KRAS4A直接调节六基酶1
Caroline R Amendola1, James P Mahaffey1, Seth J Parker1
1Perlmutter Cancer Center, NYU School of Medicine, New York, NY, USA.
Nature
|December 13, 2019
概括
KRAS4A与六基酶1 (HK1) 直接相互作用,改变其活性. 这种新的KRAS4A-HK1相互作用揭示了KRAS信号与细胞代谢之间的直接联系,为癌症提供了潜在的治疗点.
科学领域:
- 分子生物学
- 癌症学
- 细胞代谢
背景情况:
- KRAS是癌症中经常发生突变的瘤基因,产生具有明显C终端区域的KRAS4A和KRAS4B异型.
- 瘤性KRAS突变激活细胞转化并改变瘤细胞的新陈代谢,特别是诱导华堡效应.
- 之前的研究将代谢变化归因于转录变化,直接的酶调节仍不清楚.
研究的目的:
- 研究KRAS异型与代谢酶之间的潜在直接相互作用.
- 确定KRAS4A是否直接调节代谢酶的活性.
- 探索KRAS4A介导的代谢调节的功能和治疗影响.
主要方法:
- 生物化学测试以检测KRAS4A和六酶1 (HK1) 之间的GTP依赖相互作用.
- 细胞局部化研究以检查KRAS4A和HK1在线粒体外膜上的局部化.
- 用于评估KRAS4A-HK1相互作用对HK1活性的影响的功能测试.
主要成果:
- 在KRAS4A和hxokinase1 (HK1) 之间发现了直接的,依赖于GTP的相互作用.
- 这种相互作用被证明直接改变了HK1的酶活性,确定HK1是KRAS4A的效应因子.
- KRAS4A独特的棕化循环使其在线粒体外膜上与HK1的同位化更容易.
结论:
- KRAS4A直接调节HK1的活动,代表了癌症代谢控制的新机制.
- KRAS4A-HK1相互作用突出显示了KRAS在癌症代谢中的异型特异性功能.
- 针对KRAS4A-HK1相互作用可以利用KRAS4A表达癌症的独特代谢漏洞来获得治疗效益.
相关概念视频
cAMP-dependent Protein Kinase Pathways
8.1K
Cyclic Adenosine Monophosphate (cAMP) is an essential second messenger that activates protein kinase A (PKA) and regulates various biological processes. A single epinephrine molecule binds to GPCR and activates several heterotrimeric G proteins, each stimulating multiple adenylyl cyclase, amplifying the signal, and synthesizing large numbers of cAMP molecules. Small changes in cAMP concentration affect PKA activity. The binding of four cAMP molecules induces a conformational change in PKA,...
8.1K
PI3K/mTOR/AKT Signaling Pathway
5.2K
The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast, mTORC2 consists of a...
5.2K
The JAK-STAT Signaling Pathway
11.6K
Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as SH2...
11.6K
Protein Kinases and Phosphatases
14.7K
Proteins undergo chemical modifications that trigger changes in the charge, structure, and conformation of the proteins. Phosphorylation, acetylation, glycosylation, nitrosylation, ubiquitination, lipidation, methylation, and proteolysis are various protein modifications that regulate protein activity. Such modifications are usually enzyme-driven.
Protein kinases
Many proteins in the cell are regulated by phosphorylation, the addition of a phosphate group. A family of enzymes called kinases...
Protein kinases
Many proteins in the cell are regulated by phosphorylation, the addition of a phosphate group. A family of enzymes called kinases...
14.7K
Regulation of Angiogenesis and Blood Supply
3.3K
Rapidly dividing tumors, embryos, and wounded tissues require more oxygen than usual, lowering the oxygen concentration in the blood. At low oxygen or hypoxic conditions, an oxygen-sensitive transcription factor called the hypoxia-inducible factor 1 or HIF1 is activated. HIF1 is a dimeric protein of alpha (ɑ) and beta (β) subunits. Under optimal oxygen conditions, HIF1β is present in the nucleus while HIF1ɑ remains in the cytosol. HIF1ɑ is hydroxylated by prolyl...
3.3K
What is Glycolysis?
175.6K
Overview
Cells make energy by breaking down macromolecules. Cellular respiration is the biochemical process that converts "food energy" (from the chemical bonds of macromolecules) into chemical energy in the form of adenosine triphosphate (ATP). The first step of this tightly regulated and intricate process is glycolysis. The word glycolysis originates from the Latin glyco (sugar) and lysis (breakdown). Glycolysis serves two main intracellular functions: generating ATP and generating...
Cells make energy by breaking down macromolecules. Cellular respiration is the biochemical process that converts "food energy" (from the chemical bonds of macromolecules) into chemical energy in the form of adenosine triphosphate (ATP). The first step of this tightly regulated and intricate process is glycolysis. The word glycolysis originates from the Latin glyco (sugar) and lysis (breakdown). Glycolysis serves two main intracellular functions: generating ATP and generating...
175.6K


