V-raf-1 murine leukemia viral oncogene homolog 1
PDB rendering based on 1c1y. The Protein Data Bank ( PDB) is a repository for 3-D structural data of Proteins and Nucleic acids These data typically obtained by X-ray crystallography
Available structures: 1c1y, 1faq, 1far, 1gua, 1rfa
Identifiers
Symbol(s)	RAF1; CRAF; Raf-1; c-Raf
External IDs	OMIM: 164760 MGI: 97847 HomoloGene: 48145
RNA expression pattern
More reference expression data
Orthologs
	Human	Mouse
Entrez	5894	110157
Ensembl	ENSG00000132155	ENSMUSG00000000441
Uniprot	P04049	Q3UR68
Refseq	NM_002880 (mRNA) NP_002871 (protein)	NM_029780 (mRNA) NP_084056 (protein)
Location	Chr 3: 12.6 - 12.68 Mb	Chr 6: 115.58 - 115.64 Mb
Pubmed search	[1]	[2]

c-raf is gene that codes for a protein kinase. The Human Genome Organisation (HUGO is an organization involved in the Human Genome Project, a project about mapping the human genome The Mouse Genome Informatics (MGI website is run by The Jackson Laboratory. HomoloGene, a tool of the National Center for Biotechnology Information (NCBI is a system for automated detection of homologs (similarity attributable to descent The Entrez Global Query Cross-Database Search System is a powerful Federated search engine or Web portal that allows users to search many discrete Health sciences Ensembl is a joint scientific project between the European Bioinformatics Institute and the Wellcome Trust Sanger Institute, which was launched in 1999 in response to the imminent UniProt is the uni versal prot ein resource a central repository of Protein data created by combining Swiss-Prot, TrEMBL PubMed is a free search engine for accessing the MEDLINE database of citations and abstracts of biomedical research articles The genetic code is the set of rules by which information encoded in genetic material ( DNA or RNA sequences is translated into Proteins A protein kinase is a Kinase Enzyme that modifies other Proteins by chemically adding Phosphate groups to them ( Phosphorylation) 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. The MAPK/ERK pathway is a Signal transduction pathway that couples intracellular responses to the binding of Growth factors to cell surface receptors Raf-1 is a serine/threonine-specific kinase (EC 2.7.11.1). Serine/threonine Protein kinases ( phosphorylate the OH group of Serine or Threonine (which have similar sidechains This article is about the Enzyme Commission codes For the European Commission system for coding chemicals see EC-No. 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. See also Mitogen-activated protein kinase kinase Mitogen-activated protein kinase kinase 1, also known as MAP2K1, is a human Gene. See also Mitogen-activated protein kinase kinase Mitogen-activated protein kinase kinase 2, also known as MAP2K2, is a human Gene. See also Extracellular signal-regulated kinases Mitogen-activated protein kinase 3, also known as MAPK3, is a human Gene. See also Extracellular signal-regulated kinases Mitogen-activated Activated ERKs 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. See also Mitogen-activated protein kinase In Molecular biology, extracellular signal-regulated kinases (ERKs or classical MAP kinases are widely [Contributed text]^[1]

Discovery and role in cancer

The first raf gene that was found was the oncogene v-raf. An oncogene is a protein encoding Gene, which — when deregulated — participates in the onset and development of Cancer. ^[2] 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. ^[3] 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. The Mendelian Inheritance in Man project is a Database that catalogues all the known Diseases with a genetic component, and—when possible—links them The Mendelian Inheritance in Man project is a Database that catalogues all the known Diseases with a genetic component, and—when possible—links them Mutations in B-Raf genes are found in several types of cancer. The Raf kinases are targets for anticancer drug development. Chemotherapy, in its most general sense refers to treatment of disease by chemicals that kill cells specifically those of micro-organisms or Cancer. ^[4]

Regulation of Raf kinase activity

Raf-1 was shown to bind efficiently to Ras only when Ras is bound to GTP, not GDP. Guanosine-5'-triphosphate ( GTP) is a Purine Nucleotide. One role is as substrate for the synthesis of RNA during transcription. Guanosine diphosphate, abbreviated GDP, is a Nucleotide. It is an Ester of Pyrophosphoric acid with the Nucleoside Guanosine ^[5] In the MAPK/ERK pathway Raf-1 becomes activated when it binds to Ras. The MAPK/ERK pathway is a Signal transduction pathway that couples intracellular responses to the binding of Growth factors to cell surface receptors ^[6] 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. ^[7] 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). Mitogen-activated protein (MAP kinases ( are Serine/threonine-specific protein kinases that respond to extracellular stimuli ( Mitogens and regulate various cellular See also Mitogen-activated protein kinase In Molecular biology, extracellular signal-regulated kinases (ERKs or classical MAP kinases are widely ^[8]

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. ^[9] 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. Mitogen-activated protein kinase kinase ( Sic) is a Kinase Enzyme which phosphorylates Mitogen-activated protein kinase.

Targets of Raf-1

In the MAPK/ERK pathway Raf-1 phosphorylates and activates MEK, a MAPK kinase. The MAPK/ERK pathway is a Signal transduction pathway that couples intracellular responses to the binding of Growth factors to cell surface receptors Mitogen-activated protein kinase kinase ( Sic) is a Kinase Enzyme which phosphorylates Mitogen-activated protein kinase. Mitogen-activated protein (MAP kinases ( are Serine/threonine-specific protein kinases that respond to extracellular stimuli ( Mitogens and regulate various cellular ^[10] This allows Raf-1 to function as part of a kinase cascade: Raf-1 phosphorylates MEK which phosphorylates MAPK (see MAPK/ERK pathway). Mitogen-activated protein kinase kinase ( Sic) is a Kinase Enzyme which phosphorylates Mitogen-activated protein kinase. Mitogen-activated protein (MAP kinases ( are Serine/threonine-specific protein kinases that respond to extracellular stimuli ( Mitogens and regulate various cellular The MAPK/ERK pathway is a Signal transduction pathway that couples intracellular responses to the binding of Growth factors to cell surface receptors

Diagramatic representation of how Raf-1 (RAF) might shift between active and inactive conformations and control activation of MEK. Mitogen-activated protein kinase kinase ( Sic) is a Kinase Enzyme which phosphorylates Mitogen-activated protein kinase. 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. A phosphate, an Inorganic chemical, is a salt of Phosphoric acid. Serine (abbreviated as Ser or S) is an Organic compound with the formula H[[oxygen O]]2 CCH NH sub>2CH2OH Akt1, also known as "Akt" or Protein kinase B (PKB is an important molecule in mammalian cellular signaling EGF is a growth factor that activates RAS, and PP1 is a phosphatase that has been shown to dephosphorylate serine-259 of Raf-1. A phosphatase is an Enzyme that removes a Phosphate group from its Substrate by hydrolysing Phosphoric acid mono Esters into Additional details are given in the main text of this article.

See also

• Sorafenib - a Raf inhibitor

External links

• Domain structure diagrams for Raf-1, A-Raf and B-Raf. Sorafenib (Nexavar Bayer) is a drug approved for the treatment of primary kidney cancer (advanced Renal cell carcinoma) and advanced primary liver cancer ( Hepatocellular
• MeSH c-raf+Proteins

References

Further reading