RAF1

This gene is the cellular homolog of viral raf gene (v-raf). The encoded protein is a MAP kinase kinase kinase (MAP3K), which functions downstream of the Ras family of membrane associated GTPases to which it binds directly. Once activated, the cellular RAF1 protein 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 ERKs are pleiotropic 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. Mutations in this gene are associated with Noonan syndrome 5 and LEOPARD syndrome 2.

Raf-1 Proto-Oncogene, Serine/Threonine Kinase

Serine/threonine-protein kinase that acts as a regulatory link between the membrane-associated Ras GTPases and the MAPK/ERK cascade, and this critical regulatory link functions as a switch determining cell fate decisions including proliferation, differentiation, apoptosis, survival and oncogenic transformation. RAF1 activation initiates a mitogen-activated protein kinase (MAPK) cascade that comprises a sequential phosphorylation of the dual-specific MAPK kinases (MAP2K1/MEK1 and MAP2K2/MEK2) and the extracellular signal-regulated kinases (MAPK3/ERK1 and MAPK1/ERK2). The phosphorylated form of RAF1 (on residues Ser-338 and Ser-339, by PAK1) phosphorylates BAD/Bcl2-antagonist of cell death at 'Ser-75'. Phosphorylates adenylyl cyclases: ADCY2, ADCY5 and ADCY6, resulting in their activation. Phosphorylates PPP1R12A resulting in inhibition of the phosphatase activity. Phosphorylates TNNT2/cardiac muscle troponin T. Can promote NF-kB activation and inhibit signal transducers involved in motility (ROCK2), apoptosis (MAP3K5/ASK1 and STK3/MST2), proliferation and angiogenesis (RB1). Can protect cells from apoptosis also by translocating to the mitochondria where it binds BCL2 and displaces BAD/Bcl2-antagonist of cell death. Regulates Rho signaling and migration, and is required for normal wound healing. Plays a role in the oncogenic transformation of epithelial cells via repression of the TJ protein, occludin (OCLN) by inducing the up-regulation of a transcriptional repressor SNAI2/SLUG, which induces down-regulation of OCLN. Restricts caspase activation in response to selected stimuli, notably Fas stimulation, pathogen-mediated macrophage apoptosis, and erythroid differentiation.

Activation of adenylate cyclase activityManual Assertion Based On ExperimentIDA:BHF-UCL
Apoptotic processManual Assertion Based On ExperimentTAS:GO_Central
Cell differentiationIEA:Ensembl
Death-inducing signaling complex assemblyIEA:Ensembl
Face developmentIEA:Ensembl
Insulin secretion involved in cellular response to glucose stimulusIEA:Ensembl
Intermediate filament cytoskeleton organizationIEA:Ensembl
MAPK cascadeManual Assertion Based On ExperimentIBA:GO_Central
Negative regulation of apoptotic processManual Assertion Based On ExperimentIDA:UniProtKB
Negative regulation of cell population proliferationManual Assertion Based On ExperimentIDA:BHF-UCL
Negative regulation of cysteine-type endopeptidase activity involved in apoptotic processManual Assertion Based On ExperimentTAS:UniProtKB
Negative regulation of extrinsic apoptotic signaling pathway via death domain receptorsIEA:Ensembl
Negative regulation of protein-containing complex assemblyManual Assertion Based On ExperimentIDA:UniProtKB
Neurotrophin TRK receptor signaling pathwayIEA:Ensembl
Positive regulation of MAPK cascadeManual Assertion Based On ExperimentIDA:GO_Central
Positive regulation of peptidyl-serine phosphorylationManual Assertion Based On ExperimentIDA:UniProtKB
Positive regulation of transcription by RNA polymerase IIIEA:Ensembl
Protein phosphorylationManual Assertion Based On ExperimentTAS:ProtInc
Regulation of apoptotic processManual Assertion Based On ExperimentTAS:UniProtKB
Regulation of cell differentiationManual Assertion Based On ExperimentTAS:UniProtKB
Regulation of cell motilityManual Assertion Based On ExperimentTAS:UniProtKB
Regulation of Rho protein signal transductionManual Assertion Based On ExperimentTAS:UniProtKB
Response to muscle stretchIEA:Ensembl
Signal transductionManual Assertion Based On ExperimentTAS:ProtInc
Somatic stem cell population maintenanceIEA:Ensembl
Thymus developmentIEA:Ensembl
Thyroid gland developmentIEA:Ensembl
Wound healingManual Assertion Based On ExperimentTAS:UniProtKB

Cytoplasm
Cell membrane
Mitochondrion
Nucleus
Colocalizes with RGS14 and BRAF in both the cytoplasm and membranes. Phosphorylation at Ser-259 impairs its membrane accumulation. Recruited to the cell membrane by the active Ras protein. Phosphorylation at Ser-338 and Ser-339 by PAK1 is required for its mitochondrial localization. Retinoic acid-induced Ser-621 phosphorylated form of RAF1 is predominantly localized at the nucleus.

Noonan syndrome 5 (NS5):
A form of Noonan syndrome, a disease characterized by short stature, facial dysmorphic features such as hypertelorism, a downward eyeslant and low-set posteriorly rotated ears, and a high incidence of congenital heart defects and hypertrophic cardiomyopathy. Other features can include a short neck with webbing or redundancy of skin, deafness, motor delay, variable intellectual deficits, multiple skeletal defects, cryptorchidism, and bleeding diathesis. Individuals with Noonan syndrome are at risk of juvenile myelomonocytic leukemia, a myeloproliferative disorder characterized by excessive production of myelomonocytic cells.
LEOPARD syndrome 2 (LPRD2):
A disorder characterized by lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormalities of genitalia, retardation of growth, and sensorineural deafness.
Cardiomyopathy, dilated 1NN (CMD1NN):
A disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death.

Phosphorylation at Thr-269, Ser-338, Tyr-341, Thr-491 and Ser-494 results in its activation. Phosphorylation at Ser-29, Ser-43, Ser-289, Ser-296, Ser-301 and Ser-642 by MAPK1/ERK2 results in its inactivation. Phosphorylation at Ser-259 induces the interaction with YWHAZ and inactivates kinase activity. Dephosphorylation of Ser-259 by the complex containing protein phosphatase 1, SHOC2 and M-Ras/MRAS relieves inactivation, leading to stimulate RAF1 activity. Phosphorylation at Ser-338 by PAK1 and PAK5 and Ser-339 by PAK1 is required for its mitochondrial localization. Phosphorylation at Ser-621 in response to growth factor treatment stabilizes the protein, possibly by preventing proteasomal degradation. Phosphorylation at Ser-289, Ser-296, Ser-301, Ser-338 and Ser-621 are somehow linked to the methylation potential of cells. Treatment of cells with HGF in the presence of the methylation inhibitor 5'-methylthioadenosine (MTA) results in increased phosphorylation at Ser-338 and Ser-621 and decreased phosphorylation at Ser-296, Ser-301 and Ser-338. Dephosphorylation at Ser-338 by PPP5C results in an activity decrease.
Methylated at Arg-563 in response to EGF treatment. This modification leads to destabilization of the protein, possibly through proteasomal degradation.