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A non-catalytic scaffolding activity of hexokinase 2 contributes to EMT and metastasis

Cited 30 time in Web of Science Cited 32 time in Scopus

Blaha, Catherine S.; Ramakrishnan, Gopalakrishnan; Jeon, Sang-Min; Nogueira, Veronique; Rho, Hyunsoo; Kang, Soeun; Bhaskar, Prashanth; Terry, Alexander R.; Aissa, Alexandre F.; Frolov, Maxim, V; Patra, Krushna C.; Robey, R. Brooks; Hay, Nissim

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Nature Publishing Group
Nature Communications, Vol.13 No.1, p. 899
Hexokinase 2 (HK2), which catalyzes the first committed step in glucose metabolism, is induced in cancer cells. HK2's role in tumorigenesis has been attributed to its glucose kinase activity. Here, we describe a kinase independent HK2 activity, which contributes to metastasis. HK2 binds and sequesters glycogen synthase kinase 3 (GSK3) and acts as a scaffold forming a ternary complex with the regulatory subunit of protein kinase A (PRKAR1a) and GSK3 beta to facilitate GSK3 beta phosphorylation and inhibition by PKA. Thus, HK2 functions as an A-kinase anchoring protein (AKAP). Phosphorylation by GSK3 beta targets proteins for degradation. Consistently, HK2 increases the level and stability of GSK3 targets, MCL1, NRF2, and particularly SNAIL. In addition to GSK3 inhibition, HK2 kinase activity mediates SNAIL glycosylation, which prohibits its phosphorylation by GSK3. Finally, in mouse models of breast cancer metastasis, HK2 deficiency decreases SNAIL protein levels and inhibits SNAIL-mediated epithelial mesenchymal transition and metastasis.
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  • College of Pharmacy
  • Department of Pharmacy
Research Area Cancer Origin, Metabolism, Toxicology


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