RAF proto-oncogene serine/threonine-protein kinase also known as proto-oncogene c-RAF or simply c-Raf is an enzyme[1] that in humans is encoded by the RAF1 gene.[2][3] The c-Raf protein functions in the MAPK/ERK signal transduction pathway as part of a protein kinase cascade. C-Raf is a member of the Raf kinase family of serine/threonine-specific protein kinases.
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c-Raf is a MAP kinase kinase kinase (MAP3K) that functions downstream of the Ras subfamily 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 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.[4]
The first raf gene that was found was the oncogene v-raf.[5] 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.[6] 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.[7] There are several quantitative immunochemical methods available to detect Raf kinase inhibiting drugs.[8]
Raf-1 was shown to bind efficiently to Ras only when Ras is bound to GTP, not GDP.[9] In the MAPK/ERK pathway Raf-1 becomes activated when it binds to Ras.[10] 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.[11] 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).[12]
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.[13] 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.
In the MAPK/ERK pathway Raf-1 phosphorylates and activates MEK, a MAPK kinase.[14] This allows Raf-1 to function as part of a kinase cascade: Raf-1 phosphorylates MEK, which phosphorylates MAPK (see MAPK/ERK pathway).
C-Raf has been shown to interact with STUB1,[15] Retinoblastoma-like protein 2,[16] CFLAR,[17] CDC25A,[18][19] Retinoblastoma protein,[16][20] YWHAQ,[21][22][23][24] AKT1,[25] BRAF,[26] Bcl-2,[27] PAK1,[28] Prohibitin,[20] MAP2K1,[22] TSC22D3,[29] HRAS,[30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46] RHEB,[47][48][49] RAP1A,[40][50][51][52] Src,[53] Phosphatidylethanolamine binding protein 1,[22] Protein kinase Mζ,[23] GRB10,[54][55] KRAS,[35][36] MAPK7,[56] Heat shock protein 90kDa alpha (cytosolic), member A1,[15][57] ASK1,[58] FYN,[53] BAG1,[59] YWHAB,[23][34][60][61][62][63] MAPK8IP3,[64][65] YWHAZ,[23][66][67][68][69] YWHAH,[23][62][70] YWHAG,[21][23][71] YWHAE,[62][63] MAP3K1,[72] RRAS2[35][73] and SHOC2.[35]
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