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.