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This cascade participates in the regulation of several cellular mechanisms like: apoptosis, cell cycle progression, differentiation, proliferation and transformation to the cancerous state in response to growth factors, cytokines and hormones. First discovered in 1938<ref>PMID:16649144</ref> as a retroviral oncogene B-RAF plays a key role on all studies concerning cancer therapies and other biomedical applications.  

In a third study, Hatzivassiliou and colleagues reported that RAF inhibitor treatment results in the paradoxical induction of phospho-MEK and phospho-ERK levels in the wild-type RAS/RAF human Melanoma<ref>PMID:20141835</ref>. They showed that knockdown of C-RAF, but not B-RAF, in human colorectal carcinoma

HCT116 (mutant K-RAS) cells reverses the phospho-MEK induction observed after RAF inhibitor treatment, indicating that C-RAF has a major role in signaling to MEK, a result that is in agreement with the above two studies. <br />

These studies indicate that the binding of an inhibitor to C-RAF leads to the formation of a C-RAF homodimer and C-RAF activation resulting in downstream MEK-ERK activation. Another possible, but not mutually exclusive, mechanism is that binding of an inhibitor to B-RAF leads to the formation of a B-RAF–C-RAF heterodimer and C-RAF activation. That RAF-kinase-induced paradoxical activation occurs in B-RAF -/- mouse embryonic fibroblasts does not rule out the possibility that B-RAF–C-RAF heterodimers play a role in paradoxical activation. A recent study showed that A-RAF acts as a Scaffold to stabilize the heterodimers of B-RAF and C-RAF<ref>PMID:22927515</ref>.  

RAS mutations occur in 15–30% of all human cancers, and B-RAF mutations occur in 30–60% of melanomas, 30–50% of thyroid cancers, and 5–20% of colorectal cancers. B-RAF mutants occur in a variety of cancers while mutants of the other two RAF enzymes in cancers are very rare. The majority of B-RAF mutations occur in the activation segment or in the glycine-rich loop. These mutations disrupt the inactive state to favor the active state. A Val600Glu mutation is one of the more known B-RAF mutations. This mutation occurs within the activation segment where the introduction of negative charges favors the formation of an active conformation. The introduction of glutamate into the activation segment of C-RAF fails to produce an activated enzyme most likely owing to the need for a negatively charged N-region for activity. <br />

RAF kinases are attractive cancer drug targets. Pre-clinical studies with cell lines and tumor xenographs bearing B-RAF mutations indicate that RAF kinase inhibitors are effective in decreasing cell proliferation. PLX4032, which has higher affinity for B-RAF than wild-type B-RAF, inhibits cancer progression in several animal models. The compound has demonstrated efficacy in Phase I clinical<ref>PMID:20472680</ref> trials in the treatment of melanoma patients. Sorafenib has a lower affinity for B-RAF than C-RAF and is ineffective as monotherapy in the treatment of melanoma. RAF kinase inhibitor treatment of cancers with wild-type or activated mutant RAS co-expressed with wild-type B-RAF may be deleterious owing to up-regulation of RAF kinase signaling. Deciphering the mechanisms of RAS-RAF-MEK-ERK signaling continues to be an important and challenging task.

[http://www.rcsb.org/pdb/explore/explore.do?structureId=1UWH PDB file for 1UWH]

== References ==

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== Protreopedia Page Contributors and Editors ==

Kostika Sofroni and Gilles Dupouy