Emerging BRAF Mutations in Cancer Progression and Their Possible Effects on Transcriptional Networks

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.

The mechanism of activation of monomeric B-Raf V600E

“…B-Raf mutations are found in more than of melanomas, as well as being prevalent in thyroid, ovarian, and colorectal cancers [6] . These mutations are grouped into three classes [10] . Mutations involving B-Raf V600 residue belong to Class I.…”

“…Class II mutations are also kinase activated mutations independent from Ras. These mutations, however, occur on residues other than Val600, in particular residues of the AS-H1 inhibitory loop (residues 597–604), P-loop including Gly464 and Gly469, and activation segment involving Leu597 and Lys601 [10] . The final class of B-Raf mutations, Class III mutations, also occur on residues other than V600; however, they are kinase impaired mutations.…”

Immunomodulatory Properties of BRAF and MEK Inhibitors Used for Melanoma Therapy—Paradoxical ERK Activation and Beyond

“…In most cases of melanoma, the ERK pathway is constitutively activated and promotes melanoma development due to dysregulation of the cell cycle and apoptosis [ 24 ]. In about 60% of cutaneous melanomas caused by intermittent sun exposure, a genetic gain-of-function mutation of the BRAF gene causes hyperactivity of the downstream ERK kinase [ 25 ]. More than 97% of BRAF mutations are located in codon 600 of the BRAF gene.…”

The Mechanism of Activation of Monomeric B-Raf V600E

“…[6] These mutations are grouped into three classes. [10] Mutations involving B-Raf V600 residue belong to Class I. Class I mutants activate Raf through mimicking activation loop phosphorylation, causing B-Raf to adopt an active configuration.…”

“…These mutations, however, occur on residues other than Val600, in particular residues of the AS-H1 inhibitory loop (residues 597-604), P-loop including Gly464 and Gly469, and activation segment involving Leu597 and Lys601. [10] The final class of B-Raf mutations, Class III mutations, also occur on residues other than V600; however, they are kinase impaired mutations. These Class III mutations require activation via Ras and heterodimerization with C-Raf.…”