KRAS4A directly regulates hexokinase 1

The most frequently mutated oncogene in cancer is KRAS , which uses alternative fourth exons to generate two gene products (KRAS4A and KRAS4B) that differ only in their C-terminal membrane-targeting region 1 . Because oncogenic mutations occur in exons 2 or 3, two constitutively active KRAS proteins...

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Published inNature (London) Vol. 576; no. 7787; pp. 482 - 486
Main Authors Amendola, Caroline R., Mahaffey, James P., Parker, Seth J., Ahearn, Ian M., Chen, Wei-Ching, Zhou, Mo, Court, Helen, Shi, Jie, Mendoza, Sebastian L., Morten, Michael J., Rothenberg, Eli, Gottlieb, Eyal, Wadghiri, Youssef Z., Possemato, Richard, Hubbard, Stevan R., Balmain, Allan, Kimmelman, Alec C., Philips, Mark R.
Format Journal Article
LanguageEnglish
Published London Nature Publishing Group UK 19.12.2019
Nature Publishing Group
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Summary:The most frequently mutated oncogene in cancer is KRAS , which uses alternative fourth exons to generate two gene products (KRAS4A and KRAS4B) that differ only in their C-terminal membrane-targeting region 1 . Because oncogenic mutations occur in exons 2 or 3, two constitutively active KRAS proteins—each capable of transforming cells—are encoded when KRAS is activated by mutation 2 . No functional distinctions among the splice variants have so far been established. Oncogenic KRAS alters the metabolism of tumour cells 3 in several ways, including increased glucose uptake and glycolysis even in the presence of abundant oxygen 4 (the Warburg effect). Whereas these metabolic effects of oncogenic KRAS have been explained by transcriptional upregulation of glucose transporters and glycolytic enzymes 3 – 5 , it is not known whether there is direct regulation of metabolic enzymes. Here we report a direct, GTP-dependent interaction between KRAS4A and hexokinase 1 (HK1) that alters the activity of the kinase, and thereby establish that HK1 is an effector of KRAS4A. This interaction is unique to KRAS4A because the palmitoylation–depalmitoylation cycle of this RAS isoform enables colocalization with HK1 on the outer mitochondrial membrane. The expression of KRAS4A in cancer may drive unique metabolic vulnerabilities that can be exploited therapeutically. KRAS4A interacts directly with hexokinase 1 in a GTP-dependent manner at the outer mitochondrial membrane, leading to kinase activation and an increase in glucose uptake and glycolysis in tumour cells.
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These authors contributed equally to the work
Author Contributions: C.R.A, J.P.M, and M.R.P. designed and interpreted all experiments and wrote the manuscript. Unless otherwise stipulated, J.P.M. and C.R.A. performed all experiments. W.C.H. generated the CRISPR/Cas9 engineered A549 and SUIT2 cells. M.Z. performed mitochondrial purifications. I.A. and H.C. performed the 2-DG growth inhibition studies. J.S. performed hexokinase activity assays. S.L.M. performed the PET CT studies. S.J.P. performed the Seahorse analysis and 13C-glucose labeling. M.M. performed the super-resolution microscopy. E.G., A.K., Y.Z.W., R.P., S.R.H., E.R. and A.B. assisted with the interpretation of the results and edited the manuscript.
ISSN:0028-0836
1476-4687
DOI:10.1038/s41586-019-1832-9