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KRAS4A directly regulates hexokinase 1
Open accessAbstract
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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“One recent study reported the role of KRAS4A KRAS isoform in carbon metabolism through the direct regulation of the glycolytic enzyme HK1, which is of interest as it identifies the direct GTP-dependent regulation of a metabolic enzyme29 and further complicates the landscape of RAS mediated metabolism.”
From The metabolic landscape of RAS-driven cancers from biology to therapy (2021) · cites this paper as [29]
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“Gene expression and metabolic flux analyses have shown that it upregulates the expression of the GLUT1 glucose transporter to promote glucose uptake by cells, as well as inducing expression of hexokinase 1 and 2 (HK1 and HK2) rate-limiting enzymes of glycolysis, to increase glycolytic activity27–30 (Fig. 2a).”
From The metabolic landscape of RAS-driven cancers from biology to therapy (2021) · cites this paper as [29]
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Metadata
- 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
- Venue
- Nature
- Published
- 2019-12-11
- Volume
- 576
- Issue
- 7787
- Pages
- 482-486
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- 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
- 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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