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

Gaoxiang Zhao, Shudi Luo, Hong Zhao, Qingxia Ma, Hongfei Jiang, Lin Wang, Juanjuan Liu, Dong Guo, Runze Wang, Qianqian Xu, Jie Lun, Ranran Xie, Yixin Duan, Leina Ma, Wensheng Qiu (), Jing Fang () and Zhimin Lu ()
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Gaoxiang Zhao: Qingdao Cancer Institute
Shudi Luo: Zhejiang University School of Medicine
Hong Zhao: Zhejiang University School of Medicine
Qingxia Ma: Qingdao Cancer Institute
Hongfei Jiang: Qingdao Cancer Institute
Lin Wang: Qingdao Cancer Institute
Juanjuan Liu: Qingdao Cancer Institute
Dong Guo: Zhejiang University School of Medicine
Runze Wang: Qingdao Cancer Institute
Qianqian Xu: Qingdao Cancer Institute
Jie Lun: Qingdao Cancer Institute
Ranran Xie: Qingdao Cancer Institute
Yixin Duan: Qingdao Cancer Institute
Leina Ma: Qingdao Cancer Institute
Wensheng Qiu: Qingdao Cancer Institute
Jing Fang: Qingdao Cancer Institute
Zhimin Lu: Zhejiang University School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-62566-4

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