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Names & Taxonomy

Uniprot ID:: P04049
Entry Name:: RAF1_HUMAN
Status:: reviewed
Protein Names:: RAF proto-oncogene serine/threonine-protein kinase (EC 2.7.11.1) (Proto-oncogene c-RAF) (cRaf) (Raf-1)
Gene Names:: RAF1 RAF
Gene Names Primary:: RAF1
Organism:: Homo sapiens (Human)

Structure

Length:: 648
Sequence:: MEHIQGAWKTISNGFGFKDAVFDGSSCISPTIVQQFGYQRRASDDGKLTDPSKTSNTIRVFLPNKQRTVVNVRNGMSLHDCLMKALKVRGLQPECCAVFRLLHEHKGKKARLDWNTDAASLIGEELQVDFLDHVPLTTHNFARKTFLKLAFCDICQKFLLNGFRCQTCGYKFHEHCSTKVPTMCVDWSNIRQLLLFPNSTIGDSGVPALPSLTMRRMRESVSRMPVSSQHRYSTPHAFTFNTSSPSSEGSLSQRQRSTSTPNVHMVSTTLPVDSRMIEDAIRSHSESASPSALSSSPNNLSPTGWSQPKTPVPAQRERAPVSGTQEKNKIRPRGQRDSSYYWEIEASEVMLSTRIGSGSFGTVYKGKWHGDVAVKILKVVDPTPEQFQAFRNEVAVLRKTRHVNILLFMGYMTKDNLAIVTQWCEGSSLYKHLHVQETKFQMFQLIDIARQTAQGMDYLHAKNIIHRDMKSNNIFLHEGLTVKIGDFGLATVKSRWSGSQQVEQPTGSVLWMAPEVIRMQDNNPFSFQSDVYSYGIVLYELMTGELPYSHINNRDQIIFMVGRGYASPDLSKLYKNCPKAMKRLVADCVKKVKEERPLFPQILSSIELLQHSLPKINRSASEPSLHRAAHTEDINACTLTTSPRLPVF
Proteomes:: UP000005640

Subcellular location

Subcellular Location:: 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.

Function

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.
Catalytic Activity:: ATP + a protein = ADP + a phosphoprotein.
Cofactor:: COFACTOR: Name=Zn(2+); Xref=ChEBI:CHEBI:29105; ; Note=Binds 2 Zn(2+) ions per subunit.;
Enzyme Regulation:: ENZYME REGULATION: Regulation is a highly complex process involving membrane recruitment, protein-protein interactions, dimerization, and phosphorylation/dephosphorylation events. Ras-GTP recruits RAF1 to the membrane, thereby promoting its activation. The inactive conformation of RAF1 is maintained by autoinhibitory interactions occurring between the N-terminal regulatory and the C-terminal catalytic domains and by the binding of a 14-3-3 protein that contacts two phosphorylation sites, Ser-259 and Ser-621. Upon mitogenic stimulation, Ras and PPP2R1A cooperate to release autoinhibition and the subsequent phosphorylation of activating sites: Ser-338, Tyr-341, Thr-491, and Ser-494, yields a fully active kinase. Through a negative feedback mechanism involving MAPK1/ERK2, RAF1 is phosphorylated on Ser-29, Ser-43, Ser-289, Ser-296, Ser-301 and Ser-642 by MAPK1/ERK2, which yields an inactive, desensitized kinase. The signaling-competent conformation of RAF1 is finally re-established by the coordinated action of PIN1, a prolyl isomerase that converts pSer and pThr residues from the cis to the trans conformation, which is preferentially recognized and dephosphorylated by PPP2R1A. Activated by homodimerization and heterodimerization (with BRAF). Also regulated through association with other proteins such as KSR2, CNKSR1/CNK1, PEBP1/RKIP, PHB/prohibitin and SPRY4. PEBP1/RKIP acts by dissociating RAF1 from its substrates MAP2K1/MEK1 and MAP2K2/MEK2. PHB/prohibitin facilitates the displacement of 14-3-3 from RAF1 by activated Ras, thereby promoting cell membrane localization and phosphorylation of RAF1 at the activating Ser-338. SPRY4 inhibits Ras-independent, but not Ras-dependent, activation of RAF1. CNKSR1/CNK1 regulates Src-mediated RAF1 activation.
Active Site:: ACT_SITE 468 468 Proton acceptor.
Cross Reference Drug Bank:: DB08912 DB08896 DB00398
Gene Ontology Go:: cytoplasm
cytosol
Golgi apparatus
mitochondrial outer membrane
nucleus
plasma membrane
pseudopodium
ATP binding
identical protein binding
MAP kinase kinase kinase activity
metal ion binding
protein kinase activity
protein serine/threonine kinase activity
activation of adenylate cyclase activity
activation of MAPKK activity
apoptotic process
axon guidance
blood coagulation
cell proliferation
death-inducing signaling complex assembly
epidermal growth factor receptor signaling pathway
face development
Fc-epsilon receptor signaling pathway
fibroblast growth factor receptor signaling pathway
heart development
innate immune response
insulin receptor signaling pathway
insulin secretion involved in cellular response to glucose stimulus
intermediate filament cytoskeleton organization
ion transmembrane transport
MAPK cascade
negative regulation of apoptotic process
negative regulation of cell proliferation
negative regulation of cysteine-type endopeptidase activity involved in apoptotic process
negative regulation of extrinsic apoptotic signaling pathway via death domain receptors
negative regulation of protein complex assembly
neurotrophin TRK receptor signaling pathway
platelet activation
positive regulation of peptidyl-serine phosphorylation
positive regulation of transcription from RNA polymerase II promoter
protein phosphorylation
Ras protein signal transduction
regulation of apoptotic process
regulation of cell differentiation
regulation of cell motility
regulation of Rho protein signal transduction
response to hypoxia
response to muscle stretch
signal transduction
small GTPase mediated signal transduction
somatic stem cell population maintenance
stimulatory C-type lectin receptor signaling pathway
synaptic transmission
thymus development
thyroid gland development
transmembrane transport
vascular endothelial growth factor receptor signaling pathway
wound healing
Gene Ontology Biological Process:: activation of adenylate cyclase activity
activation of MAPKK activity
apoptotic process
axon guidance
blood coagulation
cell proliferation
death-inducing signaling complex assembly
epidermal growth factor receptor signaling pathway
face development
Fc-epsilon receptor signaling pathway
fibroblast growth factor receptor signaling pathway
heart development
innate immune response
insulin receptor signaling pathway
insulin secretion involved in cellular response to glucose stimulus
intermediate filament cytoskeleton organization
ion transmembrane transport
MAPK cascade
negative regulation of apoptotic process
negative regulation of cell proliferation
negative regulation of cysteine-type endopeptidase activity involved in apoptotic process
negative regulation of extrinsic apoptotic signaling pathway via death domain receptors
negative regulation of protein complex assembly
neurotrophin TRK receptor signaling pathway
platelet activation
positive regulation of peptidyl-serine phosphorylation
positive regulation of transcription from RNA polymerase II promoter
protein phosphorylation
Ras protein signal transduction
regulation of apoptotic process
regulation of cell differentiation
regulation of cell motility
regulation of Rho protein signal transduction
response to hypoxia
response to muscle stretch
signal transduction
small GTPase mediated signal transduction
somatic stem cell population maintenance
stimulatory C-type lectin receptor signaling pathway
synaptic transmission
thymus development
thyroid gland development
transmembrane transport
vascular endothelial growth factor receptor signaling pathway
wound healing
Gene Ontology Molecular Function:: ATP binding
identical protein binding
MAP kinase kinase kinase activity
metal ion binding
protein kinase activity
protein serine/threonine kinase activity
Gene Ontology Cellular Component:: cytoplasm
cytosol
Golgi apparatus
mitochondrial outer membrane
nucleus
plasma membrane
pseudopodium
Keywords:: 3D-structure
ATP-binding
Alternative splicing
Cardiomyopathy
Cell membrane
Complete proteome
Cytoplasm
Deafness
Direct protein sequencing
Disease mutation
Kinase
Membrane
Metal-binding
Methylation
Mitochondrion
Nucleotide-binding
Nucleus
Phosphoprotein
Polymorphism
Proto-oncogene
Reference proteome
Serine/threonine-protein kinase
Transferase
Zinc
Zinc-finger
Interacts With:: Itself; P31749; Q92934; P15056; P49368; P30304; Q16543; P31327; P01112; P08238; P11021; P01116-2; P28301; Q02750; P36507; Q9ESN9-2; Q12968; P03495; O39474; O43482; Q13177; P09619; P30086; Q96S96; P14618; P62834; P01120; P06400; P53805-2; P31947; Q3ZCQ8; P31946; P62258; Q04917; P27348; P63104

Names & Taxonomy

Structure

Subcellular location

Function

Publication