C-Raf
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2008-07-08T02:39:27Z
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{{lowercase|title=c-Raf}}
{{PBB|geneid=5894}}
'''c-raf''' is gene that [[Genetic code|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 pathway|MAPK/ERK signal transduction pathway]] as part of a protein kinase cascade. Raf-1 is a [[serine/threonine-specific kinase]] ({{EC number|2.7.11.1}}).
{{PBB_Summary
| section_title =
| summary_text = Raf-1 is a MAP kinase kinase kinase (MAP3K) which functions downstream of the Ras family of membrane associated GTPases to which it binds directly. Once activated Raf-1 can phosphorylate to activate the dual specificity protein kinases [[MEK1]] and [[MEK2]] which in turn phosphorylate to activate the serine/threonine specific protein kinases [[ERK1]] and [[ERK2]]. Activated [[Extracellular signal-regulated kinases|ERK]]s are pleiotropic effectors of cell physiology and play an important role in the control of gene expression involved in the cell division cycle, apoptosis, cell differentiation and cell migration. [Contributed text]<ref>{{cite web | title = Entrez Gene: RAF1 v-raf-1 murine leukemia viral oncogene homolog 1| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5894| accessdate = }}</ref>
}}
==Discovery and role in cancer==
The first ''raf'' gene that was found was the [[oncogene]] v-raf.<ref name="Mark1984">G. E. Mark and U. R. Rapp (1984) "Primary structure of v-raf: relatedness to the src family of oncogenes" in ''[[Science (journal)|Science]]'' Volume 224, pages 285-289. {{Entrez Pubmed|6324342}}</ref> 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.<ref name="Shimizu1986">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. {{Entrez Pubmed|2843497}}</ref> A-Raf ({{OMIM|311010}}) and [[BRAF (gene)|B-Raf]] ({{OMIM|164757}}) are two protein kinases with similar sequences to Raf-1. Mutations in [[BRAF (gene)|B-Raf]] genes are found in several types of cancer. The Raf kinases are targets for [[Chemotherapy|anticancer drug]] development.<ref name="Sridhar2005">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. {{Entrez Pubmed|15827342}}</ref>
==Regulation of Raf kinase activity==
Raf-1 was shown to bind efficiently to Ras only when Ras is bound to [[Guanosine triphosphate|GTP]], not [[Guanosine diphosphate|GDP]].<ref name="Zhang1993"> 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 (journal)|Nature]]'' Volume 364, pages 308-313.{{Entrez Pubmed|8332187}}</ref>
In the [[MAPK/ERK pathway]] Raf-1 becomes activated when it binds to [[Ras]].<ref name="Terai2005">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. {{Entrez Pubmed|15711535}}</ref> 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.<ref name="Avruch2001">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.{{Entrez Pubmed|11237210}}</ref> Several MAPK kinase kinase kinases have been suggested to be important for phosphorylation of Raf-1 as well as positive feedback phosphorylation by [[Mitogen-activated protein kinase|MAPK]] ([[Extracellular signal-regulated kinases|ERK]]).<ref name="Balan2006">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. {{Entrez Pubmed|16407412}}</ref>
Binding of [[14-3-3 protein|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.<ref name="Rodriguez-Viciana2006">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. {{Entrez Pubmed|16630891}}</ref> 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 [[Mitogen-activated protein kinase kinase|MEK]].
==Targets of Raf-1==
In the [[MAPK/ERK pathway]] Raf-1 phosphorylates and activates [[Mitogen-activated protein kinase kinase|MEK]], a [[Mitogen-activated protein kinase|MAPK]] kinase.<ref name="Kyriakis1992">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 (journal)|Nature]] Volume 358, pages 417-421.{{Entrez Pubmed|1322500}}</ref> This allows Raf-1 to function as part of a kinase cascade: Raf-1 phosphorylates [[Mitogen-activated protein kinase kinase|MEK]] which phosphorylates [[Mitogen-activated protein kinase|MAPK]] (see [[MAPK/ERK pathway]]).
[[Image:RAF.png|thumb|right|Diagramatic representation of how Raf-1 (RAF) might shift between active and inactive conformations and control activation of [[Mitogen-activated protein kinase kinase|MEK]]. In this diagram, "P" represents [[phosphate]], "259" indicates [[serine]]-259 in the Raf-1 structure and [[AKT]] is a protein kinase that can phosphorylate serine-259 of Raf-1. [[EGF]] is a growth factor that activates RAS, and PP1 is a [[Protein phosphatase|phosphatase]] that has been shown to dephosphorylate serine-259 of Raf-1. Additional details are given in the main text of this article.]]
==See also==
*[[Sorafenib]] - a Raf inhibitor
==External links==
*Domain structure [http://www.ebi.ac.uk/interpro/ISpy?ipr=IPR003116&tax_id=9606 diagrams] for Raf-1, A-Raf and B-Raf.
*{{MeshName|c-raf+Proteins}}
==References==
{{reflist}}
==Further reading==
{{refbegin | 2}}
{{PBB_Further_reading
| citations =
*{{cite journal | author=Li P, Wood K, Mamon H, ''et al.'' |title=Raf-1: a kinase currently without a cause but not lacking in effects. |journal=Cell |volume=64 |issue= 3 |pages= 479–82 |year= 1991 |pmid= 1846778 |doi= }}
*{{cite journal | author=Reed JC, Zha H, Aime-Sempe C, ''et al.'' |title=Structure-function analysis of Bcl-2 family proteins. Regulators of programmed cell death. |journal=Adv. Exp. Med. Biol. |volume=406 |issue= |pages= 99–112 |year= 1997 |pmid= 8910675 |doi= }}
*{{cite journal | author=Geyer M, Fackler OT, Peterlin BM |title=Structure--function relationships in HIV-1 Nef. |journal=EMBO Rep. |volume=2 |issue= 7 |pages= 580–5 |year= 2001 |pmid= 11463741 |doi= 10.1093/embo-reports/kve141 }}
*{{cite journal | author=Dhillon AS, Kolch W |title=Untying the regulation of the Raf-1 kinase. |journal=Arch. Biochem. Biophys. |volume=404 |issue= 1 |pages= 3–9 |year= 2002 |pmid= 12127063 |doi= }}
*{{cite journal | author=Greenway AL, Holloway G, McPhee DA, ''et al.'' |title=HIV-1 Nef control of cell signalling molecules: multiple strategies to promote virus replication. |journal=J. Biosci. |volume=28 |issue= 3 |pages= 323–35 |year= 2004 |pmid= 12734410 |doi= }}
*{{cite journal | author=Herbert Chen; Muthusamy Kunnimalaiyaan; Jamie J. Van Gompel |title=Medullary thyroid cancer: the functions of raf-1 and human achaete-scute homologue-1. |journal=Thyroid |volume=15 |issue= 6 |pages= 511–21 |year= 2006 |pmid= 16029117 |doi= 10.1089/thy.2005.15.511 }}
}}
{{refend}}
{{Serine/threonine-specific protein kinases}}
{{Oncogenes}}
[[Category:Protein kinases]]
[[Category:EC 2.7.11]]
[[de:Raf (Protein)]]
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