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Updated: Sep 12, 2025

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

Gaoxiang Zhao1, Shudi Luo2,3, Hong Zhao2,3

  • 1Department of Oncology, Cancer Institute of the Affiliated Hospital of Qingdao University, Qingdao University, Qingdao Cancer Institute, Qingdao, Shandong, China.

Nature Communications
|August 4, 2025
PubMed

Insights

Hypoxia triggers glucokinase (GCK) nuclear translocation, enabling it to phosphorylate TAZ. This process inhibits TAZ degradation, promoting tumour growth and highlighting GCK

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cellular Signaling

Background:

  • Tumour hypoxia is a common condition during rapid growth.
  • Cellular adaptation mechanisms to hypoxic stress are not fully understood.
  • The role of glycolytic enzymes in regulating cellular pathways under hypoxia requires further investigation.

Purpose of the Study:

  • To elucidate how tumour cells adapt to hypoxia by remodeling central cellular pathways.
  • To investigate the role of glucokinase (GCK) in tumour cell adaptation to hypoxia.
  • To uncover the moonlighting function of GCK in regulating the Hippo pathway.

Main Methods:

  • Investigated hypoxia-induced phosphorylation of glucokinase (GCK) at S398.
  • Examined the nuclear translocation of GCK and its interaction with TAZ.
  • Assessed the kinase activity of nuclear GCK on TAZ and its downstream effects on the Hippo pathway.

Main Results:

  • Hypoxia induces CK2-mediated GCK phosphorylation, exposing its NLS for nuclear import.
  • Nuclear GCK phosphorylates TAZ at T346, recruiting PIN1 and inhibiting β-TrCP-mediated degradation.
  • Activated TAZ-TEAD signaling promotes the expression of target genes, driving tumour growth.

Conclusions:

  • GCK acts as a protein kinase in the nucleus under hypoxia, modulating TAZ activity.
  • This GCK-TAZ interaction represents a novel mechanism linking glycolysis to Hippo pathway regulation.
  • The findings reveal a critical pathway for tumour adaptation to hypoxia, offering potential therapeutic targets.

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