2. Academic Validation
  3. Nucleus-translocated glucokinase functions as a protein kinase to phosphorylate TAZ and promote tumour growth

Nucleus-translocated glucokinase functions as a protein kinase to phosphorylate TAZ and promote tumour growth

  • Nat Commun. 2025 Aug 4;16(1):7156. doi: 10.1038/s41467-025-62566-4.
Gaoxiang Zhao # 1,  Shudi Luo # 2 3,  Hong Zhao 2 3,  Qingxia Ma 1,  Hongfei Jiang 1,  Lin Wang 1,  Juanjuan Liu 1,  Dong Guo 2 3,  Runze Wang 1,  Qianqian Xu 1,  Jie Lun 1,  Ranran Xie 1,  Yixin Duan 1,  Leina Ma 1,  Wensheng Qiu 4,  Jing Fang 5,  Zhimin Lu 6 7
Affiliations

Affiliations

  • 1 Department of Oncology, Cancer Institute of the Affiliated Hospital of Qingdao University, Qingdao University, Qingdao Cancer Institute, Qingdao, Shandong, China.
  • 2 Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
  • 3 Institute of Fundamental and Transdisciplinary Research, Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China.
  • 4 Department of Oncology, Cancer Institute of the Affiliated Hospital of Qingdao University, Qingdao University, Qingdao Cancer Institute, Qingdao, Shandong, China. wsqiuqdfy@qdu.edu.cn.
  • 5 Department of Oncology, Cancer Institute of the Affiliated Hospital of Qingdao University, Qingdao University, Qingdao Cancer Institute, Qingdao, Shandong, China. jfang2018@163.com.
  • 6 Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China. zhiminlu@zju.edu.cn.
  • 7 Institute of Fundamental and Transdisciplinary Research, Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China. zhiminlu@zju.edu.cn.
  • # Contributed equally.
PMID: 40759645 DOI: 10.1038/s41467-025-62566-4
Abstract

Hypoxia frequently occurs during rapid tumour growth. However, how tumour cells adapt to hypoxic stress by remodeling central cellular pathways remains largely unclear. Here, we show that hypoxia induces Casein Kinase 2 (CK2)-mediated Glucokinase (GCK) S398 phosphorylation, which exposes its nuclear localization signal (NLS) for importin α1 binding and nuclear translocation. Importantly, nuclear GCK interacts with the transcriptional coactivator with PDZ-binding motif (TAZ) and functions as a protein kinase that phosphorylates TAZ T346. Phosphorylated TAZ recruits peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1) for cis-trans isomerization of TAZ, which inhibits the binding of β-TrCP to TAZ and β-TrCP-mediated TAZ degradation. Activated TAZ-TEAD induces the expression of downstream target genes to promote tumour growth. These findings reveal an instrumental mechanism by which a glycolytic enzyme regulates the Hippo pathway under hypoxic conditions and highlight the moonlighting function of GCK as a protein kinase in modulating TAZ activity and tumour growth.

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