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

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 demonstrated that hypoxia induces casein kinase 2 (CK2)-mediated glucokinase (GCK) S398 phosphorylation, which exposes its nuclear localization signal (NLS) for importin 1 binding and nuclear translocation. Importantly, nuclear GCK interacts with TAZ and functions as a protein kinase that phosphorylates TAZ T346. Phosphorylated TAZ recruits PIN1 for cis–trans isomerization of TAZ, which inhibits the binding of -TrCP to TAZ and -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.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Gaoxiang Zhao

LAB HEAD: Gaoxiang Zhao

PROVIDER: PXD061668 | Pride | 2025-07-14

REPOSITORIES: Pride

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			Action	DRS
	Q4_CWIPAS1155_1GT_1.msf	Msf
	Q4_CWIPAS1155_1GT_1.msfView	Msf
	Q4_CWIPAS1155_1GT_1.pdResult	Other
	Q4_CWIPAS1155_1GT_1.raw	Raw

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Project description:Hypoxia rapidly alters gene expression to allow cellular adaptation to challenging conditions and support tumour growth. Hypoxia also affects the chromatin structure by modifications of histones and DNA methylation. Glioblastoma (GBM) is an aggressive, deadly primary brain tumour for which there is no effective treatment. The tumour microenvironment of GBM is highly heterogeneous, with infiltration of glioma-associated microglia and macrophages (GAMs) and the presence of necrotic, hypoxic regions. The mechanisms through which hypoxia alters the tumour microenvironment and regulates functions of infiltrating immune cells remain poorly understood. Here, we show that hypoxia modulates the expression of myeloid markers in distinct ways: upregulates the monocytic marker Lgals3 expression and downregulates the microglial markers P2ry12 and Tmem119 in microglial and monocytic GAMs in vitro and in vivo, as shown using human and mouse GBM single-cell transcriptomics datasets. The genome-wide hypoxia-dependent transcriptomic changes in microglial cells were determined in microglia-glioma co-cultures. Numerous GAM subtype markers were dysregulated in response to hypoxic stress due to associated changes in chromatin accessibility, as determined using ATACseq. While hypoxia alone drives a decrease of the overall chromatin accessibility at gene promoters, the exposure to glioma cells under hypoxic conditions leads to both increases and decreases of chromatin accessibility at promoter regions in microglial cells. Hypoxia downregulates the chromatin accessibility at the regions enriched in motifs of transcription factors regarded as master regulators of microglial cell identity and function, including SPI1 or IRF8. Moreover, changes in histone acetylation are responsible for Lgals3 upregulation and lipid accumulation in GAMs in hypoxic conditions. Overall, our data highlights the importance of hypoxic stress as a strong intratumoral regulator of myeloid cell functions, which adds complexity to the characterisation of particular GAMs subpopulations.

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

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