IMPDH2 dephosphorylation under FGFR signaling promotes S-phase progression and tumor growth
Bei Zhou,
Qin Zhao,
Guofang Hou,
Jing He,
Nannan Sha,
Ke Zheng,
Hongyu Peng,
Wang Wang,
Yue Zhou,
Tao Chen,
Yuhui Jiang
Affiliations
Bei Zhou
Department of Liver Surgery and Shanghai Cancer Institute, State Key Laboratory of Systems Medicine for Cancer, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Qin Zhao
Department of Liver Surgery and Shanghai Cancer Institute, State Key Laboratory of Systems Medicine for Cancer, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Guofang Hou
Department of Liver Surgery and Shanghai Cancer Institute, State Key Laboratory of Systems Medicine for Cancer, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Jing He
Department of Liver Surgery and Shanghai Cancer Institute, State Key Laboratory of Systems Medicine for Cancer, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Nannan Sha
Department of Liver Surgery and Shanghai Cancer Institute, State Key Laboratory of Systems Medicine for Cancer, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Ke Zheng
Department of Liver Surgery and Shanghai Cancer Institute, State Key Laboratory of Systems Medicine for Cancer, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Hongyu Peng
Department of Liver Surgery and Shanghai Cancer Institute, State Key Laboratory of Systems Medicine for Cancer, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Wang Wang
Department of Liver Surgery and Shanghai Cancer Institute, State Key Laboratory of Systems Medicine for Cancer, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Yue Zhou
Department of Liver Surgery and Shanghai Cancer Institute, State Key Laboratory of Systems Medicine for Cancer, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Tao Chen
Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
Yuhui Jiang
Department of Liver Surgery and Shanghai Cancer Institute, State Key Laboratory of Systems Medicine for Cancer, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, School of Pharmacy, East China University of Science and Technology, Shanghai, China; Corresponding author
Summary: Inosine monophosphate dehydrogenase 2 (IMPDH2) is highly expressed in human cancers; however, its physiological relevance under growth signaling remains to be investigated. Here, we show that IMPDH2 serine 122 is phosphorylated by CDK1, and this modification attenuates the catalytic activity of IMPDH2 for IMP oxidation and simultaneously represses its allosteric modulation by purine nucleotides. Fibroblast growth factor receptor (FGFR) signaling activation triggers IMPDH2-Ser122 dephosphorylation mediated by protein phosphatase 2A (PP2A), which is dependent on FGFR3-mediated PPP2R1A-Tyr261 phosphorylation leading to PPP2CA-PPP2R1A-IMPDH2 interactions. In turn, Ser122 dephosphorylation positively modulates IMPDH2 activity and contributes to guanine nucleotide synthesis and purine homeostasis, thereby facilitating S-phase completion and cell proliferation. Accordingly, IMPDH2 dephosphorylation is implicated in FGFR activation-enhanced tumorigenesis, and the low level of IMPDH2-Ser122 phosphorylation predicts the poor prognosis of patients with colorectal cancer. These findings illustrate a regulatory mechanism of purine nucleotide production under FGFR signaling, in which the oncogenic effect of reinforced IMPDH2 activity is underscored.
