RAF kinase signaling is highlighted in the RAS-RAF-MEK-ERK signal transduction cascade. Activated RAS kinase signaling results in the activation of RAF proteins. Following these events, MEK1 and MEK2 dual specificity protein kinases become phosphorylated and activated. It should be noted that RAF kinases display restricted substrate specificity for these MEK enzymes. The RAF family of protein-serine/threonine kinases comprise of A-RAF, B-RAF, and C-RAF oncogenes originally discovered in the early 1980s. RAF family proteins function as six dimeric members, either in homo- and heterodimer formation. Since there are four RAS members, the total number of RAS-RAF interactions is equivalent to twenty-four. And downstream, with two MEK members available the total number of interactions between RAF-MEK constituents is twelve.
All RAF kinases share three conserved regions (CR): CR1, CR2, and CR3. CR1 consists of cysteine-rich domain (binds to two zinc ions) and a RAS-binding domain. These properties facilitate CR1 interaction with RAS and phospholipids in the membrane. CR2, is a serine/threonine rich domain that facilitates the binding of regulatory protein 14-3-3 upon phosphorylation – this result in inactivation. At the C-terminus is the protein kinase domain, CR3, which contains a downstream stimulatory 14-3-3 binding site. Regulating RAF kinase activity are a number of protein-protein interactions, phosphorylation, dephosphorylation and conformational changes. In their inactivated state, most RAF proteins are found in the cytosol.
It was not until 2002, that B-RAF mutations were noted in cancer cells lines. Most notably, B-RAF has been associated with melanomas and papillary thyroid, ovarian, and colorectal tumors. And to a lesser degree cancers of the lung, pancreas, and bladder have also been found to have aberrant B-RAF activity. Consequently, since B-RAF mutations are involved in several different cancer types it is believed that B-RAF functions as an oncogene driver. In clinical trials, the first RAF inhibitor was Bayer’s Sorafenib (Nexavar). The compound was found to be effective in restricting tumor activity in renal cell carcinoma and hepatocellular cancers and is currently in use for these indications. Recently, PLX4032 was discovered to be a highly selective RAF inhibitor (Roche) and is currently in advanced clinical trials for testing against melanomas.
 Roskoski, R. RAF protein-serine/threonine kinases: Structure and regulation. Biochem Biophys Res Commun. 2010;80: 624-637.
 Solit, DB and Nissan, MH. The “SWOT” of BRAF Inhibition in Melanoma: RAF Inhibitors, MEK Inhibitors or Both? Curr. Oncol. Rep. 2011;13: 479-487.