2. Academic Validation
  3. IMPDH2 dephosphorylation under FGFR signaling promotes S-phase progression and tumor growth

IMPDH2 dephosphorylation under FGFR signaling promotes S-phase progression and tumor growth

  • Cell Rep. 2025 Jan 28;44(1):115116. doi: 10.1016/j.celrep.2024.115116.
Bei Zhou 1,  Qin Zhao 1,  Guofang Hou 1,  Jing He 1,  Nannan Sha 1,  Ke Zheng 1,  Hongyu Peng 1,  Wang Wang 1,  Yue Zhou 1,  Tao Chen 2,  Yuhui Jiang 3
Affiliations

Affiliations

  • 1 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.
  • 2 Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China.
  • 3 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. Electronic address: yhjiang@shsmu.edu.cn.
PMID: 39739531 DOI: 10.1016/j.celrep.2024.115116
Abstract

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.

Keywords

CDK1; CP: Cancer; FGFR; PP2A; S-phase progression; allosteric regulation; phosphorylation; purine homeostasis; tumor cell growth.; ◼◼◼IMPDH2.

Figures
Products