InnateDB: Systems Biology of the Innate Immune Response

Homo sapiens Protein: RAF1

Summary

InnateDB Protein

IDBP-364474.5

Last Modified

2014-10-13 [Report errors or provide feedback]

Gene Symbol

RAF1

Protein Name

v-raf-1 murine leukemia viral oncogene homolog 1

Synonyms

c-Raf; CMD1NN; CRAF; NS5; Raf-1;

Species

Homo sapiens

Ensembl Protein

ENSP00000401888

InnateDB Gene

IDBG-19277 (RAF1)

Protein Structure

UniProt Annotation

Function

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. {ECO:0000269PubMed:11427728, ECO:0000269PubMed:11719507, ECO:0000269PubMed:15385642, ECO:0000269PubMed:15618521, ECO:0000269PubMed:15849194, ECO:0000269PubMed:16892053, ECO:0000269PubMed:16924233, ECO:0000269PubMed:9360956}.

Subcellular Localization

Cytoplasm. Cell membrane. Mitochondrion. Nucleus. Note=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.

Disease Associations

Noonan syndrome 5 (NS5) [MIM:611553]: 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. {ECO:0000269PubMed:17603482, ECO:0000269PubMed:17603483, ECO:0000269PubMed:20683980}. Note=The disease is caused by mutations affecting the gene represented in this entry.LEOPARD syndrome 2 (LEOPARD2) [MIM:611554]: A disorder characterized by lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormalities of genitalia, retardation of growth, and sensorineural deafness. {ECO:0000269PubMed:17603483}. Note=The disease is caused by mutations affecting the gene represented in this entry.

Tissue Specificity

In skeletal muscle, isoform 1 is more abundant than isoform 2. {ECO:0000269PubMed:1886707}.

Comments

Interactions

Number of Interactions

This gene and/or its encoded proteins are associated with 252 experimentally validated interaction(s) in this database.
They are also associated with 24 interaction(s) predicted by orthology.

Experimentally validated
Total	252 [view]
Protein-Protein	252 [view]
Protein-DNA	0
Protein-RNA	0
DNA-DNA	0
RNA-RNA	0
DNA-RNA	0

Predicted by orthology
Total	24 [view]

Gene Ontology

Molecular Function

Accession	GO Term
GO:0004672	protein kinase activity
GO:0004674	protein serine/threonine kinase activity
GO:0004713	protein tyrosine kinase activity
GO:0005057	receptor signaling protein activity
GO:0005515	protein binding
GO:0005524	ATP binding
GO:0016772	transferase activity, transferring phosphorus-containing groups
GO:0042802	identical protein binding
GO:0046872	metal ion binding

Biological Process

GO:0000165	MAPK cascade
GO:0000186	activation of MAPKK activity
GO:0006468	protein phosphorylation
GO:0006915	apoptotic process
GO:0007165	signal transduction
GO:0007173	epidermal growth factor receptor signaling pathway
GO:0007190	activation of adenylate cyclase activity
GO:0007264	small GTPase mediated signal transduction
GO:0007265	Ras protein signal transduction
GO:0007268	synaptic transmission
GO:0007411	axon guidance
GO:0007596	blood coagulation
GO:0008283	cell proliferation
GO:0008285	negative regulation of cell proliferation
GO:0008286	insulin receptor signaling pathway
GO:0008543	fibroblast growth factor receptor signaling pathway
GO:0030168	platelet activation
GO:0031333	negative regulation of protein complex assembly
GO:0033138	positive regulation of peptidyl-serine phosphorylation
GO:0034220	ion transmembrane transport
GO:0035023	regulation of Rho protein signal transduction
GO:0035556	intracellular signal transduction
GO:0038095	Fc-epsilon receptor signaling pathway
GO:0042060	wound healing
GO:0042981	regulation of apoptotic process
GO:0043066	negative regulation of apoptotic process
GO:0043154	negative regulation of cysteine-type endopeptidase activity involved in apoptotic process
GO:0045087	innate immune response
GO:0045595	regulation of cell differentiation
GO:0048011	neurotrophin TRK receptor signaling pathway
GO:0055085	transmembrane transport
GO:2000145	regulation of cell motility

Cellular Component

GO:0005634	nucleus
GO:0005737	cytoplasm
GO:0005741	mitochondrial outer membrane
GO:0005794	Golgi apparatus
GO:0005829	cytosol
GO:0005886	plasma membrane

Protein Structure and Domains

PDB ID

InterPro

IPR000719 Protein kinase domain
IPR001245 Serine-threonine/tyrosine-protein kinase catalytic domain
IPR002219 Protein kinase C-like, phorbol ester/diacylglycerol-binding domain
IPR002290 Serine/threonine/dual specificity protein kinase, catalytic domain
IPR003116 Raf-like Ras-binding
IPR011009 Protein kinase-like domain
IPR020454 Diacylglycerol/phorbol-ester binding
IPR020635 Tyrosine-protein kinase, catalytic domain
IPR029071 Ubiquitin-related domain

PFAM

PF00069
PF07714
PF00130
PF02196

PRINTS

PR00109
PR00008

PIRSF

SMART

SM00109
SM00220
SM00455
SM00219

TIGRFAMs

Post-translational Modifications

Modification

Cross-References

SwissProt