Potential consequences of mutant BRAF V600E in LCH. (A) In normal LC, mitogens such as growth factors bind to and activate cell-surface receptors, which signal through a complex consisting of adaptor proteins and exchange factors (not shown) to activate the small G-protein RAS on the inner surface of the plasma membrane. Once active, RAS binds to and activates the RAF family of proteins, comprising BRAF, ARAF, and CRAF. RAF then phosphorylates and activates MEK, which subsequently phosphorylates and activates ERK. ERK phosphorylates numerous substrates within the cytoplasm and nucleus, promoting cell division and enhancing survival, movement, and differentiation. (B) In LC from LCH lesions, constitutive activity of the mutant BRAF V600E protein is predicted to bypass the requirement for mitogen induced activation of RAF by RAS. This may lead to dysregulated signaling through the MEK-ERK pathway and thereby favor the survival and proliferation of lesional LCH cells while perturbing their differentiation.