BRAF (gene)
Encyclopedia
Serine/threonine-protein kinase B-Raf or simply B-Raf, also known as proto-oncogene B-Raf or v-Raf murine sarcoma viral oncogene homolog B1, is a protein
that in humans is encoded by the BRAF gene
. The B-Raf protein is involved in sending signals
in cells and in cell growth
.
The BRAF gene may be mutated
and as a consequence, the normal functioning of the B-Raf protein may be altered. Certain inherited BRAF mutations cause birth defects. Alternatively, other acquired mutations (oncogene
) in adults may cause cancer
. Drugs that treat those cancers by inhibiting B-Raf are being studied. On August 17, 2011, one of them, PLX4032
(Vemurafenib), was approved by FDA for treatment of late-stage melanoma as the first drug come out of fragment-based drug discovery.
family of serine/threonine-specific protein kinase
s. This protein plays a role in regulating the MAP kinase
/ ERK
s signaling pathway
, which affects cell division
, differentiation
, and secretion.
.
Inherited mutations in this gene cause cardiofaciocutaneous syndrome
, a disease characterized by heart defects, mental retardation and a distinctive facial appearance.
Acquired mutations in this gene have also been found in cancers, including non-Hodgkin lymphoma
, colorectal cancer
, malignant melanoma, papillary thyroid carcinoma, non-small cell lung carcinoma, and adenocarcinoma of lung.
Some pharmaceutical firms are developing specific inhibitors of mutated B-raf protein for anticancer use.
One example is PLX4032
(RG7204).
More general B-raf inhibitors include GDC-0879, PLX-4720, Sorafenib
Tosylate.
. In 90% of the cases, thymine is substituted with adenine at nucleotide 1799. This leads to valine (V) being substituted for by glutamate (E) at codon 600 (now referred to as V600E) in the activation segment that has been found in human cancers. This mutation has been widely observed in papillary thyroid carcinoma, colorectal cancer
, melanoma
and non-small-cell lung cancer. In June 2011, a team of Italian scientists used massively parallel sequencing to pinpoint mutation V600E as a likely driver mutation in 100% of cases of Hairy cell leukaemia.
Other mutations which have been found are R461I, I462S, G463E, G463V, G465A, G465E, G465V, G468A, G468E, N580S, E585K, D593V, F594L, G595R, L596V, T598I, V599D, V599E, V599K, V599R, K600E, A727V, etc and most of these mutations are clustered to two regions: the glycine-rich P loop of the N lobe and the activation segment and flanking regions. These mutations change the activation segment from inactive state to active state, for example in the previous cited paper it has been reported that the aliphatic side chain of Val599 interacts with the phenyl ring of Phe467 in the P loop. Replacing the medium sized hydrophobic Val side chain with a larger and charged residue as found in human cancer(Glu, Asp, Lys, or Arg) would be expected to destabilize the interactions that maintain the DFG motif in an inactive conformation, so flipping the activation segment into the active position. Depending on the type of mutation the kinase activity towards MEK may also vary. In the same paper it has been reported that most of the mutants stimulate enhanced B-Raf kinase
activity toward MEK
. However, a few mutants act through a different mechanism because although their activity toward MEK is reduced, they adopt a conformation that activates wild-type C-RAF, which then signals to ERK
.
with YWHAB
, C-Raf
, AKT1
and HRAS
.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that in humans is encoded by the BRAF gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
. The B-Raf protein is involved in sending signals
Signal transduction
Signal transduction occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response...
in cells and in cell growth
Cell growth
The term cell growth is used in the contexts of cell development and cell division . When used in the context of cell division, it refers to growth of cell populations, where one cell grows and divides to produce two "daughter cells"...
.
The BRAF gene may be mutated
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
and as a consequence, the normal functioning of the B-Raf protein may be altered. Certain inherited BRAF mutations cause birth defects. Alternatively, other acquired mutations (oncogene
Oncogene
An oncogene is a gene that has the potential to cause cancer. In tumor cells, they are often mutated or expressed at high levels.An oncogene is a gene found in the chromosomes of tumor cells whose activation is associated with the initial and continuing conversion of normal cells into cancer...
) in adults may cause cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
. Drugs that treat those cancers by inhibiting B-Raf are being studied. On August 17, 2011, one of them, PLX4032
PLX4032
Vemurafenib is a B-Raf enzyme inhibitor developed by Plexxikon and Hoffmann–La Roche for the treatment of late-stage melanoma.Vemurafenib received FDA approval for the treatment of late-stage melanoma on August 17, 2011.- Mechanism of action...
(Vemurafenib), was approved by FDA for treatment of late-stage melanoma as the first drug come out of fragment-based drug discovery.
Function
B-Raf is a member of the Raf kinaseRaf kinase
Raf kinases are a family of three serine/threonine-specific protein kinases that are related to retroviral oncogenes. The mouse sarcoma virus 3611 contains a Raf kinase-related oncogene that enhances fibrosarcoma induction...
family of serine/threonine-specific protein kinase
Serine/threonine-specific protein kinase
Serine/threonine protein kinases phosphorylate the OH group of serine or threonine .At least 125 of the 500+ human protein kinases are serine/threonine kinases .-Regulation:...
s. This protein plays a role in regulating the MAP kinase
Mitogen-activated protein kinase
Mitogen-activated protein kinases are serine/threonine-specific protein kinases that respond to extracellular stimuli and regulate various cellular activities, such as gene expression, mitosis, differentiation, proliferation, and cell survival/apoptosis.-Activation:MAP kinases are activated...
/ ERK
Extracellular signal-regulated kinases
In molecular biology, extracellular-signal-regulated kinases or classical MAP kinases are widely expressed protein kinase intracellular signalling molecules that are involved in functions including the regulation of meiosis, mitosis, and postmitotic functions in differentiated cells...
s signaling pathway
MAPK/ERK pathway
The MAPK/ERK pathway is a chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell. The signal starts when a growth factor binds to the receptor on the cell surface and ends when the DNA in the nucleus expresses a...
, which affects cell division
Cell division
Cell division is the process by which a parent cell divides into two or more daughter cells . Cell division is usually a small segment of a larger cell cycle. This type of cell division in eukaryotes is known as mitosis, and leaves the daughter cell capable of dividing again. The corresponding sort...
, differentiation
Cellular differentiation
In developmental biology, cellular differentiation is the process by which a less specialized cell becomes a more specialized cell type. Differentiation occurs numerous times during the development of a multicellular organism as the organism changes from a simple zygote to a complex system of...
, and secretion.
Clinical significance
Mutations in the BRAF gene can cause disease in two ways. First, mutations can be inherited and cause birth defects. Second, mutations can appear later in life and cause cancer, as an oncogeneOncogene
An oncogene is a gene that has the potential to cause cancer. In tumor cells, they are often mutated or expressed at high levels.An oncogene is a gene found in the chromosomes of tumor cells whose activation is associated with the initial and continuing conversion of normal cells into cancer...
.
Inherited mutations in this gene cause cardiofaciocutaneous syndrome
Cardiofaciocutaneous syndrome
Cardiofaciocutaneous Syndrome is an extremely rare and serious genetic disorder.It is characterized by the following:*Distinctive facial appearance*Unusually sparse, brittle, curly scalp hair...
, a disease characterized by heart defects, mental retardation and a distinctive facial appearance.
Acquired mutations in this gene have also been found in cancers, including non-Hodgkin lymphoma
Non-Hodgkin lymphoma
The non-Hodgkin lymphomas are a diverse group of blood cancers that include any kind of lymphoma except Hodgkin's lymphomas. Types of NHL vary significantly in their severity, from indolent to very aggressive....
, colorectal cancer
Colorectal cancer
Colorectal cancer, commonly known as bowel cancer, is a cancer caused by uncontrolled cell growth , in the colon, rectum, or vermiform appendix. Colorectal cancer is clinically distinct from anal cancer, which affects the anus....
, malignant melanoma, papillary thyroid carcinoma, non-small cell lung carcinoma, and adenocarcinoma of lung.
B-raf inhibitors
Some pharmaceutical firms are developing specific inhibitors of mutated B-raf protein for anticancer use.
One example is PLX4032
PLX4032
Vemurafenib is a B-Raf enzyme inhibitor developed by Plexxikon and Hoffmann–La Roche for the treatment of late-stage melanoma.Vemurafenib received FDA approval for the treatment of late-stage melanoma on August 17, 2011.- Mechanism of action...
(RG7204).
More general B-raf inhibitors include GDC-0879, PLX-4720, Sorafenib
Sorafenib
Sorafenib , is a drug approved for the treatment of primary kidney cancer and advanced primary liver cancer ....
Tosylate.
BRAF Mutants
More than 30 mutations of the BRAF gene associated with human cancers have been identified. The frequency of BRAF mutations varies widely in human cancers from more than 80% in melanomas and nevi, to as little as 0-18% in other tumors, such as 1-3% in lung cancers and 5% in colorectal cancerColorectal cancer
Colorectal cancer, commonly known as bowel cancer, is a cancer caused by uncontrolled cell growth , in the colon, rectum, or vermiform appendix. Colorectal cancer is clinically distinct from anal cancer, which affects the anus....
. In 90% of the cases, thymine is substituted with adenine at nucleotide 1799. This leads to valine (V) being substituted for by glutamate (E) at codon 600 (now referred to as V600E) in the activation segment that has been found in human cancers. This mutation has been widely observed in papillary thyroid carcinoma, colorectal cancer
Colorectal cancer
Colorectal cancer, commonly known as bowel cancer, is a cancer caused by uncontrolled cell growth , in the colon, rectum, or vermiform appendix. Colorectal cancer is clinically distinct from anal cancer, which affects the anus....
, melanoma
Melanoma
Melanoma is a malignant tumor of melanocytes. Melanocytes are cells that produce the dark pigment, melanin, which is responsible for the color of skin. They predominantly occur in skin, but are also found in other parts of the body, including the bowel and the eye...
and non-small-cell lung cancer. In June 2011, a team of Italian scientists used massively parallel sequencing to pinpoint mutation V600E as a likely driver mutation in 100% of cases of Hairy cell leukaemia.
Other mutations which have been found are R461I, I462S, G463E, G463V, G465A, G465E, G465V, G468A, G468E, N580S, E585K, D593V, F594L, G595R, L596V, T598I, V599D, V599E, V599K, V599R, K600E, A727V, etc and most of these mutations are clustered to two regions: the glycine-rich P loop of the N lobe and the activation segment and flanking regions. These mutations change the activation segment from inactive state to active state, for example in the previous cited paper it has been reported that the aliphatic side chain of Val599 interacts with the phenyl ring of Phe467 in the P loop. Replacing the medium sized hydrophobic Val side chain with a larger and charged residue as found in human cancer(Glu, Asp, Lys, or Arg) would be expected to destabilize the interactions that maintain the DFG motif in an inactive conformation, so flipping the activation segment into the active position. Depending on the type of mutation the kinase activity towards MEK may also vary. In the same paper it has been reported that most of the mutants stimulate enhanced B-Raf kinase
Kinase
In chemistry and biochemistry, a kinase is a type of enzyme that transfers phosphate groups from high-energy donor molecules, such as ATP, to specific substrates, a process referred to as phosphorylation. Kinases are part of the larger family of phosphotransferases...
activity toward MEK
MEK
MEK or Mek may refer to:* In chemistry and industry methyl ethyl ketone, a solvent, used also to weld some plastics* The Iranian guerilla-cum-opposition group Mujahideen-e Khalq* Mek, a comic mini series by Warren Ellis...
. However, a few mutants act through a different mechanism because although their activity toward MEK is reduced, they adopt a conformation that activates wild-type C-RAF, which then signals to ERK
Extracellular signal-regulated kinases
In molecular biology, extracellular-signal-regulated kinases or classical MAP kinases are widely expressed protein kinase intracellular signalling molecules that are involved in functions including the regulation of meiosis, mitosis, and postmitotic functions in differentiated cells...
.
Interactions
BRAF (gene) has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with YWHAB
YWHAB
14-3-3 protein beta/alpha is a protein that in humans is encoded by the YWHAB gene.-Interactions:YWHAB has been shown to interact with CDC25A, CDC25B, BRAF, C-Raf, RPS6KA1, EPB41L3, CD29, Wee1-like protein kinase, PTPN3, Protein kinase Mζ, MAPK7, TESK1, TNFAIP3, Cbl gene, HDAC4 and KCNK3.-Further...
, C-Raf
C-Raf
RAF proto-oncogene serine/threonine-protein kinase also known as proto-oncogene c-RAF or simply c-Raf is an enzyme that in humans is encoded by the RAF1 gene. The c-Raf protein functions in the MAPK/ERK signal transduction pathway as part of a protein kinase cascade...
, AKT1
AKT1
RAC-alpha serine/threonine-protein kinase is an enzyme that in humans is encoded by the AKT1 gene. Multiple alternatively spliced transcript variants have been found for this gene.- Function :...
and HRAS
HRAS
GTPase HRas also known as transforming protein p21 is an enzyme that in humans is encoded by the HRAS gene. The HRAS gene is located on the short arm of chromosome 11 at position 15.5, from base pair 522,241 to base pair 525,549.- Function :...
.
External links
- GeneReviews/NCBI/NIH/UW entry on Noonan syndrome
- GeneReviews/NCBI/NIH/UW entry on Cardiofaciocutaneous Syndrome
- GeneReviews/NCBI/NIH/UW entry on LEOPARD Syndrome
- Finding faults in BRAF - Cancer Research UK blog post about the discovery of cancer-causing BRAF mutations (incl video)