C-Raf - AbsoluteAstronomy.com

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:...

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

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

).

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

Raf-1 phosphorylates and activates MEK, a MAPK

Mitogen-activated protein kinase

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

Mitogen-activated protein kinase

(see MAPK/ERK pathway

MAPK/ERK pathway

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:...

External links

GeneReviews/NCBI/NIH/UW entry on Noonan syndrome
Domain structure diagrams for Raf-1, A-Raf and B-Raf.
Drosophila pole hole - The Interactive Fly

Function

Discovery and role in cancer

Regulation of Raf kinase activity

Targets of Raf-1

Interactions

See also

External links

Further reading