# BRAF

## Overview
The BRAF gene, located on chromosome 7q34, encodes the B-Raf protein, a serine/threonine-specific protein kinase that plays a critical role in the MAPK/ERK signaling pathway. This pathway is essential for regulating cellular processes such as growth, survival, and differentiation. B-Raf, a member of the RAF kinase family, is activated by Ras proteins and is involved in transmitting signals from the cell membrane to the nucleus. Mutations in the BRAF gene, particularly the V600E mutation, are associated with various cancers, making it a significant focus in cancer research and therapy. The protein's structure includes a kinase domain essential for its function and interactions with other proteins, which are crucial for its regulation and activity within cellular signaling pathways (Kannengiesser2008Gene; Wellbrock2010BRAF).

## Structure
The molecular structure of the BRAF protein, encoded by the BRAF gene, is complex and involves multiple domains that contribute to its function as a serine/threonine kinase. The protein structure includes a kinase domain divided into a small N-terminal lobe and a large C-terminal lobe. The N-terminal lobe contains the nucleotide-binding pocket and the phosphate-binding loop, essential for kinase activity, while the C-terminal lobe binds protein substrates and contains the catalytic loop (Kiel2016The). These lobes are connected by a hinge region and an activation segment, which plays a critical role in the regulation of kinase activity (Kiel2016The).

BRAF also features a cysteine-rich domain (CRD), which is crucial for its interaction with other proteins such as the 14-3-3 dimer and MEK1, and is involved in Ras-driven activation and membrane recruitment (Park2019Architecture). The CRD's interaction with the 14-3-3 dimer is particularly important for maintaining BRAF in an autoinhibited state, preventing unwanted activation (Park2019Architecture).

Additionally, the BRAF protein is regulated through phosphorylation at specific sites, such as Ser365 and Ser729, which are engaged by the 14-3-3 dimer to maintain the kinase in its inactive conformation (Park2019Architecture). The structure and interactions of BRAF are critical for its role in cell signaling pathways, and mutations in this protein, particularly in the kinase domain and the CRD, are linked to various cancers (Roskoski2010RAF).

## Function
The BRAF gene encodes the B-Raf protein, a serine/threonine-specific protein kinase that plays a pivotal role in the MAPK/ERK signaling pathway. This pathway is crucial for transmitting signals from the cell membrane to the DNA in the cell nucleus, regulating a variety of cellular processes including growth, survival, and differentiation (Kannengiesser2008Gene; Wellbrock2010BRAF). 

B-Raf, as part of the RAF kinase family, is activated by the binding of Ras-GTP, which recruits it to the plasma membrane where it undergoes phosphorylation. Once activated, B-Raf phosphorylates MEK1 and MEK2, which in turn activate ERK1 and ERK2. These activated ERKs can phosphorylate target proteins in the cytoplasm or translocate into the nucleus to phosphorylate transcription factors that regulate genes involved in proliferation, differentiation, or survival (Tuveson2003BRAF; Michaloglou2007BRAFE600).

In healthy cells, BRAF activity is tightly regulated through receptor tyrosine kinases (RTKs), ensuring that its activity contributes to normal cellular function and signaling. This regulation helps maintain cellular homeostasis and prevents uncontrolled cell proliferation (Michaloglou2007BRAFE600). The protein is expressed in most tissues, with notably high expression in neuronal tissues, underscoring its importance in physiological processes across the organism (Tuveson2003BRAF).

## Clinical Significance
Mutations in the BRAF gene, particularly the V600E mutation, are significant in various cancers, influencing both the prognosis and the therapeutic approach. In melanoma, the presence of BRAF mutations, especially V600E, is pivotal for the administration of targeted therapies with BRAF inhibitors such as vemurafenib and dabrafenib, which have improved survival rates in metastatic cases (Heinzerling2013Mutation). However, resistance to these inhibitors often develops, complicating long-term management (Sclafani2013BRAF).

In colorectal cancer (CRC), BRAF mutations are associated with poor prognosis, particularly in metastatic CRC, where they indicate lower overall survival and resistance to epidermal growth factor receptor (EGFR) inhibitors (Orlandi2015BRAF; Chen2021Pathological). These mutations are also prevalent in serrated polyps and linked with the CpG island methylator phenotype (CIMP) and microsatellite instability (MSI), serving as a marker to rule out Lynch Syndrome (Sclafani2013BRAF).

In papillary thyroid cancer (PTC), BRAF mutations correlate with more aggressive disease features, such as extrathyroidal invasion and higher recurrence rates, significantly impacting clinical management and prognosis (Xing2007BRAF). These mutations are almost exclusively found in PTC, highlighting their critical role in the pathogenesis and progression of this cancer type (Xing2007BRAF).

## Interactions
The BRAF protein, encoded by the BRAF gene, is involved in various protein-protein interactions that are crucial for the MAPK signaling pathway. BRAF forms stable dimers and its kinase activity is significantly enhanced when it is in its full-length form. It interacts with MEK1, acting as a scaffold protein that stabilizes BRAF's active conformation and facilitates its autophosphorylation, which is necessary for full kinase activation. This interaction leads to the phosphorylation of MEK1, a key step in downstream signaling (Cope2018Mechanism).

BRAF also heterodimerizes with CRAF, and this heterodimer has been identified as the most active configuration of BRAF, linked to the development of lung adenocarcinoma in the presence of oncogenic kinase-dead BRAF mutants. The BRAF/CRAF heterodimer exhibits resistance to RAF inhibitors like dabrafenib, suggesting a mechanism for drug resistance in treatments targeting RAF proteins in melanoma (Cope2018Mechanism).

Additionally, BRAF interacts with various macromolecular complexes depending on its mutation status. The oncogenic BRAF V600E mutation, for instance, forms a complex with CDC37 and HSP90, which is crucial for the activity of BRAF V600E. This interaction is significantly stronger than with the wild-type BRAF, affecting the formation and activity of these complexes (Diedrich2017Discrete).


## References


[1. (Tuveson2003BRAF) David A Tuveson, Barbara L Weber, and Meenhard Herlyn. Braf as a potential therapeutic target in melanoma and other malignancies. Cancer Cell, 4(2):95–98, August 2003. URL: http://dx.doi.org/10.1016/s1535-6108(03)00189-2, doi:10.1016/s1535-6108(03)00189-2. (209 citations) 10.1016/s1535-6108(03)00189-2](https://doi.org/10.1016/s1535-6108(03)00189-2)

[2. (Cope2018Mechanism) Nicholas Cope, Christine Candelora, Kenneth Wong, Sujeet Kumar, Haihan Nan, Michael Grasso, Borna Novak, Yana Li, Ronen Marmorstein, and Zhihong Wang. Mechanism of braf activation through biochemical characterization of the recombinant full‐length protein. ChemBioChem, 19(18):1988–1997, August 2018. URL: http://dx.doi.org/10.1002/cbic.201800359, doi:10.1002/cbic.201800359. (43 citations) 10.1002/cbic.201800359](https://doi.org/10.1002/cbic.201800359)

[3. (Wellbrock2010BRAF) Claudia Wellbrock and Adam Hurlstone. Braf as therapeutic target in melanoma. Biochemical Pharmacology, 80(5):561–567, September 2010. URL: http://dx.doi.org/10.1016/j.bcp.2010.03.019, doi:10.1016/j.bcp.2010.03.019. (231 citations) 10.1016/j.bcp.2010.03.019](https://doi.org/10.1016/j.bcp.2010.03.019)

[4. (Kannengiesser2008Gene) Caroline Kannengiesser, Alain Spatz, Stefan Michiels, Alain Eychène, Philippe Dessen, Vladimir Lazar, Véronique Winnepenninckx, Fabienne Lesueur, Sabine Druillennec, Caroline Robert, Joost J. van den Oord, Alain Sarasin, and Brigitte Bressac-de Paillerets. Gene expression signature associated with braf mutations in human primary cutaneous melanomas. Molecular Oncology, 1(4):425–430, January 2008. URL: http://dx.doi.org/10.1016/j.molonc.2008.01.002, doi:10.1016/j.molonc.2008.01.002. (61 citations) 10.1016/j.molonc.2008.01.002](https://doi.org/10.1016/j.molonc.2008.01.002)

[5. (Kiel2016The) Christina Kiel, Hannah Benisty, Veronica Lloréns-Rico, and Luis Serrano. The yin–yang of kinase activation and unfolding explains the peculiarity of val600 in the activation segment of braf. eLife, January 2016. URL: http://dx.doi.org/10.7554/elife.12814, doi:10.7554/elife.12814. (27 citations) 10.7554/elife.12814](https://doi.org/10.7554/elife.12814)

[6. (Diedrich2017Discrete) Britta Diedrich, Kristoffer TG Rigbolt, Michael Röring, Ricarda Herr, Stephanie Kaeser‐Pebernard, Christine Gretzmeier, Robert F Murphy, Tilman Brummer, and Jörn Dengjel. Discrete cytosolic macromolecular <scp>braf</scp> complexes exhibit distinct activities and composition. The EMBO Journal, 36(5):646–663, January 2017. URL: http://dx.doi.org/10.15252/embj.201694732, doi:10.15252/embj.201694732. (61 citations) 10.15252/embj.201694732](https://doi.org/10.15252/embj.201694732)

[7. (Orlandi2015BRAF) Armando Orlandi, Maria Alessandra Calegari, Alessandro Inno, Rosa Berenato, Marta Caporale, Monica Niger, Ilaria Bossi, Maria Di Bartolomeo, Filippo de Braud, and Filippo Pietrantonio. Braf in metastatic colorectal cancer: the future starts now. Pharmacogenomics, 16(18):2069–2081, November 2015. URL: http://dx.doi.org/10.2217/pgs.15.140, doi:10.2217/pgs.15.140. (14 citations) 10.2217/pgs.15.140](https://doi.org/10.2217/pgs.15.140)

[8. (Xing2007BRAF) Mingzhao Xing. Braf mutation in papillary thyroid cancer: pathogenic role, molecular bases, and clinical implications. Endocrine Reviews, 28(7):742–762, October 2007. URL: http://dx.doi.org/10.1210/er.2007-0007, doi:10.1210/er.2007-0007. (1198 citations) 10.1210/er.2007-0007](https://doi.org/10.1210/er.2007-0007)

[9. (Heinzerling2013Mutation) L Heinzerling, M Baiter, S Kühnapfel, G Schuler, P Keikavoussi, A Agaimy, F Kiesewetter, A Hartmann, and R Schneider-Stock. Mutation landscape in melanoma patients clinical implications of heterogeneity of braf mutations. British Journal of Cancer, 109(11):2833–2841, November 2013. URL: http://dx.doi.org/10.1038/bjc.2013.622, doi:10.1038/bjc.2013.622. (116 citations) 10.1038/bjc.2013.622](https://doi.org/10.1038/bjc.2013.622)

[10. (Park2019Architecture) Eunyoung Park, Shaun Rawson, Kunhua Li, Byeong-Won Kim, Scott B. Ficarro, Gonzalo Gonzalez-Del Pino, Humayun Sharif, Jarrod A. Marto, Hyesung Jeon, and Michael J. Eck. Architecture of autoinhibited and active braf–mek1–14-3-3 complexes. Nature, 575(7783):545–550, October 2019. URL: http://dx.doi.org/10.1038/s41586-019-1660-y, doi:10.1038/s41586-019-1660-y. (224 citations) 10.1038/s41586-019-1660-y](https://doi.org/10.1038/s41586-019-1660-y)

[11. (Sclafani2013BRAF) F. Sclafani, G. Gullo, K. Sheahan, and J. Crown. Braf mutations in melanoma and colorectal cancer: a single oncogenic mutation with different tumour phenotypes and clinical implications. Critical Reviews in Oncology/Hematology, 87(1):55–68, July 2013. URL: http://dx.doi.org/10.1016/j.critrevonc.2012.11.003, doi:10.1016/j.critrevonc.2012.11.003. (87 citations) 10.1016/j.critrevonc.2012.11.003](https://doi.org/10.1016/j.critrevonc.2012.11.003)

[12. (Chen2021Pathological) Kabytto Chen, Geoffrey Collins, Henry Wang, and James Wei Tatt Toh. Pathological features and prognostication in colorectal cancer. Current Oncology, 28(6):5356–5383, December 2021. URL: http://dx.doi.org/10.3390/curroncol28060447, doi:10.3390/curroncol28060447. (62 citations) 10.3390/curroncol28060447](https://doi.org/10.3390/curroncol28060447)

[13. (Roskoski2010RAF) Robert Roskoski. Raf protein-serine/threonine kinases: structure and regulation. Biochemical and Biophysical Research Communications, 399(3):313–317, August 2010. URL: http://dx.doi.org/10.1016/j.bbrc.2010.07.092, doi:10.1016/j.bbrc.2010.07.092. (476 citations) 10.1016/j.bbrc.2010.07.092](https://doi.org/10.1016/j.bbrc.2010.07.092)

[14. (Michaloglou2007BRAFE600) C Michaloglou, L C W Vredeveld, W J Mooi, and D S Peeper. Brafe600 in benign and malignant human tumours. Oncogene, 27(7):877–895, August 2007. URL: http://dx.doi.org/10.1038/sj.onc.1210704, doi:10.1038/sj.onc.1210704. (329 citations) 10.1038/sj.onc.1210704](https://doi.org/10.1038/sj.onc.1210704)