Abstract
Gene mutations can induce cellular alteration and malignant transformation. Development of many types of cancer is associated with mutations in the B-raf proto-oncogene (BRAF) gene. The encoded protein is a component of the mitogen-activated protein kinases/extracellular signal-regulated kinases (MAPK/ERK) signaling pathway, transmitting information from the outside to the cell nucleus. The main function of the MAPK/ERK pathway is to regulate cell growth, migration, and proliferation. The most common mutations in the BRAF gene encode the V600E mutant (class I), which causes continuous activation and signal transduction, regardless of external stimulus. Consequently, cell proliferation and invasion are enhanced in cancer patients with such mutations. The V600E mutation has been linked to melanoma, colorectal cancer, multiple myeloma, and other types of cancers. Importantly, emerging evidence has recently indicated that new types of mutations (classes II and III) also play a paramount role in the development of cancer. In this minireview, we discuss the influence of various BRAF mutations in cancer, including aberrant transcriptional gene regulation in the affected tissues.
Highlights
In the human genome, the B-raf proto-oncogene (BRAF) gene is located on chromosome 7 (7q34)and encodes the BRAF protein, which is composed of 766 amino acids
Dysregulation of the MAPK/extracellular signal-regulated kinases (ERK) signaling pathway is caused by upregulated BRAF activity or impaired kinase activity depending on the BRAF mutation locus [8]
BRAF D594 is located at the active site and its mutation reduces the kinase activity and has been identified in patients suffering from several types of cancer
Summary
The B-raf proto-oncogene (BRAF) gene is located on chromosome 7 (7q34). Dysregulation in the MAPK/ERK cascade due to mutations in constituent proteins of this pathway, including RAS (KRAS and NRAS) and RAF (BRAF), is associated with many types of cancer [7,8]. CR3 has a kinase domain that is located on the C-terminal and is regulated through phosphorylation (Figure 1A) [9,10,11]. Among all the proteins of RAF family members, BRAF is the main activator of MEK kinases. This is due to BRAF’s constant phosphorylation at residue S446 and negatively charged aspartic acid residues at position D448 and D449. The mechanism of how the mutations induce malignancy is different in terms of their interaction with RAS pathway and partners to form dimers, they all are known to activate ERK phosphorylation. The signal is transferred downstream in the presents of RAS mutant (RAS Mut)
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