KRAS4A directly regulates hexokinase 1

Caroline R. Amendola, James P. Mahaffey, Seth J. Parker, Ian M. Ahearn, Wei-Ching Chen, Mo Zhou, Helen Court, Jie Shi, Sebastian L. Mendoza, Michael J. Morten, Eli Rothenberg, Eyal Gottlieb, Youssef Z. Wadghiri, Richard Possemato, Stevan R. Hubbard, Allan Balmain, Alec C. Kimmelman and Mark R. Philips ()
Additional contact information
Caroline R. Amendola: NYU School of Medicine
James P. Mahaffey: NYU School of Medicine
Seth J. Parker: NYU School of Medicine
Ian M. Ahearn: NYU School of Medicine
Wei-Ching Chen: University of California at San Francisco School of Medicine
Mo Zhou: NYU School of Medicine
Helen Court: NYU School of Medicine
Jie Shi: NYU School of Medicine
Sebastian L. Mendoza: NYU School of Medicine
Michael J. Morten: NYU School of Medicine
Eli Rothenberg: NYU School of Medicine
Eyal Gottlieb: Technion Israel Institute of Technology
Youssef Z. Wadghiri: NYU School of Medicine
Richard Possemato: NYU School of Medicine
Stevan R. Hubbard: NYU School of Medicine
Allan Balmain: University of California at San Francisco School of Medicine
Alec C. Kimmelman: NYU School of Medicine
Mark R. Philips: NYU School of Medicine

Nature, 2019, vol. 576, issue 7787, 482-486

Abstract: Abstract 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 region1. 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 mutation2. No functional distinctions among the splice variants have so far been established. Oncogenic KRAS alters the metabolism of tumour cells3 in several ways, including increased glucose uptake and glycolysis even in the presence of abundant oxygen4 (the Warburg effect). Whereas these metabolic effects of oncogenic KRAS have been explained by transcriptional upregulation of glucose transporters and glycolytic enzymes3–5, 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.

Date: 2019
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DOI: 10.1038/s41586-019-1832-9

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