c-raf is gene that codes for a protein kinase. That protein is sometimes called c-Raf and will be called "Raf-1" here. The Raf-1 protein functions in the MAPK/ERK signal transduction pathway as part of a protein kinase cascade. Raf-1 is a serine/threonine-specific kinase ().

Discovery and role in cancer

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The first raf gene that was found was the oncogene v-raf G. E. Mark and U. R. Rapp (1984) "Primary structure of v-raf: relatedness to the src family of oncogenes" in Science Volume 224, pages 285-289. . Normal (non-oncogenic) cellular homologs of v-raf were soon found to be conserved components of eukaryotic genomes and it was shown that they could mutate and become oncogenes K. Shimizu, Y. Nakatsu, S. Nomoto and M. Sekiguchi. (1986) "Structure of the activated c-raf-1 gene from human stomach cancer" in Int. Symp. Princess Takamatsu Cancer Res. Fund Volume 17, pages 85-91. . A-Raf () and Raf-B () are two protein kinases with similar sequences to Raf-1. Mutations in B-Raf genes are found in several types of cancer. The Raf kinases are targets for anticancer drug development S. S. Sridhar, D. Hedley and L. L. Siu (2005) "Raf kinase as a target for anticancer therapeutics" in Molecular cancer therapeutics Volume 4, pages 677-685. .

Regulation of Raf kinase activity

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Raf-1 was shown to bind efficiently to Ras only when Ras is bound to GTP, not GDP X. F. Zhang, J. Settleman, J. M. Kyriakis, E. Takeuchi-Suzuki, S. J. Elledge, M. S. Marshall, J. T. Bruder, U. R. Rapp and J. Avruch (1993) "Normal and oncogenic p21ras proteins bind to the amino-terminal regulatory domain of c-Raf-1" in Nature Volume 364, pages 308-313.. In the MAPK/ERK pathway Raf-1 becomes activated when it binds to Ras K. Terai and M. Matsuda (2005) "Ras binding opens c-Raf to expose the docking site for mitogen-activated protein kinase kinase" in EMBO reports Volume 6, page 251-255. . It is thought that phosphorylation of Raf-1 (at sites such as serine-338) upon binding of Raf-1 to Ras locks Raf-1 into an activated conformation that is then independent of binding to Ras for the continued activity of Raf-1J. Avruch, A. Khokhlatchev, J. M. Kyriakis, Z. Luo, G. Tzivion, D. Vavvas X. F. Zhang (2001) "Ras activation of the Raf kinase: tyrosine kinase recruitment of the MAP kinase cascade" in Recent Progress in Hormone Research Volume 56, pages 127-155.. Several MAPK kinase kinase kinases have been suggested to be important for phosphorylation of Raf-1 as well as positive feedback phosphorylation by MAPK (ERK)V. Balan, D. T. Leicht, J. Zhu, K. Balan, A. Kaplun, V. Singh-Gupta, J. Qin, H. Ruan, M. J. Comb and G. Tzivion (2006) "Identification of novel in vivo Raf-1 phosphorylation sites mediating positive feedback Raf-1 regulation by extracellular signal-regulated kinase" in Molecular biology of the cell Volume 17, pages 1141-1153. .

Binding of 14-3-3ζ to phosphorylated serine-259 of Raf-1 is associated with inhibition of Raf-1 kinase activity. As shown in the figure (to the right), it is thought that a 14-3-3 dimer can bind to two phosphoserines of Raf-1 when it is inactive. Dephosphorylation of serine-259 has been associated with activation of Raf-1 P. Rodriguez-Viciana, J. Oses-Prieto, A. Burlingame, M. Fried and F. McCormick (2006) "A phosphatase holoenzyme comprised of Shoc2/Sur8 and the catalytic subunit of PP1 functions as an M-Ras effector to modulate Raf activity" Molecular Cell Volume 22, pages 217-230. . In the model shown, the binding of GTP to Ras and the dephosphorylation of serine-259 of Raf-1 allows Raf-1 to take on a conformation that allows binding of Raf-1 to Ras-GTP. This represents a conformation in which Raf-1 can phosphorylate the downstream target MEK.

Targets of Raf-1

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In the MAPK/ERK pathway Raf-1 phosphorylates and activates MEK, a MAPK kinase J. M. Kyriakis, H. App, X. F. Zhang, P. Banerjee, D. L. Brautigan, U. R. Rapp and J. Avruch (1992) "Raf-1 activates MAP kinase-kinase" in ''Nature Volume 358, pages 417-421.. This allows Raf-1 to function as part of a kinase cascade: Raf-1 phosphorylates MEK which phosphorylates MAPK (see MAPK/ERK pathway).

See also

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• Sorafenib - a Raf inhibitor

External links

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• Domain structure diagrams for Raf-1, A-Raf and B-Raf.

References

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Protein kinases | EC 2.7.11