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RAF Inhibitors Activate the MAPK Pathway by Relieving Inhibitory Autophosphorylation

Holderfield, Matthew and Merritt, Hanne and Chan, John and Wallroth, Marco and Tandeske, Laura and Zhai, Huili and Hardy, Stephen and Hekmat-Nejad, Mohammad and Stuart, Darrin and McCormick, Frank and Nagel, Tobi (2013) RAF Inhibitors Activate the MAPK Pathway by Relieving Inhibitory Autophosphorylation. Cancer Cell, 23 (5). pp. 594-602. ISSN 1535-6108

Abstract

ATP competitive inhibitors of the BRAFV600E oncogene paradoxically activate downstream signaling in cells bearing wild-type BRAF (BRAFWT). In this study, we investigate the biochemical mechanism of wild-type RAF (RAFWT) activation by multiple catalytic inhibitors using kinetic analysis of purified BRAFV600E and RAFWT enzymes. We show that activation of RAFWT 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 BRAFWT cells but also offers a biochemical mechanism for BRAF oncogenesis. © 2013 Elsevier Inc.

Item Type: Article
Date Deposited: 22 Nov 2017 00:45
Last Modified: 25 Jan 2019 00:46
URI: https://oak.novartis.com/id/eprint/8748

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