A-Raf, B-Raf, and c-Raf are the main effectors recruited by GTP-bound Ras to activate the MEK-MAP kinase pathway . Activation of c-Raf is the best understood and involves phosphorylation at multiple activating sites, including Ser338, Tyr341, Thr491, Ser494, Ser497, and Ser499 . p21-activated kinase (PAK) has been shown to phosphorylate c-Raf at Ser338, and the Src family phosphorylates Tyr341 to induce c-Raf activity. Ser338 of c-Raf corresponds to similar sites in A-Raf and B-Raf , although this site is constitutively phosphorylated in B-Raf . Inhibitory 14-3-3 binding sites on c-Raf can be phosphorylated by Akt and AMPK, respectively . While A-Raf, B-Raf, and c-Raf are similar in sequence and function, differential regulation has been observed. Of particular interest, B-Raf contains three consensus Akt phosphorylation sites and lacks a site equivalent to Tyr341 of c-Raf . Research studies have shown that the B-Raf mutation V600E results in elevated kinase activity and is commonly found in malignant melanoma . Six residues of c-Raf become hyperphosphorylated in a manner consistent with c-Raf inactivation. The hyperphosphorylation of these six sites is dependent on downstream MEK signaling and renders c-Raf unresponsive to subsequent activation events .