JOURNAL ARTICLE

RAF inhibitors activate the MAPK pathway by relieving inhibitory autophosphorylation

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
Cancer Cell 2013 May 13, 23 (5): 594-602
23680146
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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