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

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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Publication Details

Journal
Nature Communications
Published
2025-08-04
DOI
https://doi.org/10.1038/s41467-025-62566-4
Citations
3
Primary Topic
Hippo pathway signaling and YAP/TAZ
Type
article
Field-Weighted Citation Impact
3.45

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article

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

Zhimin Lu, Yixin Duan, R Xie, Dong Guo et al.
3 citations
Nature Communications
Hippo pathway signaling and YAP/TAZ
3.45
article

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

Zhimin Lu, Yixin Duan, R Xie, Dong Guo, Jie Lun, Qianqian Xu, Shudi Luo, Leina Ma, Wensheng Qiu, Hongfei Jiang, Hong Zhao, Lin Wang, Runze Wang, Juanjuan Liu, Jing Fang, Gaoxiang Zhao, Qingxia Ma
article en
3 citations

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.

Nature CommunicationsVol. 16(1)
Qingdao University (CN), Zhejiang Chinese Medical University (CN), Zhejiang Cancer Hospital (CN), Affiliated Hospital of Qingdao University (CN)
National Natural Science Foundation of China, Ministry of Science and Technology of the People's Republic of China
Zero hunger
Openalex Percentile: Top 8%
Hippo pathway signaling and YAP/TAZ
3.45
DOIOpen Access PDFOpenAlex
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