description
While BRAF-specific inhibitors inhibit MAPK/ERK activation in the presence of the BRAF V600E mutant, paradoxical activation of ERK signaling has been observed after treatment of cells with inhibitor in the presence of WT BRAF (Wan et al, 2004; Garnett et al, 2005; Heidorn et al, 2010; Hazivassiliou et al, 2010; Poulikakos et al, 2010). This paradoxical ERK activation is also seen in cells expressing kinase-dead or impaired versions of BRAF such as D594V, which occur with low frequency in some cancers (Wan et al, 2004; Heidorn et al, 2010). Unlike BRAF V600E, which occurs exclusively of activating RAS mutations, kinase-impaired versions of BRAF are coincident with RAS mutations in human cancers, and indeed, paradoxical activation of ERK signaling in the presence of inactive BRAF is enhanced in the presence of oncogenic RAS (Heidorn et al, 2010; reviewed in Holderfield et al, 2014). Although the details remain to be worked out, paradoxical ERK activation in the presence of inactive BRAF appears to rely on enhanced dimerization with and transactivation of CRAF (Heidorn et al, 2010; Hazivassiliou et al, 2010; Poulikakos et al, 2010; Roring et al, 2012; Rajakulendran et al, 2009; Holderfield et al, 2013; Freeman et al, 2013; reviewed in Roskoski, 2010; Samatar and Poulikakos, 2014; Lavoie and Therrien, 2015)

external resources
NCBI:1457785
REACTOME:R-HSA-6802955
PUBMED:25435214
PUBMED:20674547
PUBMED:24957944
PUBMED:23352452
PUBMED:20130576
PUBMED:23680146
PUBMED:16364920
PUBMED:25907612
PUBMED:15035987
PUBMED:20179705
PUBMED:19727074
PUBMED:20141835
PUBMED:22510884

genes
ARAF , ARRB1 , ARRB2 , BRAF , CSK , FGA , FGB , FGG , FN1 , HRAS , ITGA2B , ITGB3 , JAK2 , KRAS , MARK3 , MAP3K11 , NRAS , PEBP1 , PHB , MAPK1 , MAPK3 , MAP2K1 , MAP2K2 , RAF1 , RAP1A , RAP1B , SRC , TLN1 , VCL , VWF , YWHAB , BRAP , IQGAP1 , KSR1 , CNKSR1 , CNKSR2 , APBB1IP , KSR2 ,