Cited by 203Cancer, Hypoxia, and MetabolismProtein Kinase Regulation and GTPase SignalingMetabolism, Diabetes, and Cancer

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KRAS4A directly regulates hexokinase 1

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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.·2019·Nature

DOI 10.1038/s41586-019-1832-9PMC PMC6923592

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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 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.

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Authors: Amendola, C. R., Mahaffey, J. P., Parker, S. J., Ahearn, I. M., Chen, W.-C., Zhou, M., Court, H., Shi, J., Mendoza, S. L., Morten, M. J., Rothenberg, E., Gottlieb, E., Wadghiri, Y. Z., Possemato, R., Hubbard, S. R., Balmain, A., Kimmelman, A. C., & Philips, M. R.
Affiliations: NYU Langone’s Laura and Isaac Perlmutter Cancer Center (US)
University of California, San Francisco (US)
Technion – Israel Institute of Technology (IL)
NYU Langone Health (US)
Corresponding author: Philips, Mark R.
ORCID: Parker, Seth J.
Ahearn, Ian M.
Zhou, Mo
Court, Helen
Morten, Michael J.
Rothenberg, Eli
Gottlieb, Eyal
Wadghiri, Youssef Z.
Possemato, Richard
Hubbard, Stevan R.
Balmain, Allan
Kimmelman, Alec C.
Philips, Mark R.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2019-12-11
Volume: 576
Issue: 7787
Pages: 482-486
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/s41586-019-1832-9
PMC: PMC6923592
OpenAlex: W2994883186
Cited by: 203
References: 33
Citations by year: 2026: 23 · 2025: 22 · 2024: 30 · 2023: 50 · 2022: 28 · 2021: 34 · 2020: 16
FWCI: 6.15
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
RePEc: Research Papers in Economics (submittedVersion)
eScholarship (California Digital Library) (submittedVersion)
Funders: National Cancer Institute (R01CA116034, R01CA163489, R01CA188048, R35CA232124, T32CA009161, U01CA217864, R01CA214948, R01CA157490, R35CA210018, P01CA117969, P30CA016087)
National Institute of General Medical Sciences (R01GM095567, T32GM088118)
National Institute of Biomedical Imaging and Bioengineering (P41EB017183)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Keywords: K-Ras4B, hexokinase 1, oncogenic KRAS, alternative splicing, palmitoylation, depalmitoylation, mitochondrial outer membrane, glycolysis, Warburg effect, glucose uptake, cancer metabolism, metabolic vulnerability
MeSH terms: Allosteric Regulation, Animals, Enzyme Activation, Glycolysis, Guanosine Triphosphate, Hexokinase, Humans, Isoenzymes, Male, Mitochondria, Neoplasms, Protein Binding, Proto-Oncogene Proteins p21(ras), Protein Transport, Cell Line, Tumor, Mitochondrial Membranes, Mice, Lipoylation, In Vitro Techniques

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KRAS4A directly regulates hexokinase 1

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