InnateDB: Systems Biology of the Innate Immune Response

Mus musculus Protein: Raf1

Summary

InnateDB Protein

IDBP-254897.6

Last Modified

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

Gene Symbol

Raf1

Protein Name

v-raf-leukemia viral oncogene 1

Synonyms

6430402F14Rik; AA990557; BB129353; c-Raf; Craf1; D830050J10Rik; Raf-1; v-Raf;

Species

Mus musculus

Ensembl Protein

ENSMUSP00000108571

InnateDB Gene

IDBG-179428 (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. 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 (By similarity). Regulates Rho signaling and migration, and is required for normal wound healing. {ECO:0000250, ECO:0000269PubMed:15753127}.

Subcellular Localization

Cytoplasm {ECO:0000250}. Cell membrane {ECO:0000250}. Mitochondrion {ECO:0000250}. Nucleus {ECO:0000269PubMed:19298812}. 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 (By similarity). Retinoic acid-induced Ser-621 phosphorylated form of RAF1 is predominantly localized at the nucleus. {ECO:0000250}.

Disease Associations

Tissue Specificity

Present in all tissues tested: testis, ovary, small intestine, colon, peripheral blood leukocytes, fetal liver, bone marrow, thymus, lymph node and spleen, and the cell lines melanoma G-361, lung carcinoma A-549, colorectal adenocarcinoma SW480, Burkitt's lymphoma Raji and lymphoblastic leukemia MOLT-4. In skeletal muscle, isoform 1 is more abundant than isoform 2. {ECO:0000269PubMed:11597136, ECO:0000269PubMed:1886707}.

Comments

Interactions

Number of Interactions

This gene and/or its encoded proteins are associated with 47 experimentally validated interaction(s) in this database.
They are also associated with 139 interaction(s) predicted by orthology.

Experimentally validated
Total	47 [view]
Protein-Protein	47 [view]
Protein-DNA	0
Protein-RNA	0
DNA-DNA	0
RNA-RNA	0
DNA-RNA	0

Predicted by orthology
Total	139 [view]

Gene Ontology

Molecular Function

Accession	GO Term
GO:0004672	protein kinase activity
GO:0004709	MAP kinase kinase 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:0017016	Ras GTPase binding
GO:0031434	mitogen-activated protein kinase kinase binding
GO:0042802	identical protein binding
GO:0046872	metal ion binding
GO:0046982	protein heterodimerization activity

Biological Process

GO:0000165	MAPK cascade
GO:0000186	activation of MAPKK activity
GO:0001666	response to hypoxia
GO:0006468	protein phosphorylation
GO:0007165	signal transduction
GO:0007507	heart development
GO:0008285	negative regulation of cell proliferation
GO:0030154	cell differentiation
GO:0031333	negative regulation of protein complex assembly
GO:0033138	positive regulation of peptidyl-serine phosphorylation
GO:0035019	somatic stem cell maintenance
GO:0035556	intracellular signal transduction
GO:0043066	negative regulation of apoptotic process
GO:0045104	intermediate filament cytoskeleton organization
GO:0048011	neurotrophin TRK receptor signaling pathway
GO:0071550	death-inducing signaling complex assembly
GO:1902042	negative regulation of extrinsic apoptotic signaling pathway via death domain receptors

Cellular Component

GO:0005634	nucleus
GO:0005737	cytoplasm
GO:0005739	mitochondrion
GO:0005794	Golgi apparatus
GO:0005829	cytosol
GO:0005886	plasma membrane
GO:0031143	pseudopodium

Protein Structure and Domains

PDB ID

MGI:97847

InterPro

IPR000719 Protein kinase domain
IPR001245 Serine-threonine/tyrosine-protein kinase catalytic domain
IPR002219 Protein kinase C-like, phorbol ester/diacylglycerol binding
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