KRAS4A directly regulates hexokinase 1

Abstract

The most frequently mutated oncogene in cancer is KRAS, which utilizes 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, when KRAS is activated by mutation two constitutively active KRAS proteins are encoded, each capable of transforming cells 2. No functional distinctions among the splice variants have been established. Oncogenic KRAS alters tumor metabolism 3. Among these alterations is 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 , direct regulation of metabolic enzymes has not been examined. We report a direct, GTP-dependent interaction between KRAS4A and hexokinase 1 (HK1) that alters the activity of the kinase, establishing HK1 as an effector of KRAS4A. The interaction is unique to KRAS4A because the palmitoylation/depalmitoylation cycle of this RAS isoform permits co-localization with HK1 on the outer mitochondrial membrane (OMM). KRAS4A expression in cancer may drive unique metabolic vulnerabilities that can be exploited therapeutically. Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Non-Small-Cell Lung Cancer Signaling Pathways, Metabolism, and PD-1/PD-L1 Antibodies

“…The combination of avasimibe with anti-PD-1 antibody inhibits tumor progression in mice models. Avasimibe monotherapy potentiates the effector function of both, PD-1 high , and PD-1 low , CD8 + T cells in the tumor microenvironment [ 115 ]. ACAT1 inhibition could be complementary to IMT ( Table 2 ).…”

Splice variants of RAS—translational significance

“…However, the two KRAS variants can also show alternative localisation, different from each other. Interaction with the lysosome membrane-bound v-ATPase a2 links KRAS4B to the lysosome membrane, while the depalmitoylated KRAS4A is co-localised with hexokinase 1(HK1) at the outer mitochondrial membrane (OMM) with a direct GTP-dependent interaction [ 73 ]. Most of our knowledge about a number of biological functions of the two variants come from the examination of exon 4 deleted K-ras(tmDelta4A/tmDelta4A) mice, its heterozygous variant (K-ras(tmDelta4A/+) and the in vitro cell cultures created from them.…”

The biological role of metabolic reprogramming in pancreatic cancer

“…[18][19][20][21] In addition to the transcriptional upregulation of glucose transporters and glycolytic enzymes, KRAS4A interacts with HK1 in mitochondria and regulates HK1 directly. 22 Glucose also plays a crucial role in the anabolic pathway. Oncogenic KRAS activates the hexosamine biosynthetic pathway (HBP), 10,23 producing uridine diphosphate-N-acetylglucosamine, which has numerous functions, including intracellular signaling and posttranslational modification.…”