Figure 3.

Regulation of survival pathways by mutant B-RAF. (A) Mutant B-RAF activation of the mitogen-activated protein kinase (MAPK) pathway. B-RAF mutants, with elevated kinase activity, interact with the microenvironment to hyperactively phosphorylate MAP, which results in the phosphorylation downstream of the kinase MEK and the translocation of ERK into the nucleus. B-RAF mutants with lowered kinase activity regulate the MAPK pathway indirectly through C-RAF. Translocation of ERK to the nucleus via B-RAF/C-RAF signaling results in the expression of metalloproteinases and EMT. (B) Mutant B-RAF activation of the NF-κB pathway. The constitutively active mutant B-RAF activates the NF-κB pathway via IKKβ activation. Activation of NF-κB results in EMT via up-regulation of the metastasis inducer, Snail, as well as other metastatic gene products. NF-κB is inhibited directly through the metastasis suppressor, RKIP. RKIP also indirectly inhibits NF-κB through inhibition of B-RAF activity. (C) Up-regulation of mutant B-RAF via PTEN deletion, PI3K signaling, and AKT overexpression. RAS signaling results in PI3K activation and AKT expression. Normally, PI3K-induced expression of AKT is antagonized by PTEN. However, deletion of PTEN as well as signals from the microenvironment can result in uncontrolled AKT production. Higher levels of AKT expression inhibit mutant B-RAF signaling levels. Inhibition of B-RAF signaling by AKT counterintuitively promotes EMT. When mutant B-RAF signaling is extremely high, cellular defense mechanisms will induce the cells into senescence. AKT inhibition of B-RAF lowers B-RAF signaling to levels high enough to promote EMT and low enough to evade senescence.