C-Raf

The Raf proteins ( englspr. Abbreviation for accelerated fibrosarcoma proceed rapidly or rat fibrosarcoma ) is a family of protein kinases that isoforms A- Raf, B -Raf and C -Raf and includes (or Raf -1) belongs to the serine / threonine protein kinases of the heterogeneous class EC 2.7.11.1. They play an important role in the MAP kinase pathway and the Ras -Raf signaling pathway.

Occurrence and function

C-Raf occurs in all mammalian tissues. B-Raf is expressed in mammals, particularly in neural tissue, and in the testes, while the A- Raf occurs especially in urogenital tissue.

The Raf play an important role in the MAP kinase signaling pathway by acting as a MAP -3K (MAP kinase kinase kinase) and specific MEK -1 and activate MEK -2. It has been shown that all three isoforms are capable of MEK -1 and MEK -2 to phosphorylate directly, and that they are probably the only MEK-1-/MEK-2-spezifischen kinases ( experiments with Drosophila melanogaster and C. elegans). Regulation is effected probably - as a function of the individual isoforms - by the small G- protein Ras, which has to be in its active, GTP - bound form.

From the C- Raf Raf - 1 also known, it is believed that its activity as a function of interactions with other proteins, phosphorylation of serine, threonine and tyrosine residues, as well as the location in the cell can be adjusted gradually. Important for the activation of this is primarily a binding to Ras. However can be disabled by the specific 14-3 -3- C-Raf proteins may be by tying it to the phosphorylated serine of the C- Raf. The phosphorylation is carried out by various kinases themselves ( among others c- Src, protein kinase C, protein kinase PAK and B).

Recently B -Raf was identified as a potent oncogene (especially multiple myeloma ). Some data indicate that the mutation in B -Raf occurs early in the development of a tumor, even if a B-Raf mutation in the sole is not sufficient to generate a cancer cell from a normal cell. In contrast to C-Raf Raf - B may also Rap1 ( Ras -related proteins) are activated, which may may even be the dominant mechanism. This difference is most probably the different CRD (cysteine ​​- rich domains ) basis.

BRAF protein, and skin cancer

The BRAF protein is a key component of the RAS - RAF pathway, which is involved in normal growth and survival of cells. Mutated forms of the BRAF protein can cause this pathway to be active, which can lead to uncontrolled cell growth and cancer. Such mutations in the BRAF protein found to be around 60 % of all melanomas.

BRAF Mutation Test

BRAF mutation test is a diagnostic test, which makes it possible to identify tumors with BRAF mutation. This allows physicians to quickly and with high security one possible response of tumors to treatment with BRAF inhibitors such as vemurafenib estimate. Thus, patients can be selected at an early stage, in which a therapy is promising.

Structure

All three isoforms have three highly conserved regions (CR1, CR2 and CR3 ), respectively. The first two regions likely to regulate the catalytic activity of Raf, while the kinase activity to be localized in the region of CR3. Binding to Ras happens at the CR1 domain.