Raf (protein)

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Raf (protein)
Mass / length primary structure 606/765/648 amino acids (A-Raf / B-Raf / C-Raf)
Cofactor 2 Zn 2+
Identifier
Gene name (s) ARAF , BRAF , RAF1
Enzyme classification
EC, category 2.7.11.1 ,  protein kinase
Response type Phosphorylation
Substrate ATP + protein
Products ADP + protein phosphate

The Raf proteins (English abbreviation for r apidly a ccelerated f ibrosarcoma or ra t f ibrosarcoma ) are a family of protein kinases that contain the isoforms A-Raf, B-Raf and C-Raf (or Raf- 1) and 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 signaling pathway and Ras-Raf signaling pathway .

Occurrence and function

C-Raf occurs in all tissues of mammals before. B-Raf is in mammals, especially in neuronal tissues and testis expressed , A-Raf during which occurs especially in urogenital tissue.

The Raf play an important role in the MAP kinase signaling pathway by acting as MAP-3K (MAP kinase kinase kinase) and specifically activating MEK-1 and MEK-2 . It has been shown that all three isoforms are able to phosphorylate MEK-1 and MEK-2 directly, as well as that they are probably the only MEK-1 / MEK-2 specific kinases (experiments with Drosophila melanogaster and C. elegans ). Regulation probably takes place - also depending on the individual isoforms - by the small G protein Ras, which must be present in its active, GTP- bound form.

C-Raf

C-Raf, also called Raf-1, is believed to be able to gradually regulate its activity depending on interactions with other proteins, phosphorylation of serine, threonine and tyrosine residues as well as the localization in the cell. A bond with Ras is particularly important for activation. In contrast, C-Raf can possibly be deactivated by specific 14-3-3 proteins by binding to the phosphorylated serine of C-Raf. The phosphorylation itself is carried out by various kinases (including c-Src , protein kinase C , PAK and protein kinase B ).

B-Raf

B-Raf has been identified as a potent oncogene (especially in melanoma and multiple myeloma ). Some data suggest that the mutation in B-Raf occurs early in the development of a tumor , even if a mutation in B-Raf alone is not enough to generate a cancer cell from a normal cell . In contrast to C-Raf, B-Raf can also be activated by Rap1 ( Ra s-related p roteine), which u. U. could even be the dominant mechanism. This difference is probably due to the different CRD ( cysteine- rich domains).

BRAF protein and skin cancer

The BRAF protein is an important component of the RAS-RAF-MEK-ERK (MAPK) signaling pathway, which is involved in the normal growth and survival of cells. Mutations in the BRAF protein at amino acid position 600 make this signaling pathway overactive. In combination with other mutations, this can lead to uncontrolled cell growth and thus the development of cancer. It is estimated that such mutations of the BRAF protein are found in 50–60% of all melanomas. Patients with advanced melanoma who have such a mutation can be treated with BRAF or MEK inhibitors. For example, treatment with the BRAF inhibitor vemurafenib leads to tumor regression in half of the patients. However, the tumors usually become resistant after a short time.

BRAF mutation test

The BRAF mutation test can identify tumors with the BRAF mutation and should determine their possible response to BRAF inhibitors such as B. Vemurafenib help to assess. Testing can be done using DNA-based methods or immunohistochemistry for the most common mutation (BRAF-V600E).

structure

All three isoforms each have three highly conserved regions (CR1, CR2 and CR3). The first two regions probably regulate the catalytic activity of Raf, while the kinase activity is located in the CR3 region. The binding to Ras occurs on the CR1 domain.

literature

  • R. Marais, CJ Marshall: Control of the ERK MAP kinase cascade by Ras and Raf . In: Cancer Surv. tape 27 , 1996, pp. 101-125 , PMID 8909797 .
  • KE Mercer, CA Pritchard: Raf proteins and cancer: B-Raf is identified as a mutational target . In: Biochim. Biophys. Acta . tape 1653 , no. 1 , June 2003, p. 25-40 , PMID 12781369 .

Individual evidence

  1. ^ R. Dummer, KT Flaherty: Resistance patterns with tyrosine kinase inhibitors in melanoma: new insights. In: Current Opinion in Oncology . Volume 24, Number 2, March 2012. PMID 22316627 . (Review).
  2. ↑ J. Avruch, A. Khokhlatchev, JM Kyriakis, Z. Luo, G. Tzivion, D. Vavvas, XF Zhang: Ras activation of the Raf kinase: tyrosine kinase recruitment of the MAP kinase cascade. In: Recent Prog Horm Res. 56, 2001, pp. 127-155. PMID 11237210
  3. ↑ a b c G. Pearson, F. Robinson, T. Beers Gibson, BE Xu, M. Karandikar, K. Berman, MH Cobb: Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. In: Endocr Rev . 22 (2), Apr 2001, pp. 153-183. PMID 11294822
  4. ↑ MJ Garnett, R. Marais: Guilty as charged: B-RAF is a human oncogene. In: Cancer Cell . Volume 6, Number 4, October 2004, pp. 313-319. ISSN  1535-6108 . doi: 10.1016 / j.ccr.2004.09.022 . PMID 15488754 . (Review).
  5. ↑ Mutations of the BRAF gene in human cancer , www.nature.com (June 20, 2012)
  6. ↑ C. Garbe, S. Abusaif, TK Eigenler: Vemurafenib. In: Recent results in cancer research. Advances in cancer research. Progre? S dans les recherches sur le cancer. Volume 201, 2014, pp. 215-225. doi : 10.1007 / 978-3-642-54490-3_13 . PMID 24756795 (Review).
  7. ↑ D. Capper, AS Berghoff, M. Magerle, A. Ilhan, A. Wöhrer, M. Hackl, J. Pichler, S. Pusch, J. Meyer, A. Habel, P. Petzelbauer, P. Birner, A. von Deimling, M. Preusser : Immunohistochemical testing of BRAF V600E status in 1,120 tumor tissue samples of patients with brain metastases. In: Acta Neuropathol. 123 (2), Feb 2012, pp. 223-233. doi: 10.1007 / s00401-011-0887-y .
  8. ↑ D. Capper, M. Preusser, A. Habel, F. Sahm, U. Ackermann, G. Schindler, S. Pusch, G. Mechtersheimer, H. Zentgraf, A. von Deimling: Assessment of BRAF V600E mutation status by immunohistochemistry with a mutation-specific monoclonal antibody. In: Acta Neuropathol. 122 (1), Jul 2011, pp. 11-19. doi: 10.1007 / s00401-011-0841-z .

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