Figure 7. Schematic representation of RAF paradoxical activation.

(A) In physiological conditions, upon Receptor Tyrosine Kinase (RTK) activation, receptor clustering induces RAS recruitment to the membrane. This results in dimerization of B/CRAF and subsequent phosphorylation that, in fine, induces ERK phosphorylation. (B) When BRAF is mutated to BRAF^V600E it is able to dimerize without RAS recruitment and induce ERK activation independently from upstream signals. ERK activation results in Sprouty’s up-regulation (SPRY) and therefore moderation of the pathway. (C) When treated with PLX-4720, BRAF^V600E is stabilized in a form that allows its dimerization with CRAF. This complex is then further stimulated by hyperactive PI3’K, leading to paradoxical ERK activation.