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C-Raf

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

The first raf gene that was found was the oncogene v-raf. 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. A-Raf and B-Raf 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.

Regulation of Raf kinase activity

Raf-1 was shown to bind efficiently to Ras only when Ras is bound to GTP, not GDP. In the MAPK/ERK pathway Raf-1 becomes activated when it binds to Ras. 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. 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).

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. 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. This allows Raf-1 to function as part of a kinase cascade: Raf-1 phosphorylates MEK which phosphorylates MAPK (see MAPK/ERK pathway).