c-Raf
Template:PBB 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 (EC 2.7.11.1). Template:PBB Summary
Discovery and role in cancer
The first raf gene that was found was the oncogene v-raf.[1] 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.[2] A-Raf (Online Mendelian Inheritance in Man (OMIM): 311010) and B-Raf (Online Mendelian Inheritance in Man (OMIM): 164757) 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.[3]
Regulation of Raf kinase activity
Raf-1 was shown to bind efficiently to Ras only when Ras is bound to GTP, not GDP.[4] In the MAPK/ERK pathway Raf-1 becomes activated when it binds to Ras.[5] 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-1.[6] 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).[7]
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.[8] 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
In the MAPK/ERK pathway Raf-1 phosphorylates and activates MEK, a MAPK kinase.[9] 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
- Sorafenib - a Raf inhibitor
External links
- Domain structure diagrams for Raf-1, A-Raf and B-Raf.
- c-raf+Proteins at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
References
- ^ 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. Template:Entrez Pubmed
- ^ 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. Template:Entrez Pubmed
- ^ 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. Template:Entrez Pubmed
- ^ 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.Template:Entrez Pubmed
- ^ 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. Template:Entrez Pubmed
- ^ J. 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.Template:Entrez Pubmed
- ^ 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. Template:Entrez Pubmed
- ^ 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. Template:Entrez Pubmed
- ^ 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.Template:Entrez Pubmed
Further reading