| Note | The real sequence A31 G32 A33 was erroneously considered R31 P32. As the A33 was missing in previous sequences, some articles have erroneously assigned wrong numbers to coding mutations and amino acids (i.e. V599E mutation instead of V600E). |
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| | Diagram of the BRAF protein in scale. Numbers inside the blue boxes indicate the exon from which is translated each part of the protein. The three boxes inside represent the conserved regions of the protein with the ARAF and RAF-1 genes (CR1, CR2 and CR3). With green bars are represented three different domains: RBD (Ras binding domain), CRD (Cysteine-rich domain) and KD (Kinase domain). A conserved glycine motif (G-loop) in exon 11 is indicated with a red bar and the activation segment (AS) in exon 15 with a pink bar. The black arrows indicate the major phosphorylation sites of the protein. C: Carboxyl-terminal; N: Amino-terminal. |
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| Description | Amino acids: 766. Molecular Weight: 84436 Daltons. The BRAF gene is a proto-oncogene that belongs to the Serine/Threonine Kinase Family. It is also a member of the RAF Subfamily together with the ARAF and RAF1 genes. |
| Expression | BRAF is expressed in most tissues with high expression in neuronal tissue. |
| Localisation | Cytoplasmic. |
| Function | BRAF is a serine/threonine kinase that belongs to the RAS/RAF/MEK/ERK/MAPK pathway, which is involved in the transduccion of mitogenic signals from the cell membrane to the nucleus. RAS is inactive when binded to GDP, but when it binds to GTP becomes active and promotes phosphorylation and activation of BRAF and the activation of the pathway signal. Several genes have been found to be activated by this pathway, among them, cyclin D1, cyclin D2 and cyclin D3 (self-sufficiency in growth), VEGF (angiogenesis), c-myc (insensitivity to antigrowth signals), b3-integrin (tissue invasion and metastasis) and mdm2 (apoptosis evasion, limitless replicative potential and angiogenesis). |
| Homology | BRAF shares three conserved regions (CR1, CR2 and CR3) with the other two RAF genes: ARAF and RAF1. CR1, which has 131 aa, contains the cysteine-rich domain (CRD) and most of the Ras binding domain (RBD). These two domains bind to RAS-GTP. CR2, which has 16 aa, is rich in serine and threonine residues, including S365 as an inhibitory phosphorylation site. Finally CR3, which has 293 aa and has the kinase domain, contains also the G-loop GXGXXG motif (highly conserved in most of the human kinases), the activation segment and the regulatory phosphorylation sites S446, S447, D448, D449, T599 and S602. |
| Entity | Melanoma |
| Note | BRAF is mutated in 70% of malignant melanomas. The mutation V600E is an early event and alone is insufficient for the development of melanoma as it is present in 80% of primary melanomas and 80% of nevi, which are the first lesions associated with this tumor. No BRAF mutations are associated with uveal melanoma. |
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| Diagram with BRAF mutations found in melanoma. The black arrows indicate the mutations. The mutations inside a box are in the same amino acid. The hotspot mutation V600E is in red. Numbers inside the blue boxes indicate the exon from which is translated each part of the protein. The three boxes inside represent the conserved regions of the protein with the ARAF and RAF-1 genes (CR1, CR2 and CR3). A conserved glycine motif (G-loop) in exon 11 is indicated with a red bar and the activation segment (AS) in exon 15 with a pink bar. C: Carboxyl-terminal; N: Amino-terminal. |
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| Entity | Colorectal cancer |
| Note | BRAF mutation V600E is associated with mismatch repair deficiency (MSI) and found in 40% of the cases while in mismatch repair proficient tumors (MSS) the frequency is around 5%. Gastric and endometrial MSI and MSS tumors do not have BRAF mutations. In sporadic MSI colon cases this mutation is found in proximal colon tumors with MLH1 methylation (80% of cases), while in tumors from the hereditary nonpolyposis colorectal cancer (HNPCC), either with MLH1, MSH2 or MSH6 germline mutations or none, no BRAF mutations are detected. Because of this it has been proposed the use of the BRAF V600E mutation for HNPCC diagnostic as a exclusion criteria for germline mutation in mismatch repair genes. |
| Prognosis | Even though its association with sporadic MSI suggest BRAF as a good prognosis factor, it has been also associated to metastatic colorectal MSS cancers. In this cases, BRAF associates with poor prognosis. |
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| Diagram with BRAF mutations found in colorectal cancer. The black arrows indicate the mutations. The mutations inside a box are in the same amino acid. The hotspot mutation V600E is in red. Numbers inside the blue boxes indicate the exon from which is translated each part of the protein. The three boxes inside represent the conserved regions of the protein with the ARAF and RAF-1 genes (CR1, CR2 and CR3). A conserved glycine motif (G-loop) in exon 11 is indicated with a red bar and the activation segment (AS) in exon 15 with a pink bar. C: Carboxyl-terminal; N: Amino-terminal. |
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| Entity | Ovarian cancer |
| Note | The only BRAF mutation is V600E which is found in 30% of low-grade serous carcinoma and borderline tumors. The mutation seems to occur very early in the development. High-grade tumors do not show BRAF mutations. |
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| Entity | Thyroid cancer |
| Note | In thyroid papillary cancer the only BRAF mutation present is V600E with a frequency around 50%. The K601E mutation has also been found in some cases of the follicular variant of thyroid cancer. |
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| Entity | cell lines |
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| Mutations of BRAF in cell lines from colorectal cancer, gastric cancer, endometrial cancer, melanoma and thyroid cancer. It is indicated the MSI status and KRAS mutations in the colorectal, gastric and endometrial cell lines. NRAS mutations are indicated in melanoma and thyroid cell lines. |
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