RAF inhibitors activate the MAPK pathway by relieving inhibitory autophosphorylation.

IF 48.8 1区医学 Q1 CELL BIOLOGY

Cancer Cell Pub Date : 2013-05-13 DOI:10.1016/j.ccr.2013.03.033

Matthew Holderfield, Hanne Merritt, John Chan, Marco Wallroth, Laura Tandeske, Huili Zhai, John Tellew, Stephen Hardy, Mohammad Hekmat-Nejad, Darrin D Stuart, Frank McCormick, Tobi E Nagel

引用次数: 117

Abstract

ATP competitive inhibitors of the BRAF(V600E) oncogene paradoxically activate downstream signaling in cells bearing wild-type BRAF (BRAF(WT)). In this study, we investigate the biochemical mechanism of wild-type RAF (RAF(WT)) activation by multiple catalytic inhibitors using kinetic analysis of purified BRAF(V600E) and RAF(WT) enzymes. We show that activation of RAF(WT) is ATP dependent and directly linked to RAF kinase activity. These data support a mechanism involving inhibitory autophosphorylation of RAF's phosphate-binding loop that, when disrupted either through pharmacologic or genetic alterations, results in activation of RAF and the mitogen-activated protein kinase (MAPK) pathway. This mechanism accounts not only for compound-mediated activation of the MAPK pathway in BRAF(WT) cells but also offers a biochemical mechanism for BRAF oncogenesis.

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RAF抑制剂通过缓解抑制性自磷酸化激活MAPK通路。

BRAF(V600E)癌基因的ATP竞争性抑制剂在携带野生型BRAF的细胞中矛盾地激活下游信号传导(BRAF(WT))。在本研究中，我们通过对纯化的BRAF(V600E)和RAF(WT)酶的动力学分析，探讨了多种催化抑制剂激活野生型RAF(RAF(WT))的生化机制。我们发现，RAF(WT)的激活依赖于ATP，并与RAF激酶活性直接相关。这些数据支持一种机制，涉及RAF的磷酸盐结合环的抑制性自磷酸化，当通过药理学或遗传改变破坏时，导致RAF和丝裂原活化蛋白激酶(MAPK)途径的激活。这一机制不仅解释了BRAF(WT)细胞中化合物介导的MAPK通路激活，还提供了BRAF肿瘤发生的生化机制。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancer Cell 医学-肿瘤学

CiteScore

55.20

自引率

1.20%

发文量

179

审稿时长

4-8 weeks

期刊介绍： Cancer Cell is a journal that focuses on promoting major advances in cancer research and oncology. The primary criteria for considering manuscripts are as follows: Major advances: Manuscripts should provide significant advancements in answering important questions related to naturally occurring cancers. Translational research: The journal welcomes translational research, which involves the application of basic scientific findings to human health and clinical practice. Clinical investigations: Cancer Cell is interested in publishing clinical investigations that contribute to establishing new paradigms in the treatment, diagnosis, or prevention of cancers. Insights into cancer biology: The journal values clinical investigations that provide important insights into cancer biology beyond what has been revealed by preclinical studies. Mechanism-based proof-of-principle studies: Cancer Cell encourages the publication of mechanism-based proof-of-principle clinical studies, which demonstrate the feasibility of a specific therapeutic approach or diagnostic test.