C-Raf
Encyclopedia
RAF proto-oncogene serine/threonine-protein kinase also known as proto-oncogene c-RAF or simply c-Raf is an enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...

 that in humans is encoded
Genetic code
The genetic code is the set of rules by which information encoded in genetic material is translated into proteins by living cells....

 by the RAF1 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 c-Raf protein functions in the MAPK/ERK signal transduction 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...

 as part of a protein kinase cascade. C-Raf is a member of the Raf kinase
Raf 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.

Function

c-Raf is a MAP kinase kinase kinase (MAP3K) that functions downstream of the Ras subfamily of membrane associated GTPases to which it binds directly. Once activated Raf-1 can phosphorylate to activate the dual specificity protein kinases MEK1 and MEK2, which, in turn, phosphorylate to activate the serine/threonine-specific protein kinases ERK1 and ERK2. 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 are pleiotropic
Pleiotropy
Pleiotropy occurs when one gene influences multiple phenotypic traits. Consequently, a mutation in a pleiotropic gene may have an effect on some or all traits simultaneously...

 effectors of cell physiology and play an important role in the control of gene expression involved in the cell division cycle, apoptosis, cell differentiation, and cell migration.

Discovery and role in cancer

The first raf gene that was found was the 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...

 v-raf. Normal (non-oncogenic) cellular homologs of v-raf were soon found to be conserved components of eukaryotic genomes, and it was shown that they could mutate and become oncogenes. A-Raf
ARAF
Serine/threonine-protein kinase A-Raf or simply A-Raf is an enzyme that in humans is encoded by the ARAF gene. A-Raf is a member of the Raf kinase family of serine/threonine-specific protein kinases.-Interactions:...

 and B-Raf
BRAF (gene)
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...

 are two protein kinases with similar sequences to Raf-1. Mutations in B-Raf
BRAF (gene)
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...

 genes are found in several types of cancer. The Raf kinases are targets for anticancer drug
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....

 development. There are several quantitative immunochemical methods available to detect Raf kinase inhibiting drugs.

Regulation of Raf kinase activity

Raf-1 was shown to bind efficiently to Ras only when Ras is bound to GTP
Guanosine triphosphate
Guanosine-5'-triphosphate is a purine nucleoside triphosphate. It can act as a substrate for the synthesis of RNA during the transcription process...

, not GDP
Guanosine diphosphate
Guanosine diphosphate, abbreviated GDP, is a nucleoside diphosphate. It is an ester of pyrophosphoric acid with the nucleoside guanosine. GDP consists of the pyrophosphate group, the pentose sugar ribose, and the nucleobase guanine....

.
In the MAPK/ERK 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...

 Raf-1 becomes activated when it binds to Ras. It is thought that phosphorylation of Raf-1 (at sites such as serine-338) upon binding of Raf-1 to Ras locks Raf-1 into an activated conformation that is then independent of binding to Ras for the continued activity of Raf-1. Several MAPK kinase kinase kinases have been suggested to be important for phosphorylation of Raf-1 as well as positive feedback phosphorylation by MAPK
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...

).

Binding of 14-3-3ζ
14-3-3 protein
14-3-3 proteins are a family of conserved regulatory molecules expressed in all eukaryotic cells. 14-3-3 proteins have the ability to bind a multitude of functionally diverse signaling proteins, including kinases, phosphatases, and transmembrane receptors...

 to phosphorylated serine-259 of Raf-1 is associated with inhibition of Raf-1 kinase activity. As shown in the figure (to the right), it is thought that a 14-3-3 dimer can bind to two phosphoserines of Raf-1 when it is inactive. Dephosphorylation of serine-259 has been associated with activation of Raf-1. In the model shown, the binding of GTP to Ras and the dephosphorylation of serine-259 of Raf-1 allows Raf-1 to take on a conformation that allows binding of Raf-1 to Ras-GTP. This represents a conformation in which Raf-1 can phosphorylate the downstream target MEK.

Targets of Raf-1

In the MAPK/ERK 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...

 Raf-1 phosphorylates and activates MEK, a MAPK
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...

 kinase. This allows Raf-1 to function as part of a kinase cascade: Raf-1 phosphorylates MEK, which phosphorylates MAPK
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...

 (see MAPK/ERK 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...

).

Interactions

C-Raf has been shown to interact
Protein-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 STUB1
STUB1
STUB1 , also known as CHIP , is a human gene.- Function :...

, Retinoblastoma-like protein 2
Retinoblastoma-like protein 2
Retinoblastoma-like protein 2 is a protein that in humans is encoded by the RBL2 gene.-Interactions:Retinoblastoma-like protein 2 has been shown to interact with HDAC1, C-Raf, RBBP8, Cyclin E1, Prohibitin, Cyclin-dependent kinase 2, BRF1 and BRCA1....

, CFLAR
CFLAR
CASP8 and FADD-like apoptosis regulator is a protein that in humans is encoded by the CFLAR gene. Also called FLICE-like inhibitory protein .-Further reading:...

, CDC25A
CDC25A
Cell division cycle 25 homolog A , also known as CDC25A, is a mammalian gene.-Interactions:CDC25A has been shown to interact with ASK1, Epidermal growth factor receptor, C-Raf, CHEK1, Cyclin E1, PIM1 and YWHAB.-Further reading:...

, Retinoblastoma protein
Retinoblastoma protein
The retinoblastoma protein is a tumor suppressor protein that is dysfunctional in the majority types of cancer. One highly studied function of pRb is to prevent excessive cell growth by inhibiting cell cycle progression until a cell is ready to divide...

, YWHAQ
YWHAQ
14-3-3 protein theta is a protein that in humans is encoded by the YWHAQ gene.-Interactions:YWHAQ has been shown to interact with MEF2D, Bcl-2-associated X protein, CRTC2, C-Raf, Histone deacetylase 5, NRIP1, Protein kinase Mζ, UCP3, PFKFB2, Telomerase reverse transcriptase, Bcl-2-associated death...

, 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 :...

, BRAF
BRAF (gene)
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...

, Bcl-2
Bcl-2
Bcl-2 is the founding member of the Bcl-2 family of apoptosis regulator proteins encoded by the BCL2 gene. Bcl-2 derives its name from B-cell lymphoma 2, as it is the second member of a range of proteins initially described in chromosomal translocations involving chromosomes 14 and 18 in...

, PAK1
PAK1
Serine/threonine-protein kinase PAK 1 is an enzyme that in humans is encoded by the PAK1 gene.-Interactions:PAK1 has been shown to interact with C-Raf, NCK1, LIMK1, RAC1, ARHGEF2, BMX, ARPC1B, DYNLL1, Cyclin-dependent kinase 5, PAK1IP1 and CDC42....

, Prohibitin
Prohibitin
Prohibitin, also known as PHB, is a protein that in humans is encoded by the PHB gene.The Phb gene has also been described in animals, fungi, plants, and unicellular eukaryotes. Prohibitins are divided in two classes, termed Type-I and Type-II prohibitins, based on their similarity to yeast PHB1...

, MAP2K1
MAP2K1
Dual specificity mitogen-activated protein kinase kinase 1 is an enzyme that in humans is encoded by the MAP2K1 gene.- Function :The protein encoded by this gene is a member of the dual specificity protein kinase family, which acts as a mitogen-activated protein kinase kinase...

, TSC22D3
TSC22D3
TSC22 domain family protein 3 is a protein that in humans is encoded by the TSC22D3 gene.-Interactions:TSC22D3 has been shown to interact with C-Raf, NFKB2 and NFKB1.-Further reading:...

, 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 :...

, RHEB
RHEB
GTP-binding protein Rheb also known as Ras homolog enriched in brain is a protein that in humans is encoded by the RHEB gene.- Function :Rheb is a recently discovered member of the Ras superfamily that may be involved in neural plasticity...

, RAP1A
RAP1A
Ras-related protein Rap-1A is a protein that in humans is encoded by the RAP1A gene.- Function :The product of this gene belongs to the family of Ras-related proteins. These proteins share approximately 50% amino acid identity with the classical RAS proteins and have numerous structural features in...

, Src
Src (gene)
Proto-oncogene tyrosine-protein kinase Src is an enzyme that in humans is encoded by the SRC gene.Src is a proto-oncogene encoding a tyrosine kinase originally discovered by J. Michael Bishop and Harold E. Varmus, for which they won the 1989 Nobel Prize in Physiology or Medicine. It belongs to a...

, Phosphatidylethanolamine binding protein 1
Phosphatidylethanolamine binding protein 1
Phosphatidylethanolamine-binding protein 1 is a protein that in humans is encoded by the PEBP1 gene.-Interactions:Phosphatidylethanolamine binding protein 1 has been shown to interact with MAP2K1, C-Raf and MAPK1.-Further reading:...

, Protein kinase Mζ, GRB10
GRB10
Growth factor receptor-bound protein 10 also known as insulin receptor-binding protein Grb-IR is a protein that in humans is encoded by the GRB10 gene.- Function :...

, KRAS
KRAS
GTPase KRas also known as V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog and KRAS, is a protein that in humans is encoded by the KRAS gene. Like other members of the Ras family, the KRAS protein is a GTPase and is an early player in many signal transduction pathways...

, MAPK7
MAPK7
Mitogen-activated protein kinase 7 also known as MAP kinase 7 is an enzyme that in humans is encoded by the MAPK7 gene.- Function :MAPK7 is a member of the MAP kinase family...

, Heat shock protein 90kDa alpha (cytosolic), member A1, ASK1
ASK1
Apoptosis signal-regulating kinase 1 also known as mitogen-activated protein kinase kinase kinase 5 is a member of MAP kinase kinase kinase family and as such a part of mitogen-activated protein kinase pathway...

, FYN
FYN
Proto-oncogene tyrosine-protein kinase Fyn is an enzyme that in humans is encoded by the FYN gene.This gene is a member of the protein-tyrosine kinase oncogene family. It encodes a membrane-associated tyrosine kinase that has been implicated in the control of cell growth...

, BAG1
BAG1
BAG family molecular chaperone regulator 1 is a protein that in humans is encoded by the BAG1 gene.BAG gene has been implicated in age related neurodegenerative diseases as Alzheimer's...

, 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...

, MAPK8IP3
MAPK8IP3
C-jun-amino-terminal kinase-interacting protein 3 is an enzyme that in humans is encoded by the MAPK8IP3 gene.-Interactions:MAPK8IP3 has been shown to interact with ASK1, C-Raf, PTK2, MAPK10, Mitogen-activated protein kinase 9, MAPK8, MAP2K1, KLC2, MAP2K7, KLC1, MAPK8IP2 and MAP2K4.-Further reading:...

, YWHAZ
YWHAZ
14-3-3 protein zeta/delta is a protein that in humans is encoded by the YWHAZ gene.-Interactions:YWHAZ has been shown to interact with TSC2, LIMK1, CDC25B, AKT1, BCAR1, Interleukin-9 receptor, C-Raf, HMGN1, Vimentin, Tau protein, Protein kinase Mζ, GP1BB, GP1BA, TNFAIP3, Bcl-2-associated death...

, YWHAH
YWHAH
14-3-3 protein eta is a protein that in humans is encoded by the YWHAH gene.-Interactions:YWHAH has been shown to interact with TNFAIP3, KLC3, C-Raf, Phosphoinositide-dependent kinase-1, RIMS2, KIF5B, RIMS1, CDC25B, ZFP36, EPB41L3, Glucocorticoid receptor and TLX2.-Further reading:...

, YWHAG
YWHAG
14-3-3 protein gamma is a protein that in humans is encoded by the YWHAG gene.-Interactions:YWHAG has been shown to interact with C-Raf, EPB41L3, KIF1C and Stratifin.-Further reading:...

, YWHAE
YWHAE
14-3-3 protein epsilon is a protein that in humans is encoded by the YWHAE gene.-Interactions:YWHAE has been shown to interact with CDC25B, Insulin-like growth factor 1 receptor, NGFRAP1, TGF beta 1, HERG, C-Raf, NDEL1, HDAC4, IRS1 and MAP3K3....

, MAP3K1
MAP3K1
Mitogen-activated protein kinase kinase kinase 1 is an enzyme that in humans is encoded by the MAP3K1 gene.Mouse genetics has revealed that the kinase is important in: correct embryogenesis, keratinocyte migration, T cell cytokine production and B cell antibody production.-Interactions:MAP3K1 has...

, RRAS2
RRAS2
Ras-related protein R-Ras2 is a protein that in humans is encoded by the RRAS2 gene.-Further reading:...

 and SHOC2
SHOC2
Leucine-rich repeat protein SHOC-2 is a protein that in humans is encoded by the SHOC2 gene.-Interactions:SHOC2 has been shown to interact with C-Raf and HRAS.-Further reading:...

.

See also

  • A-Raf
    ARAF
    Serine/threonine-protein kinase A-Raf or simply A-Raf is an enzyme that in humans is encoded by the ARAF gene. A-Raf is a member of the Raf kinase family of serine/threonine-specific protein kinases.-Interactions:...

     and B-Raf
    BRAF (gene)
    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...

    , two protein kinases with similar sequences to Raf-1.
  • Sorafenib
    Sorafenib
    Sorafenib , is a drug approved for the treatment of primary kidney cancer and advanced primary liver cancer ....

     - a Raf inhibitor (approved for some kidney and liver cancers)
  • 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...

     - a B-Raf inhibitor (being developed for late stage melanoma)
  • XL281 - a Raf inhibitor
  • GSK2118436 - a Raf inhibitor

External links


Further reading

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