@article{7360dc209ee34394b0177cc2d267d69e,
title = "PPM1K Regulates Hematopoiesis and Leukemogenesis through CDC20-Mediated Ubiquitination of MEIS1 and p21",
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.",
keywords = "CDC20, MEIS1/p21, PPM1K, branched-chain amino acids, hematopoietic stem cells, leukemia-initiating cells, ubiquitination",
author = "Xiaoye Liu and Feifei Zhang and Yaping Zhang and Xie Li and Chiqi Chen and Meiyi Zhou and Zhuo Yu and Yunxia Liu and Yuzheng Zhao and Xiaoxin Hao and Yabin Tang and Liang Zhu and Ligen Liu and Li Xie and Hao Gu and Hongfang Shao and Fangzhen Xia and Chunrong Yin and Minfang Tao and Jingjing Xie and Chengcheng Zhang and Yi Yang and Haipeng Sun and Chen, {Guo Qiang} and Junke Zheng",
note = "Funding Information: We appreciate the kind help in the isolation of cortex neural cells provided by Prof. Nanjie Xu and Suya Sun at Shanghai Jiaotong University School of Medicine. BCAA sensors are available from East China University of Science and Technology (ECUST) under a material transfer agreement with Prof. Yi Yang. This work was supported by grants from National Natural Science Foundation of China ( 81422001 , 81570093 , 81721004 , 81471524 , 30971094 , 81270317 , 81570717 , and 81522011 ), and its innovative group (No. 81721004 ), the 1000-Youth Elite Program , National Basic Research Program of China ( 973Program , 2014CB965000 , and NO2015CB910403 ), the NIH ( 1R01CA172268 ), CPRIT RP140402 , Taishan Scholar Immunology Program, Ministry of Science and Technology of China ( 2012BAI02B05 and 2013YQ030923 ), Science and Technology Commission of Shanghai Municipality ( 14411968300 , 13ZR1423300 , 16JC1404400 , and 17DZ2260100 ), and Natural Science Foundation of Shanghai ( 17ZR1415500 ). Funding Information: We appreciate the kind help in the isolation of cortex neural cells provided by Prof. Nanjie Xu and Suya Sun at Shanghai Jiaotong University School of Medicine. BCAA sensors are available from East China University of Science and Technology (ECUST) under a material transfer agreement with Prof. Yi Yang. This work was supported by grants from National Natural Science Foundation of China (81422001, 81570093, 81721004, 81471524, 30971094, 81270317, 81570717, and 81522011), and its innovative group (No. 81721004), the 1000-Youth Elite Program, National Basic Research Program of China (973Program, 2014CB965000, and NO2015CB910403), the NIH (1R01CA172268), CPRIT RP140402, Taishan Scholar Immunology Program, Ministry of Science and Technology of China (2012BAI02B05 and 2013YQ030923), Science and Technology Commission of Shanghai Municipality (14411968300, 13ZR1423300, 16JC1404400, and 17DZ2260100), and Natural Science Foundation of Shanghai (17ZR1415500). Publisher Copyright: {\textcopyright} 2018 The Authors",
year = "2018",
month = may,
day = "1",
doi = "10.1016/j.celrep.2018.03.140",
language = "English (US)",
volume = "23",
pages = "1461--1475",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "5",
}