Embedded Files
Diseases Associated with Braf (21)
Diseases Associated with Braf (21)
- Melanoma
- In 70% of melanoma cases there is a Braf mutation. The most common mutation, in 92% of mutations, in Braf is at residue 600 where Valine becomes Glutamine. (15)
- Colorectal Cancer
- The V600E mutation is also associated with colorectal cancer. (21)
- Thyroid Cancer
- V600E mutation in Braf is the mutation most associated with thyroid cancers. (21)
- Lung Cancer
- A mutation in Braf for nonsmall cell lung cancer was a leucine to valine mutation at exon 15 residue 596. (21)
- Cardiofaciocutaneous Syndrome
- Numerous variations in Braf have been found to be associated with Cardiofaciocutaneous Syndrome by compaing sequences between unrelated individuals who all present with this syndrome. Among the mutations listed were A246P, Q257R, G469E, L485F, K499E, E501K, E501G, N581D, G534R, and D638E (21)
Cardiofaciocutaneous Syndrome
Cardiofaciocutaneous Syndrome
Cardiofacioucutaneous Syndrome (CFC) is a genetic disease caused by mutations in proteins involved in the Ras/mitogen-activated protein kinase pathway. The most significant clinical features of the diseases include facial dysformities, congenital heart diseases, skin abnormalities, stunted growth and neurocognitive delay. (25)
CFC is an autosomal dominant hereditery disease of mutations in BRAF, MEK1, MEK2, or KRAS genes. Mutations in these genes caused the loss of regulation in the Ras/MAPK signaling cascade pathways. In 75% of CFC patients there are mutations in BRAF. (25)
Most mutations in BRAF causing CFC are the result of mutations in exons 6 or 12. The most common BRAF mutations that cause CFC are Q257R and G469E. (25)
Correlated phenotypic expressions of CFC Braf mutations are pulmonic stenosis, hypertrophic cardiomyopathy, septal defects, feeding problems and neurocognitive delay. (25)
Braf and Cancers
Braf and Cancers
As an integral member of the MAPK signaling pathway, which is responsible for controlling cell proliferation, growth, and death, it is unsurprising that mutations in Braf are associated with so many different forms of cancers.
From the biochemical pathways shown in the above diagram, it is clear to see the relationship of Braf with many of the cell problems that is associated with cancer: proliferation, evading apoptosis, and sustained angiogenesis.
As discussed in the earlier section of Braf related cancers and their corresponding mutations, it was easy to see a pattern of V600E being a common Braf mutation leading to cancers. This one mutation has such large implications because it causes the protein to act as though residues T599 and/or S602 were phosphorylated, causing Braf to act as though it is always in its active state. (15)
Available Treatments
Available Treatments
Inhibitors to Braf have been developed but were met with surprise when researchers realized the phosphorylation of EPK in the MAPK signaling cascade increased phosphorylation rather than decrease it as they were expecting an inhibitor of Braf to. (27)
Further research led to the understanding that using these Braf inhibitors promotes dimerization of Raf proteins, which then have increased efficiency in phosphorylating its substrates. (27)
A better understanding of the dimer structure that Braf forms will allow for future drugs to target the dimerized form as well, and cause it to remain in an inactive state in order to prevent Braf from increased kinase activities. A new dimer structure of Braf in its inactive state shows that it is inactive due to a structural change preventing Braf from binding with its substrates. (13)
Vemurafenib is a cancer therapy used in advance melanoma patients. It works by selectively inhibiting the common V600E Braf mutation, so it is only a relevant treatment option for patients with this mutation. Inhibiting Braf causes decreased kinase function, preventing the oversignaling of other proteins down the signaling cascade that would have otherwise been activated by Braf's kinase abilities. (28) Vemurafenib has varying effectiveness between patients. (20)
Google Sites
Report abuse