Isoform-Specific KRAS–Hexokinase 1 Interaction Affects Metabolism

KRAS, the proto-oncogene most commonly mutated in cancer, encodes two splice variants: KRAS4A and KRAS4B. These variants are identical except for their fourth exons, which encode their C-terminal membrane-targeting domains. Activating mutations in the first or second exons give rise to oncogenic forms of both variants. Despite evolutionary conservation, no functional differences between the two isoforms have been conclusively identified. Amendola, Mahaffey, and colleagues found that KRAS4A interacted much more strongly with the ubiquitously expressed metabolic enzyme hexokinase 1 (HK1) than did KRAS4B. This interaction was dependent on prenylation of KRAS4A, which is required for membrane targeting. Additionally, palmitoylation—a modification that affects KRAS4A but not KRAS4B and allows for continuous cycling of RAS proteins from one membrane compartment to another—negatively regulated the interaction between HK1 and KRAS4A. Further supporting the interaction between KRAS4A and HK1, depalmitoylated KRAS4A and HK1 colocalized on the outer mitochondrial membrane (OMM), where HK1 normally resides. The association between KRAS4A and HK1 was dependent on GTP, implying an interaction between KRAS4A's G domain and HK1, and further experiments suggested that HK1 contains a functional RAS-binding domain. The observed colocalization of KRAS4A and HK1 on the OMM was shown to be required for their interaction, supporting the idea that the specificity of the isoform-specific interaction between HK1 and KRAS4A is due to the latter's membrane-targeting sequence. Functionally, biochemical experiments demonstrated a direct effect of KRAS4A on the allosteric feedback inhibition of HK1, which increased HK1 activity both in vitro and in human cancer cell lines, enhancing glycolytic flux. Together, these results indicate that HK1 is a KRAS effector specific to the 4A isoform and imply that KRAS4A-mediated HK1 regulation may contribute to the metabolic perturbations observed in KRAS-mutant tumor cells. Interestingly, HK1 inhibitors have been investigated as anticancer drugs, and these results suggest that it may be worthwhile to examine whether expression levels of the two KRAS isoforms affect tumors' susceptibility to these drugs.

Amendola CR, Mahaffey JP, Parker SJ, Ahearn IM, Chen WC, Zhou M, et al. KRAS4A directly regulates hexokinase 1. Nature 2019;576:482–6.

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