K
  • branched-chain amino acids
  • hematopoietic stem cells
  • leukemia-initiating cells
  • ubiquitination

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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