RAF Inhibitors Activate the MAPK Pathway by Relieving Inhibitory Autophosphorylation
Cancer Cell, Volume 23, Issue 5, 594-602, 13 May 2013
(Also comment at http://www.sciencedirect.com/science/article/pii/S1535610813001347)
People in this field have been trying to figure out why RAF drugs induce the Erk MAPK pathway. This paper reports a new mechanism for RAF regulation and MAPK activation. Normally p-loop autphosphorylation (in trans as a dimer) of RAF inhibits the kinase. By adding low amounts of the inhibitors they developed, one of the monomers remains unphosphorylated and can activate the MEK-ERK pathway. But if they add even more inhibitor, both monomers are inhibited. Pretty neat.
