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KRAS4A可直接调控己糖激酶1
2019-12-12 19:59

美国纽约大学医学院Mark R. Philips团队的近期研究发现,KRAS4A可直接调控己糖激酶120191211日,国际学术期刊《自然》在线发表了这项研究成果。

 

研究人员发现KRAS4A和己糖激酶1HK1)之间直接的、GTP依赖性的相互作用,其改变了激酶的活性,从而确定HK1KRAS4A的效应因子。这种相互作用是KRAS4A特有的,因为该RAS亚型的棕榈酰化-去棕榈酸酯化循环使其能够与线粒体外膜上的HK1共定位。 KRAS4A在癌症中的表达可能导致独特的代谢脆弱性,进而可以在治疗上加以利用。

 

据了解,癌症中最常见的突变癌基因是KRAS,其使用可变的第四外显子来生成两个基因产物(KRAS4AKRAS4B),它们的C末端膜靶向区域不同。因为致癌突变发生在外显子23中,所以当突变激活KRAS时,会编码两个组成型活性KRAS蛋白(每个蛋白都能够转化细胞)。到目前为止,尚未确定剪接变体之间的功能区别。致癌性KRAS以多种方式改变肿瘤细胞的代谢,包括葡萄糖摄取和糖酵解的增加,即便是在存在大量氧气的情况下(即Warburg效应)。致癌性KRAS的这些代谢作用已通过葡萄糖转运蛋白和糖酵解酶的转录上调得到了解释,但尚不清楚是否直接调节了代谢酶。

附:英文原文

Title: KRAS4A directly regulates hexokinase 1

Author: 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, Mark R. Philips

Issue&Volume: 2019-12-11

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 enzymes3,4,5, 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.

DOI: 10.1038/s41586-019-1832-9

Source: https://www.nature.com/articles/s41586-019-1832-9

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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