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UniProtKB - P04049 (RAF1_HUMAN)

Entry version 231 (13 Feb 2019)
Sequence version 1 (01 Nov 1986)
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Protein

RAF proto-oncogene serine/threonine-protein kinase

Gene

RAF1

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score:

Annotation score:5 out of 5

<p>The annotation score provides a heuristic measure of the annotation content of a UniProtKB entry or proteome. This score <strong>cannot</strong> be used as a measure of the accuracy of the annotation as we cannot define the ‘correct annotation’ for any given protein.<p><a href='/help/annotation_score' target='_top'>More...</a></p>-Experimental evidence at protein leveli <p>This indicates the type of evidence that supports the existence of the protein. Note that the ‘protein existence’ evidence does not give information on the accuracy or correctness of the sequence(s) displayed.<p><a href='/help/protein_existence' target='_top'>More...</a></p>

<p>This section provides any useful information about the protein, mostly biological knowledge.<p><a href='/help/function_section' target='_top'>More...</a></p>Functioni

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.8 Publications

<p>This subsection of the <a href="http://www.uniprot.org/help/function_section">Function</a> section describes the catalytic activity of an enzyme, i.e. a chemical reaction that the enzyme catalyzes.<p><a href='/help/catalytic_activity' target='_top'>More...</a></p>Catalytic activityi

<p>This subsection of the ‘Function’ section provides information relevant to cofactors. A cofactor is any non-protein substance required for a protein to be catalytically active. Some cofactors are inorganic, such as the metal atoms zinc, iron, and copper in various oxidation states. Others, such as most vitamins, are organic.<p><a href='/help/cofactor' target='_top'>More...</a></p>Cofactori

Zn2+Note: Binds 2 Zn2+ ions per subunit.

<p>This subsection of the ‘Function’ section describes regulatory mechanisms for enzymes, transporters or microbial transcription factors, and reports the components which regulate (by activation or inhibition) the reaction.<p><a href='/help/activity_regulation' target='_top'>More...</a></p>Activity regulationi

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.8 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
<p>This subsection of the ‘Function’ section indicates at which position the protein binds a given metal ion. The nature of the metal is indicated in the ‘Description’ field.<p><a href='/help/metal' target='_top'>More...</a></p>Metal bindingi139Zinc 11
Metal bindingi152Zinc 21
Metal bindingi155Zinc 21
Metal bindingi165Zinc 11
Metal bindingi168Zinc 11
Metal bindingi173Zinc 21
Metal bindingi176Zinc 21
Metal bindingi184Zinc 11
<p>This subsection of the ‘Function’ section describes the interaction between a single amino acid and another chemical entity. Priority is given to the annotation of physiological ligands.<p><a href='/help/binding' target='_top'>More...</a></p>Binding sitei375ATPPROSITE-ProRule annotation1
<p>This subsection of the ‘Function’ section is used for enzymes and indicates the residues directly involved in catalysis.<p><a href='/help/act_site' target='_top'>More...</a></p>Active sitei468Proton acceptor1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
<p>This subsection of the ‘Function’ section specifies the position(s) and type(s) of zinc fingers within the protein.<p><a href='/help/zn_fing' target='_top'>More...</a></p>Zinc fingeri138 – 184Phorbol-ester/DAG-typePROSITE-ProRule annotationAdd BLAST47
<p>This subsection of the ‘Function’ section describes a region in the protein which binds nucleotide phosphates. It always involves more than one amino acid and includes all residues involved in nucleotide-binding.<p><a href='/help/np_bind' target='_top'>More...</a></p>Nucleotide bindingi355 – 363ATPPROSITE-ProRule annotation9

<p>The <a href="http://www.geneontology.org/">Gene Ontology (GO)</a> project provides a set of hierarchical controlled vocabulary split into 3 categories:<p><a href='/help/gene_ontology' target='_top'>More...</a></p>GO - Molecular functioni

View the complete GO annotation on QuickGO ...

GO - Biological processi

View the complete GO annotation on QuickGO ...

<p>UniProtKB Keywords constitute a <a href="http://www.uniprot.org/keywords">controlled vocabulary</a> with a hierarchical structure. Keywords summarise the content of a UniProtKB entry and facilitate the search for proteins of interest.<p><a href='/help/keywords' target='_top'>More...</a></p>Keywordsi

Molecular functionKinase, Serine/threonine-protein kinase, Transferase
LigandATP-binding, Metal-binding, Nucleotide-binding, Zinc

Enzyme and pathway databases

BRENDA Comprehensive Enzyme Information System

More...BRENDAi		2.7.10.2 2681

Reactome - a knowledgebase of biological pathways and processes

More...Reactomei		R-HSA-2672351 Stimuli-sensing channels
R-HSA-392517 Rap1 signalling
R-HSA-430116 GP1b-IX-V activation signalling
R-HSA-5621575 CD209 (DC-SIGN) signaling
R-HSA-5673000 RAF activation
R-HSA-5674135 MAP2K and MAPK activation
R-HSA-5674499 Negative feedback regulation of MAPK pathway
R-HSA-5675221 Negative regulation of MAPK pathway
R-HSA-6802946 Signaling by moderate kinase activity BRAF mutants
R-HSA-6802948 Signaling by high-kinase activity BRAF mutants
R-HSA-6802949 Signaling by RAS mutants
R-HSA-6802952 Signaling by BRAF and RAF fusions
R-HSA-6802955 Paradoxical activation of RAF signaling by kinase inactive BRAF

SignaLink: a signaling pathway resource with multi-layered regulatory networks

More...SignaLinki		P04049

SIGNOR Signaling Network Open Resource

More...SIGNORi		P04049

Protein family/group databases

MoonDB Database of extreme multifunctional and moonlighting proteins

More...MoonDBi		P04049 Predicted

<p>This section provides information about the protein and gene name(s) and synonym(s) and about the organism that is the source of the protein sequence.<p><a href='/help/names_and_taxonomy_section' target='_top'>More...</a></p>Names & Taxonomyi

<p>This subsection of the <a href="http://www.uniprot.org/help/names_and_taxonomy_section">Names and taxonomy</a> section provides an exhaustive list of all names of the protein, from commonly used to obsolete, to allow unambiguous identification of a protein.<p><a href='/help/protein_names' target='_top'>More...</a></p>Protein namesi
Recommended name:
RAF proto-oncogene serine/threonine-protein kinase (EC:2.7.11.1)
Alternative name(s):
Proto-oncogene c-RAF
Short name:
cRaf
Raf-1
<p>This subsection of the <a href="http://www.uniprot.org/help/names_and_taxonomy_section">Names and taxonomy</a> section indicates the name(s) of the gene(s) that code for the protein sequence(s) described in the entry. Four distinct tokens exist: ‘Name’, ‘Synonyms’, ‘Ordered locus names’ and ‘ORF names’.<p><a href='/help/gene_name' target='_top'>More...</a></p>Gene namesi
Name:RAF1
Synonyms:RAF
<p>This subsection of the <a href="http://www.uniprot.org/help/names_and_taxonomy_section">Names and taxonomy</a> section provides information on the name(s) of the organism that is the source of the protein sequence.<p><a href='/help/organism-name' target='_top'>More...</a></p>OrganismiHomo sapiens (Human)
<p>This subsection of the <a href="http://www.uniprot.org/help/names_and_taxonomy_section">Names and taxonomy</a> section shows the unique identifier assigned by the NCBI to the source organism of the protein. This is known as the ‘taxonomic identifier’ or ‘taxid’.<p><a href='/help/taxonomic_identifier' target='_top'>More...</a></p>Taxonomic identifieri9606 [NCBI]
<p>This subsection of the <a href="http://www.uniprot.org/help/names_and_taxonomy_section">Names and taxonomy</a> section contains the taxonomic hierarchical classification lineage of the source organism. It lists the nodes as they appear top-down in the taxonomic tree, with the more general grouping listed first.<p><a href='/help/taxonomic_lineage' target='_top'>More...</a></p>Taxonomic lineageiEukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo
<p>This subsection of the <a href="http://www.uniprot.org/help/names_and_taxonomy_section">Names and taxonomy</a> section is present for entries that are part of a <a href="http://www.uniprot.org/proteomes">proteome</a>, i.e. of a set of proteins thought to be expressed by organisms whose genomes have been completely sequenced.<p><a href='/help/proteomes_manual' target='_top'>More...</a></p>Proteomesi
  • UP000005640 <p>A UniProt <a href="http://www.uniprot.org/manual/proteomes_manual">proteome</a> can consist of several components. <br></br>The component name refers to the genomic component encoding a set of proteins.<p><a href='/help/proteome_component' target='_top'>More...</a></p> Componenti: Chromosome 3

Organism-specific databases

Eukaryotic Pathogen Database Resources

More...EuPathDBi		HostDB:ENSG00000132155.11

Human Gene Nomenclature Database

More...HGNCi		HGNC:9829 RAF1

Online Mendelian Inheritance in Man (OMIM)

More...MIMi		164760 gene

neXtProt; the human protein knowledge platform

More...neXtProti		NX_P04049

<p>This section provides information on the location and the topology of the mature protein in the cell.<p><a href='/help/subcellular_location_section' target='_top'>More...</a></p>Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte & Seán O’Donoghue; Source: COMPARTMENTS

Keywords - Cellular componenti

Cell membrane, Cytoplasm, Membrane, Mitochondrion, Nucleus

<p>This section provides information on the disease(s) and phenotype(s) associated with a protein.<p><a href='/help/pathology_and_biotech_section' target='_top'>More...</a></p>Pathology & Biotechi

<p>This subsection of the ‘Pathology and Biotech’ section provides information on the disease(s) associated with genetic variations in a given protein. The information is extracted from the scientific literature and diseases that are also described in the <a href="http://www.ncbi.nlm.nih.gov/sites/entrez?db=omim">OMIM</a> database are represented with a <a href="http://www.uniprot.org/diseases">controlled vocabulary</a> in the following way:<p><a href='/help/involvement_in_disease' target='_top'>More...</a></p>Involvement in diseasei

Noonan syndrome 5 (NS5)3 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA 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.
See also OMIM:611553
Feature keyPosition(s)DescriptionActionsGraphical viewLength
<p>This subsection of the ‘Sequence’ section describes natural variant(s) of the protein sequence.<p><a href='/help/variant' target='_top'>More...</a></p>Natural variantiVAR_037807256R → S in NS5. 1 PublicationCorresponds to variant dbSNP:rs397516826EnsemblClinVar.1
Natural variantiVAR_037808257S → L in NS5 and LPRD2; shows in vitro greater kinase activity and enhanced ERK activation than wild-type. 2 PublicationsCorresponds to variant dbSNP:rs80338796EnsemblClinVar.1
Natural variantiVAR_037809259S → F in NS5. 1 PublicationCorresponds to variant dbSNP:rs397516827EnsemblClinVar.1
Natural variantiVAR_037811260T → R in NS5. 1 Publication1
Natural variantiVAR_037812261P → A in NS5; shows in vitro greater kinase activity and enhanced MAPK1 activation than wild-type. 1 PublicationCorresponds to variant dbSNP:rs121434594EnsemblClinVar.1
Natural variantiVAR_037813261P → L in NS5; shows greater kinase activity and enhanced MAPK1 activation than wild-type. 1 PublicationCorresponds to variant dbSNP:rs397516828EnsemblClinVar.1
Natural variantiVAR_037814261P → S in NS5; shows in vitro greater kinase activity and enhanced MAPK1 activation than wild-type. 3 PublicationsCorresponds to variant dbSNP:rs121434594EnsemblClinVar.1
Natural variantiVAR_037815263V → A in NS5; shows in vitro greater kinase activity and enhanced MAPK1 activation than wild-type. 1 PublicationCorresponds to variant dbSNP:rs397516830EnsemblClinVar.1
Natural variantiVAR_037816486D → G in NS5. 1 PublicationCorresponds to variant dbSNP:rs397516815EnsemblClinVar.1
Natural variantiVAR_037817486D → N in NS5; has reduced or absent kinase activity. 1 PublicationCorresponds to variant dbSNP:rs80338798EnsemblClinVar.1
Natural variantiVAR_037818491T → I in NS5; has reduced or absent kinase activity. 1 PublicationCorresponds to variant dbSNP:rs80338799EnsemblClinVar.1
Natural variantiVAR_037819491T → R in NS5. 1 PublicationCorresponds to variant dbSNP:rs80338799EnsemblClinVar.1
Natural variantiVAR_037820612S → T in NS5. 1 PublicationCorresponds to variant dbSNP:rs1448392469Ensembl.1
Natural variantiVAR_037821613L → V in NS5 and LPRD2; shows in vitro greater kinase activity and enhanced MAPK1 activation than wild-type. 2 PublicationsCorresponds to variant dbSNP:rs80338797EnsemblClinVar.1
LEOPARD syndrome 2 (LPRD2)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA disorder characterized by lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormalities of genitalia, retardation of growth, and sensorineural deafness.
See also OMIM:611554
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_037808257S → L in NS5 and LPRD2; shows in vitro greater kinase activity and enhanced ERK activation than wild-type. 2 PublicationsCorresponds to variant dbSNP:rs80338796EnsemblClinVar.1
Natural variantiVAR_037821613L → V in NS5 and LPRD2; shows in vitro greater kinase activity and enhanced MAPK1 activation than wild-type. 2 PublicationsCorresponds to variant dbSNP:rs80338797EnsemblClinVar.1
Cardiomyopathy, dilated 1NN (CMD1NN)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death.
See also OMIM:615916
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_071844237A → T in CMD1NN; shows a mild increase in kinase activity. 1 PublicationCorresponds to variant dbSNP:rs587777588EnsemblClinVar.1
Natural variantiVAR_071845310T → A in CMD1NN; shows a mild increase in kinase activity. 1 PublicationCorresponds to variant dbSNP:rs778155315Ensembl.1
Natural variantiVAR_071846332P → A in CMD1NN; shows a mild increase in kinase activity. 1 PublicationCorresponds to variant dbSNP:rs1057403865Ensembl.1
Natural variantiVAR_071847603L → P in CMD1NN; shows impaired kinase activity and reduced MAPK3 activation with this mutation. 1 PublicationCorresponds to variant dbSNP:rs587777586EnsemblClinVar.1
Natural variantiVAR_071848626H → R in CMD1NN; shows a mild increase in kinase activity. 1 Publication1
Natural variantiVAR_071849641T → M in CMD1NN; shows a mild increase in kinase activity. 1 PublicationCorresponds to variant dbSNP:rs587777587EnsemblClinVar.1

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
<p>This subsection of the <a href="http://www.uniprot.org/manual/pathology_and_biotech_section">'Pathology and Biotech'</a> section describes the effect of the experimental mutation of one or more amino acid(s) on the biological properties of the protein.<p><a href='/help/mutagen' target='_top'>More...</a></p>Mutagenesisi338 – 339SS → AA: Reduced kinase activity; when associated with 340-D-D-341. 1 Publication2
Mutagenesisi338 – 339SS → DE: Non-inhibited by PPP5C. Constitutively active and non-inhibited by PPP5C; when associated with 340-D-D-341. 1 Publication2
Mutagenesisi340 – 341YY → DD: Constitutively active and highly phosphorylated on S-338, inhibited by PPP5C. Reduced kinase activity; when associated with 338-A-A-339. Constitutively active and non-inhibited by PPP5C; when associated with 338-D-E-339. 1 Publication2
Mutagenesisi491T → D: Increased kinase activity but can still be inhibited by PPP5C; when associated with D-494. 1 Publication1
Mutagenesisi494S → D: Increased kinase activity but can still be inhibited by PPP5C; when associated with D-491. 1 Publication1
Mutagenesisi563R → K: Loss of methylation. Increased stability and catalytic activity in response to EGF treatment. 1 Publication1

Keywords - Diseasei

Cardiomyopathy, Deafness, Disease mutation, Proto-oncogene

Organism-specific databases

DisGeNET

More...DisGeNETi		5894

GeneReviews a resource of expert-authored, peer-reviewed disease descriptions.

More...GeneReviewsi		RAF1

MalaCards human disease database

More...MalaCardsi		RAF1
MIMi611553 phenotype
611554 phenotype
615916 phenotype

Open Targets

More...OpenTargetsi		ENSG00000132155

Orphanet; a database dedicated to information on rare diseases and orphan drugs

More...Orphaneti		154 Familial isolated dilated cardiomyopathy
648 Noonan syndrome
500 Noonan syndrome with multiple lentigines
251615 Pilomyxoid astrocytoma

The Pharmacogenetics and Pharmacogenomics Knowledge Base

More...PharmGKBi		PA34183

Chemistry databases

ChEMBL database of bioactive drug-like small molecules

More...ChEMBLi		CHEMBL1906

Drug and drug target database

More...DrugBanki		DB08912 Dabrafenib
DB05268 iCo-007
DB04973 LErafAON
DB08896 Regorafenib
DB00398 Sorafenib
DB05190 XL281

IUPHAR/BPS Guide to PHARMACOLOGY

More...GuidetoPHARMACOLOGYi		2184

Polymorphism and mutation databases

BioMuta curated single-nucleotide variation and disease association database

More...BioMutai		RAF1

Domain mapping of disease mutations (DMDM)

More...DMDMi		125651

<p>This section describes post-translational modifications (PTMs) and/or processing events.<p><a href='/help/ptm_processing_section' target='_top'>More...</a></p>PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
<p>This subsection of the ‘PTM / Processing’ section describes the extent of a polypeptide chain in the mature protein following processing.<p><a href='/help/chain' target='_top'>More...</a></p>ChainiPRO_00000865961 – 648RAF proto-oncogene serine/threonine-protein kinaseAdd BLAST648

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
<p>This subsection of the ‘PTM / Processing’ section specifies the position and type of each modified residue excluding <a href="http://www.uniprot.org/manual/lipid">lipids</a>, <a href="http://www.uniprot.org/manual/carbohyd">glycans</a> and <a href="http://www.uniprot.org/manual/crosslnk">protein cross-links</a>.<p><a href='/help/mod_res' target='_top'>More...</a></p>Modified residuei29Phosphoserine; by MAPK1By similarity1
Modified residuei43Phosphoserine; by PKA and MAPK11 Publication1
Modified residuei252PhosphoserineCombined sources1
Modified residuei259Phosphoserine; by PKA, PKC and PKB/AKT17 Publications1
Modified residuei268Phosphothreonine; by autocatalysis1 Publication1
Modified residuei269Phosphothreonine; by PKA1 Publication1
Modified residuei289Phosphoserine; by MAPK1Combined sources1 Publication1
Modified residuei296PhosphoserineCombined sources1
Modified residuei301Phosphoserine; by MAPK1Combined sources1 Publication1
Modified residuei338Phosphoserine; by PAK1, PAK2, PAK3 and PAK55 Publications1
Modified residuei339Phosphoserine; by PAK1, PAK2 and PAK31 Publication1
Modified residuei340Phosphotyrosine; by SRC1 Publication1
Modified residuei341Phosphotyrosine; by SRC1 Publication1
Modified residuei471Phosphoserine1 Publication1
Modified residuei491Phosphothreonine1 Publication1
Modified residuei494Phosphoserine1 Publication1
Modified residuei499Phosphoserine; by PKC1 Publication1
Modified residuei563Symmetric dimethylarginine; by PRMT51 Publication1
Modified residuei621Phosphoserine4 Publications1
Modified residuei642Phosphoserine; by MAPK1Combined sources1

<p>This subsection of the <a href="http://www.uniprot.org/help/ptm_processing_section">PTM/processing</a> section describes post-translational modifications (PTMs). This subsection <strong>complements</strong> the information provided at the sequence level or describes modifications for which <strong>position-specific data is not yet available</strong>.<p><a href='/help/post-translational_modification' target='_top'>More...</a></p>Post-translational modificationi

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.15 Publications
Methylated at Arg-563 in response to EGF treatment. This modification leads to destabilization of the protein, possibly through proteasomal degradation.1 Publication

Keywords - PTMi

Methylation, Phosphoprotein

Proteomic databases

Encyclopedia of Proteome Dynamics

More...EPDi		P04049

jPOST - Japan Proteome Standard Repository/Database

More...jPOSTi		P04049

MaxQB - The MaxQuant DataBase

More...MaxQBi		P04049

PaxDb, a database of protein abundance averages across all three domains of life

More...PaxDbi		P04049

PeptideAtlas

More...PeptideAtlasi		P04049

PRoteomics IDEntifications database

More...PRIDEi		P04049

ProteomicsDB human proteome resource

More...ProteomicsDBi		51637
51638 [P04049-2]

PTM databases

iPTMnet integrated resource for PTMs in systems biology context

More...iPTMneti		P04049

Comprehensive resource for the study of protein post-translational modifications (PTMs) in human, mouse and rat.

More...PhosphoSitePlusi		P04049

Miscellaneous databases

CutDB - Proteolytic event database

More...PMAP-CutDBi		P04049

<p>This section provides information on the expression of a gene at the mRNA or protein level in cells or in tissues of multicellular organisms.<p><a href='/help/expression_section' target='_top'>More...</a></p>Expressioni

<p>This subsection of the ‘Expression’ section provides information on the expression of a gene at the mRNA or protein level in cells or in tissues of multicellular organisms. By default, the information is derived from experiments at the mRNA level, unless specified ‘at protein level’. <br></br>Examples: <a href="http://www.uniprot.org/uniprot/P92958#expression">P92958</a>, <a href="http://www.uniprot.org/uniprot/Q8TDN4#expression">Q8TDN4</a>, <a href="http://www.uniprot.org/uniprot/O14734#expression">O14734</a><p><a href='/help/tissue_specificity' target='_top'>More...</a></p>Tissue specificityi

In skeletal muscle, isoform 1 is more abundant than isoform 2.1 Publication

Gene expression databases

Bgee dataBase for Gene Expression Evolution

More...Bgeei		ENSG00000132155 Expressed in 234 organ(s), highest expression level in cerebellar hemisphere

ExpressionAtlas, Differential and Baseline Expression

More...ExpressionAtlasi		P04049 baseline and differential

Genevisible search portal to normalized and curated expression data from Genevestigator

More...Genevisiblei		P04049 HS

Organism-specific databases

Human Protein Atlas

More...HPAi		CAB019291
HPA002640

<p>This section provides information on the quaternary structure of a protein and on interaction(s) with other proteins or protein complexes.<p><a href='/help/interaction_section' target='_top'>More...</a></p>Interactioni

<p>This subsection of the <a href="http://www.uniprot.org/help/interaction_section">'Interaction'</a> section provides information about the protein quaternary structure and interaction(s) with other proteins or protein complexes (with the exception of physiological receptor-ligand interactions which are annotated in the <a href="http://www.uniprot.org/help/function_section">'Function'</a> section).<p><a href='/help/subunit_structure' target='_top'>More...</a></p>Subunit structurei

Monomer. Homodimer. Heterodimerizes with BRAF and this heterodimer possesses a highly increased kinase activity compared to the respective homodimers or monomers (PubMed:16508002). Heterodimerization is mitogen-regulated and enhanced by 14-3-3 proteins (PubMed:16508002). MAPK1/ERK2 activation can induce a negative feedback that promotes the dissociation of the heterodimer (PubMed:16508002). Forms a multiprotein complex with Ras (M-Ras/MRAS), SHOC2 and protein phosphatase 1 (PPP1CA, PPP1CB and PPP1CC) (PubMed:16630891). Interacts with LZTR1 (PubMed:30368668). Interacts with Ras proteins; the interaction is antagonized by RIN1 (PubMed:11784866). Weakly interacts with RIT1. Interacts (via N-terminus) with RGS14 (via RBD domains); the interaction mediates the formation of a ternary complex with BRAF, a ternary complex inhibited by GNAI1 (By similarity). Probably forms a complex composed of chaperones HSP90 and HSP70, co-chaperones CDC37, PPP5C, TSC1 and client protein TSC2, CDK4, AKT, RAF1 and NR3C1; this complex does not contain co-chaperones STIP1/HOP and PTGES3/p23 (PubMed:29127155). Interacts with STK3/MST2; the interaction inhibits its pro-apoptotic activity (PubMed:15618521). Interacts (when phosphorylated at Ser-259) with YWHAZ (unphosphorylated at 'Thr-232') (PubMed:9360956). Interacts with MAP2K1/MEK1 and MAP2K2/MEK2 (By similarity). Interacts with MAP3K5/ASF1 (via N-terminus) and this interaction inhibits the proapoptotic function of MAP3K5/ASK1 (PubMed:11427728). Interacts with PAK1 (via kinase domain) (PubMed:11733498). The phosphorylated form interacts with PIN1 (By similarity). The Ser-338 and Ser-339 phosphorylated form (by PAK1) interacts with BCL2 (PubMed:15849194). Interacts with PEBP1/RKIP and this interaction is enhanced if RAF1 is phosphorylated on residues Ser-338, Ser-339, Tyr-340 and Tyr-341 (PubMed:18294816). Interacts with ADCY2, ADCY5, ADCY6, DGKH, RCAN1/DSCR1, PPP1R12A, PKB/AKT1, PPP2CA, PPP2R1B, SPRY2, SPRY4, CNKSR1/CNK1, KSR2 and PHB/prohibitin (PubMed:10801873, PubMed:11719507, PubMed:12717443, PubMed:15385642, PubMed:15935327, PubMed:19710016, PubMed:10576742). Interacts with ROCK2 (By similarity). In its active form, interacts with PRMT5 (PubMed:21917714). Interacts with FAM83B; displaces 14-3-3 proteins from RAF1 and activates RAF1 (PubMed:22886302). Interacts with PDE8A; the interaction promotes RAF1 activity (PubMed:23509299). Interacts with MFHAS1 (PubMed:23327923).By similarity22 Publications

<p>This subsection of the '<a href="http://www.uniprot.org/help/interaction_section%27">Interaction</a> section provides information about binary protein-protein interactions. The data presented in this section are a quality-filtered subset of binary interactions automatically derived from the <a href="http://www.ebi.ac.uk/intact/">IntAct database</a>. It is updated on a monthly basis. Each binary interaction is displayed on a separate line.<p><a href='/help/binary_interactions' target='_top'>More...</a></p>Binary interactionsi

GO - Molecular functioni

View the complete GO annotation on QuickGO ...

Protein-protein interaction databases

The Biological General Repository for Interaction Datasets (BioGrid)

More...BioGridi		111831, 209 interactors

CORUM comprehensive resource of mammalian protein complexes

More...CORUMi		P04049

Database of interacting proteins

More...DIPi		DIP-1048N

Protein interaction database and analysis system

More...IntActi		P04049, 120 interactors

Molecular INTeraction database

More...MINTi		P04049

STRING: functional protein association networks

More...STRINGi		9606.ENSP00000251849

Chemistry databases

BindingDB database of measured binding affinities

More...BindingDBi		P04049

<p>This section provides information on the tertiary and secondary structure of a protein.<p><a href='/help/structure_section' target='_top'>More...</a></p>Structurei

Secondary structure

1648
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details

3D structure databases

Select the link destinations:

Protein Data Bank Europe

More...PDBei

Protein Data Bank RCSB

More...RCSB PDBi

Protein Data Bank Japan

More...PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1C1YX-ray1.90B55-131[»]
1FAQNMR-A136-187[»]
1FARNMR-A136-187[»]
1GUAX-ray2.00B51-131[»]
1RFANMR-A55-132[»]
3CU8X-ray2.40P/Q256-264[»]
3IQJX-ray1.15P255-264[»]
3IQUX-ray1.05P255-260[»]
3IQVX-ray1.20P255-260[»]
3KUCX-ray1.92B51-131[»]
3KUDX-ray2.15B51-131[»]
3NKXX-ray2.40P/Q255-264[»]
3O8IX-ray2.00B255-264[»]
3OMVX-ray4.00A/B323-618[»]
4FJ3X-ray1.95P229-264[»]
4G0NX-ray2.45B54-131[»]
4G3XX-ray3.25B55-131[»]
4IEAX-ray1.70P618-625[»]
4IHLX-ray2.20P229-264[»]

Database of protein disorder

More...DisProti		DP00171

Protein Model Portal of the PSI-Nature Structural Biology Knowledgebase

More...ProteinModelPortali		P04049

SWISS-MODEL Repository - a database of annotated 3D protein structure models

More...SMRi		P04049

Database of comparative protein structure models

More...ModBasei		Search...

MobiDB: a database of protein disorder and mobility annotations

More...MobiDBi		Search...

Miscellaneous databases

Relative evolutionary importance of amino acids within a protein sequence

More...EvolutionaryTracei		P04049

<p>This section provides information on sequence similarities with other proteins and the domain(s) present in a protein.<p><a href='/help/family_and_domains_section' target='_top'>More...</a></p>Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
<p>This subsection of the <a href="http://www.uniprot.org/help/family_and_domains_section">Family and Domains</a> section describes the position and type of a domain, which is defined as a specific combination of secondary structures organized into a characteristic three-dimensional structure or fold.<p><a href='/help/domain' target='_top'>More...</a></p>Domaini56 – 131RBDPROSITE-ProRule annotationAdd BLAST76
Domaini349 – 609Protein kinasePROSITE-ProRule annotationAdd BLAST261

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
<p>This subsection of the ‘Family and Domains’ section describes a region of interest that cannot be described in other subsections.<p><a href='/help/region' target='_top'>More...</a></p>Regioni331 – 349Interaction with PEBP1/RKIPAdd BLAST19

<p>This subsection of the ‘Family and domains’ section provides information about the sequence similarity with other proteins.<p><a href='/help/sequence_similarities' target='_top'>More...</a></p>Sequence similaritiesi

Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. RAF subfamily.Curated

Zinc finger

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Zinc fingeri138 – 184Phorbol-ester/DAG-typePROSITE-ProRule annotationAdd BLAST47

Keywords - Domaini

Zinc-finger

Phylogenomic databases

evolutionary genealogy of genes: Non-supervised Orthologous Groups

More...eggNOGi		KOG0193 Eukaryota
ENOG410Y4UP LUCA

Ensembl GeneTree

More...GeneTreei		ENSGT00940000156084

The HOGENOM Database of Homologous Genes from Fully Sequenced Organisms

More...HOGENOMi		HOG000252972

The HOVERGEN Database of Homologous Vertebrate Genes

More...HOVERGENi		HBG001886

InParanoid: Eukaryotic Ortholog Groups

More...InParanoidi		P04049

KEGG Orthology (KO)

More...KOi		K04366

Identification of Orthologs from Complete Genome Data

More...OMAi		FQMFQLM

Database of Orthologous Groups

More...OrthoDBi		1344247at2759

Database for complete collections of gene phylogenies

More...PhylomeDBi		P04049

TreeFam database of animal gene trees

More...TreeFami		TF317006

Family and domain databases

Conserved Domains Database

More...CDDi		cd00029 C1, 1 hit

Integrated resource of protein families, domains and functional sites

More...InterProi		View protein in InterPro
IPR020454 DAG/PE-bd
IPR011009 Kinase-like_dom_sf
IPR002219 PE/DAG-bd
IPR000719 Prot_kinase_dom
IPR017441 Protein_kinase_ATP_BS
IPR003116 RBD_dom
IPR001245 Ser-Thr/Tyr_kinase_cat_dom
IPR008271 Ser/Thr_kinase_AS
IPR029071 Ubiquitin-like_domsf

Pfam protein domain database

More...Pfami		View protein in Pfam
PF00130 C1_1, 1 hit
PF07714 Pkinase_Tyr, 1 hit
PF02196 RBD, 1 hit

Protein Motif fingerprint database; a protein domain database

More...PRINTSi		PR00008 DAGPEDOMAIN

Simple Modular Architecture Research Tool; a protein domain database

More...SMARTi		View protein in SMART
SM00109 C1, 1 hit
SM00455 RBD, 1 hit
SM00220 S_TKc, 1 hit

Superfamily database of structural and functional annotation

More...SUPFAMi		SSF54236 SSF54236, 1 hit
SSF56112 SSF56112, 1 hit

PROSITE; a protein domain and family database

More...PROSITEi		View protein in PROSITE
PS00107 PROTEIN_KINASE_ATP, 1 hit
PS50011 PROTEIN_KINASE_DOM, 1 hit
PS00108 PROTEIN_KINASE_ST, 1 hit
PS50898 RBD, 1 hit
PS00479 ZF_DAG_PE_1, 1 hit
PS50081 ZF_DAG_PE_2, 1 hit

<p>This section displays by default the canonical protein sequence and upon request all isoforms described in the entry. It also includes information pertinent to the sequence(s), including <a href="http://www.uniprot.org/help/sequence_length">length</a> and <a href="http://www.uniprot.org/help/sequences">molecular weight</a>.<p><a href='/help/sequences_section' target='_top'>More...</a></p>Sequences (2+)i

<p>This subsection of the <a href="http://www.uniprot.org/help/sequences_section">Sequence</a> section indicates if the <a href="http://www.uniprot.org/help/canonical_and_isoforms">canonical sequence</a> displayed by default in the entry is complete or not.<p><a href='/help/sequence_status' target='_top'>More...</a></p>Sequence statusi: Complete.

This entry describes 2 <p>This subsection of the ‘Sequence’ section lists the alternative protein sequences (isoforms) that can be generated from the same gene by a single or by the combination of up to four biological events (alternative promoter usage, alternative splicing, alternative initiation and ribosomal frameshifting). Additionally, this section gives relevant information on each alternative protein isoform.<p><a href='/help/alternative_products' target='_top'>More...</a></p> isoformsi produced by alternative splicing. AlignAdd to basket

This entry has 2 described isoforms and 2 potential isoforms that are computationally mapped.Show allAlign All

Isoform 1 (identifier: P04049-1) [UniParc]FASTAAdd to basket
Also known as: 6C

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide
        10         20         30         40         50
MEHIQGAWKT ISNGFGFKDA VFDGSSCISP TIVQQFGYQR RASDDGKLTD 
        60         70         80         90        100
PSKTSNTIRV FLPNKQRTVV NVRNGMSLHD CLMKALKVRG LQPECCAVFR 
       110        120        130        140        150
LLHEHKGKKA RLDWNTDAAS LIGEELQVDF LDHVPLTTHN FARKTFLKLA 
       160        170        180        190        200
FCDICQKFLL NGFRCQTCGY KFHEHCSTKV PTMCVDWSNI RQLLLFPNST 
       210        220        230        240        250
IGDSGVPALP SLTMRRMRES VSRMPVSSQH RYSTPHAFTF NTSSPSSEGS 
       260        270        280        290        300
LSQRQRSTST PNVHMVSTTL PVDSRMIEDA IRSHSESASP SALSSSPNNL 
       310        320        330        340        350
SPTGWSQPKT PVPAQRERAP VSGTQEKNKI RPRGQRDSSY YWEIEASEVM 
       360        370        380        390        400
LSTRIGSGSF GTVYKGKWHG DVAVKILKVV DPTPEQFQAF RNEVAVLRKT 
       410        420        430        440        450
RHVNILLFMG YMTKDNLAIV TQWCEGSSLY KHLHVQETKF QMFQLIDIAR 
       460        470        480        490        500
QTAQGMDYLH AKNIIHRDMK SNNIFLHEGL TVKIGDFGLA TVKSRWSGSQ 
       510        520        530        540        550
QVEQPTGSVL WMAPEVIRMQ DNNPFSFQSD VYSYGIVLYE LMTGELPYSH 
       560        570        580        590        600
INNRDQIIFM VGRGYASPDL SKLYKNCPKA MKRLVADCVK KVKEERPLFP 
       610        620        630        640 
QILSSIELLQ HSLPKINRSA SEPSLHRAAH TEDINACTLT TSPRLPVF
Length:648
Mass (Da):73,052
Last modified:November 1, 1986 - v1
<p>The checksum is a form of redundancy check that is calculated from the sequence. It is useful for tracking sequence updates.</p> <p>It should be noted that while, in theory, two different sequences could have the same checksum value, the likelihood that this would happen is extremely low.</p> <p>However UniProtKB may contain entries with identical sequences in case of multiple genes (paralogs).</p> <p>The checksum is computed as the sequence 64-bit Cyclic Redundancy Check value (CRC64) using the generator polynomial: x<sup>64</sup> + x<sup>4</sup> + x<sup>3</sup> + x + 1. The algorithm is described in the ISO 3309 standard. </p> <p class="publication">Press W.H., Flannery B.P., Teukolsky S.A. and Vetterling W.T.<br /> <strong>Cyclic redundancy and other checksums</strong><br /> <a href="http://www.nrbook.com/b/bookcpdf.php">Numerical recipes in C 2nd ed., pp896-902, Cambridge University Press (1993)</a>)</p> Checksum:iEF821B5349711BC3
GO
Isoform 2 (identifier: P04049-2) [UniParc]FASTAAdd to basket
Also known as: 1A

The sequence of this isoform differs from the canonical sequence as follows:
     278-278: E → ENNNLSASPRAWSRRFCLRGR

Show »
Length:668
Mass (Da):75,395
Checksum:iBD64D7A649342F5D
GO

<p>In eukaryotic reference proteomes, unreviewed entries that are likely to belong to the same gene are computationally mapped, based on gene identifiers from Ensembl, EnsemblGenomes and model organism databases.<p><a href='/help/gene_centric_isoform_mapping' target='_top'>More...</a></p>Computationally mapped potential isoform sequencesi

There are 2 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
H7C155H7C155_HUMAN
RAF proto-oncogene serine/threonine...
RAF1
527Annotation score:

Annotation score:1 out of 5

<p>The annotation score provides a heuristic measure of the annotation content of a UniProtKB entry or proteome. This score <strong>cannot</strong> be used as a measure of the accuracy of the annotation as we cannot define the ‘correct annotation’ for any given protein.<p><a href='/help/annotation_score' target='_top'>More...</a></p>
A0A0B4J1W9A0A0B4J1W9_HUMAN
RAF proto-oncogene serine/threonine...
RAF1
69Annotation score:

Annotation score:1 out of 5

<p>The annotation score provides a heuristic measure of the annotation content of a UniProtKB entry or proteome. This score <strong>cannot</strong> be used as a measure of the accuracy of the annotation as we cannot define the ‘correct annotation’ for any given protein.<p><a href='/help/annotation_score' target='_top'>More...</a></p>

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
<p>This subsection of the ‘Sequence’ section reports difference(s) between the canonical sequence (displayed by default in the entry) and the different sequence submissions merged in the entry. These various submissions may originate from different sequencing projects, different types of experiments, or different biological samples. Sequence conflicts are usually of unknown origin.<p><a href='/help/conflict' target='_top'>More...</a></p>Sequence conflicti240F → L in AAA60247 (PubMed:2993863).Curated1
Sequence conflicti542M → I in AAA60247 (PubMed:2993863).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_071844237A → T in CMD1NN; shows a mild increase in kinase activity. 1 PublicationCorresponds to variant dbSNP:rs587777588EnsemblClinVar.1
Natural variantiVAR_037807256R → S in NS5. 1 PublicationCorresponds to variant dbSNP:rs397516826EnsemblClinVar.1
Natural variantiVAR_037808257S → L in NS5 and LPRD2; shows in vitro greater kinase activity and enhanced ERK activation than wild-type. 2 PublicationsCorresponds to variant dbSNP:rs80338796EnsemblClinVar.1
Natural variantiVAR_041037259S → A in an ovarian serous carcinoma sample; somatic mutation; increased ERK activation. 2 Publications1
Natural variantiVAR_037809259S → F in NS5. 1 PublicationCorresponds to variant dbSNP:rs397516827EnsemblClinVar.1
Natural variantiVAR_037810260T → I in hypertrophic cardiomyopathy. 1 PublicationCorresponds to variant dbSNP:rs869025501EnsemblClinVar.1
Natural variantiVAR_037811260T → R in NS5. 1 Publication1
Natural variantiVAR_037812261P → A in NS5; shows in vitro greater kinase activity and enhanced MAPK1 activation than wild-type. 1 PublicationCorresponds to variant dbSNP:rs121434594EnsemblClinVar.1
Natural variantiVAR_037813261P → L in NS5; shows greater kinase activity and enhanced MAPK1 activation than wild-type. 1 PublicationCorresponds to variant dbSNP:rs397516828EnsemblClinVar.1
Natural variantiVAR_037814261P → S in NS5; shows in vitro greater kinase activity and enhanced MAPK1 activation than wild-type. 3 PublicationsCorresponds to variant dbSNP:rs121434594EnsemblClinVar.1
Natural variantiVAR_037815263V → A in NS5; shows in vitro greater kinase activity and enhanced MAPK1 activation than wild-type. 1 PublicationCorresponds to variant dbSNP:rs397516830EnsemblClinVar.1
Natural variantiVAR_018840308P → L2 PublicationsCorresponds to variant dbSNP:rs5746220EnsemblClinVar.1
Natural variantiVAR_071845310T → A in CMD1NN; shows a mild increase in kinase activity. 1 PublicationCorresponds to variant dbSNP:rs778155315Ensembl.1
Natural variantiVAR_071846332P → A in CMD1NN; shows a mild increase in kinase activity. 1 PublicationCorresponds to variant dbSNP:rs1057403865Ensembl.1
Natural variantiVAR_041038335Q → H in a lung adenocarcinoma sample; somatic mutation. 1 Publication1
Natural variantiVAR_037816486D → G in NS5. 1 PublicationCorresponds to variant dbSNP:rs397516815EnsemblClinVar.1
Natural variantiVAR_037817486D → N in NS5; has reduced or absent kinase activity. 1 PublicationCorresponds to variant dbSNP:rs80338798EnsemblClinVar.1
Natural variantiVAR_037818491T → I in NS5; has reduced or absent kinase activity. 1 PublicationCorresponds to variant dbSNP:rs80338799EnsemblClinVar.1
Natural variantiVAR_037819491T → R in NS5. 1 PublicationCorresponds to variant dbSNP:rs80338799EnsemblClinVar.1
Natural variantiVAR_071847603L → P in CMD1NN; shows impaired kinase activity and reduced MAPK3 activation with this mutation. 1 PublicationCorresponds to variant dbSNP:rs587777586EnsemblClinVar.1
Natural variantiVAR_037820612S → T in NS5. 1 PublicationCorresponds to variant dbSNP:rs1448392469Ensembl.1
Natural variantiVAR_037821613L → V in NS5 and LPRD2; shows in vitro greater kinase activity and enhanced MAPK1 activation than wild-type. 2 PublicationsCorresponds to variant dbSNP:rs80338797EnsemblClinVar.1
Natural variantiVAR_071848626H → R in CMD1NN; shows a mild increase in kinase activity. 1 Publication1
Natural variantiVAR_071849641T → M in CMD1NN; shows a mild increase in kinase activity. 1 PublicationCorresponds to variant dbSNP:rs587777587EnsemblClinVar.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
<p>This subsection of the ‘Sequence’ section describes the sequence of naturally occurring alternative protein isoform(s). The changes in the amino acid sequence may be due to alternative splicing, alternative promoter usage, alternative initiation, or ribosomal frameshifting.<p><a href='/help/var_seq' target='_top'>More...</a></p>Alternative sequenceiVSP_034649278E → ENNNLSASPRAWSRRFCLRG R in isoform 2. Curated1

Sequence databases

Select the link destinations:

EMBL nucleotide sequence database

More...EMBLi

GenBank nucleotide sequence database

More...GenBanki

DNA Data Bank of Japan; a nucleotide sequence database

More...DDBJi
Links Updated
X03484 mRNA Translation: CAA27204.1
AY271661 Genomic DNA Translation: AAP03432.1
AK312248 mRNA Translation: BAG35180.1
EU332868 Genomic DNA Translation: ABY87557.1
CH471055 Genomic DNA Translation: EAW64134.1
BC018119 mRNA Translation: AAH18119.1
L00212
, L00206, L00207, L00208, L00209, L00210, L00211, L00213, M11376 Genomic DNA Translation: AAA60247.1
X54851 Genomic DNA No translation available.

The Consensus CDS (CCDS) project

More...CCDSi		CCDS2612.1 [P04049-1]
CCDS87047.1 [P04049-2]

Protein sequence database of the Protein Information Resource

More...PIRi		A00637 TVHUF6
S60341

NCBI Reference Sequences

More...RefSeqi		NP_002871.1, NM_002880.3 [P04049-1]
XP_005265412.1, XM_005265355.2
XP_011532276.1, XM_011533974.2 [P04049-1]

UniGene gene-oriented nucleotide sequence clusters

More...UniGenei		Hs.159130

Genome annotation databases

Ensembl eukaryotic genome annotation project

More...Ensembli		ENST00000251849; ENSP00000251849; ENSG00000132155 [P04049-1]
ENST00000442415; ENSP00000401888; ENSG00000132155 [P04049-2]

Database of genes from NCBI RefSeq genomes

More...GeneIDi		5894

KEGG: Kyoto Encyclopedia of Genes and Genomes

More...KEGGi		hsa:5894

UCSC genome browser

More...UCSCi		uc003bxf.5 human [P04049-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

<p>This section provides links to proteins that are similar to the protein sequence(s) described in this entry at different levels of sequence identity thresholds (100%, 90% and 50%) based on their membership in UniProt Reference Clusters (<a href="http://www.uniprot.org/help/uniref">UniRef</a>).<p><a href='/help/similar_proteins_section' target='_top'>More...</a></p>Similar proteinsi

<p>This section is used to point to information related to entries and found in data collections other than UniProtKB.<p><a href='/help/cross_references_section' target='_top'>More...</a></p>Cross-referencesi

<p>This subsection of the <a href="http://www.uniprot.org/manual/cross_references_section">Cross-references</a> section provides links to various web resources that are relevant for a specific protein.<p><a href='/help/web_resource' target='_top'>More...</a></p>Web resourcesi

NIEHS-SNPs
Atlas of Genetics and Cytogenetics in Oncology and Haematology

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X03484 mRNA Translation: CAA27204.1
AY271661 Genomic DNA Translation: AAP03432.1
AK312248 mRNA Translation: BAG35180.1
EU332868 Genomic DNA Translation: ABY87557.1
CH471055 Genomic DNA Translation: EAW64134.1
BC018119 mRNA Translation: AAH18119.1
L00212
, L00206, L00207, L00208, L00209, L00210, L00211, L00213, M11376 Genomic DNA Translation: AAA60247.1
X54851 Genomic DNA No translation available.
CCDSiCCDS2612.1 [P04049-1]
CCDS87047.1 [P04049-2]
PIRiA00637 TVHUF6
S60341
RefSeqiNP_002871.1, NM_002880.3 [P04049-1]
XP_005265412.1, XM_005265355.2
XP_011532276.1, XM_011533974.2 [P04049-1]
UniGeneiHs.159130

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1C1YX-ray1.90B55-131[»]
1FAQNMR-A136-187[»]
1FARNMR-A136-187[»]
1GUAX-ray2.00B51-131[»]
1RFANMR-A55-132[»]
3CU8X-ray2.40P/Q256-264[»]
3IQJX-ray1.15P255-264[»]
3IQUX-ray1.05P255-260[»]
3IQVX-ray1.20P255-260[»]
3KUCX-ray1.92B51-131[»]
3KUDX-ray2.15B51-131[»]
3NKXX-ray2.40P/Q255-264[»]
3O8IX-ray2.00B255-264[»]
3OMVX-ray4.00A/B323-618[»]
4FJ3X-ray1.95P229-264[»]
4G0NX-ray2.45B54-131[»]
4G3XX-ray3.25B55-131[»]
4IEAX-ray1.70P618-625[»]
4IHLX-ray2.20P229-264[»]
DisProtiDP00171
ProteinModelPortaliP04049
SMRiP04049
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi111831, 209 interactors
CORUMiP04049
DIPiDIP-1048N
IntActiP04049, 120 interactors
MINTiP04049
STRINGi9606.ENSP00000251849

Chemistry databases

BindingDBiP04049
ChEMBLiCHEMBL1906
DrugBankiDB08912 Dabrafenib
DB05268 iCo-007
DB04973 LErafAON
DB08896 Regorafenib
DB00398 Sorafenib
DB05190 XL281
GuidetoPHARMACOLOGYi2184

Protein family/group databases

MoonDBiP04049 Predicted

PTM databases

iPTMnetiP04049
PhosphoSitePlusiP04049

Polymorphism and mutation databases

BioMutaiRAF1
DMDMi125651

Proteomic databases

EPDiP04049
jPOSTiP04049
MaxQBiP04049
PaxDbiP04049
PeptideAtlasiP04049
PRIDEiP04049
ProteomicsDBi51637
51638 [P04049-2]

Protocols and materials databases

The DNASU plasmid repository

More...DNASUi		5894
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000251849; ENSP00000251849; ENSG00000132155 [P04049-1]
ENST00000442415; ENSP00000401888; ENSG00000132155 [P04049-2]
GeneIDi5894
KEGGihsa:5894
UCSCiuc003bxf.5 human [P04049-1]

Organism-specific databases

Comparative Toxicogenomics Database

More...CTDi		5894
DisGeNETi5894
EuPathDBiHostDB:ENSG00000132155.11

GeneCards: human genes, protein and diseases

More...GeneCardsi		RAF1
GeneReviewsiRAF1
HGNCiHGNC:9829 RAF1
HPAiCAB019291
HPA002640
MalaCardsiRAF1
MIMi164760 gene
611553 phenotype
611554 phenotype
615916 phenotype
neXtProtiNX_P04049
OpenTargetsiENSG00000132155
Orphaneti154 Familial isolated dilated cardiomyopathy
648 Noonan syndrome
500 Noonan syndrome with multiple lentigines
251615 Pilomyxoid astrocytoma
PharmGKBiPA34183

GenAtlas: human gene database

More...GenAtlasi		Search...

Phylogenomic databases

eggNOGiKOG0193 Eukaryota
ENOG410Y4UP LUCA
GeneTreeiENSGT00940000156084
HOGENOMiHOG000252972
HOVERGENiHBG001886
InParanoidiP04049
KOiK04366
OMAiFQMFQLM
OrthoDBi1344247at2759
PhylomeDBiP04049
TreeFamiTF317006

Enzyme and pathway databases

BRENDAi2.7.10.2 2681
ReactomeiR-HSA-2672351 Stimuli-sensing channels
R-HSA-392517 Rap1 signalling
R-HSA-430116 GP1b-IX-V activation signalling
R-HSA-5621575 CD209 (DC-SIGN) signaling
R-HSA-5673000 RAF activation
R-HSA-5674135 MAP2K and MAPK activation
R-HSA-5674499 Negative feedback regulation of MAPK pathway
R-HSA-5675221 Negative regulation of MAPK pathway
R-HSA-6802946 Signaling by moderate kinase activity BRAF mutants
R-HSA-6802948 Signaling by high-kinase activity BRAF mutants
R-HSA-6802949 Signaling by RAS mutants
R-HSA-6802952 Signaling by BRAF and RAF fusions
R-HSA-6802955 Paradoxical activation of RAF signaling by kinase inactive BRAF
SignaLinkiP04049
SIGNORiP04049

Miscellaneous databases

ChiTaRS: a database of human, mouse and fruit fly chimeric transcripts and RNA-sequencing data

More...ChiTaRSi		RAF1 human
EvolutionaryTraceiP04049

The Gene Wiki collection of pages on human genes and proteins

More...GeneWikii		C-Raf

Database of phenotypes from RNA interference screens in Drosophila and Homo sapiens

More...GenomeRNAii		5894
PMAP-CutDBiP04049

Protein Ontology

More...PROi		PR:P04049

The Stanford Online Universal Resource for Clones and ESTs

More...SOURCEi		Search...

Gene expression databases

BgeeiENSG00000132155 Expressed in 234 organ(s), highest expression level in cerebellar hemisphere
ExpressionAtlasiP04049 baseline and differential
GenevisibleiP04049 HS

Family and domain databases

CDDicd00029 C1, 1 hit
InterProiView protein in InterPro
IPR020454 DAG/PE-bd
IPR011009 Kinase-like_dom_sf
IPR002219 PE/DAG-bd
IPR000719 Prot_kinase_dom
IPR017441 Protein_kinase_ATP_BS
IPR003116 RBD_dom
IPR001245 Ser-Thr/Tyr_kinase_cat_dom
IPR008271 Ser/Thr_kinase_AS
IPR029071 Ubiquitin-like_domsf
PfamiView protein in Pfam
PF00130 C1_1, 1 hit
PF07714 Pkinase_Tyr, 1 hit
PF02196 RBD, 1 hit
PRINTSiPR00008 DAGPEDOMAIN
SMARTiView protein in SMART
SM00109 C1, 1 hit
SM00455 RBD, 1 hit
SM00220 S_TKc, 1 hit
SUPFAMiSSF54236 SSF54236, 1 hit
SSF56112 SSF56112, 1 hit
PROSITEiView protein in PROSITE
PS00107 PROTEIN_KINASE_ATP, 1 hit
PS50011 PROTEIN_KINASE_DOM, 1 hit
PS00108 PROTEIN_KINASE_ST, 1 hit
PS50898 RBD, 1 hit
PS00479 ZF_DAG_PE_1, 1 hit
PS50081 ZF_DAG_PE_2, 1 hit

ProtoNet; Automatic hierarchical classification of proteins

More...ProtoNeti		Search...

<p>This section provides general information on the entry.<p><a href='/help/entry_information_section' target='_top'>More...</a></p>Entry informationi

<p>This subsection of the ‘Entry information’ section provides a mnemonic identifier for a UniProtKB entry, but it is not a stable identifier. Each reviewed entry is assigned a unique entry name upon integration into UniProtKB/Swiss-Prot.<p><a href='/help/entry_name' target='_top'>More...</a></p>Entry nameiRAF1_HUMAN
<p>This subsection of the ‘Entry information’ section provides one or more accession number(s). These are stable identifiers and should be used to cite UniProtKB entries. Upon integration into UniProtKB, each entry is assigned a unique accession number, which is called ‘Primary (citable) accession number’.<p><a href='/help/accession_numbers' target='_top'>More...</a></p>AccessioniPrimary (citable) accession number: P04049
Secondary accession number(s): B0LPH8
, B2R5N3, Q15278, Q9UC20
<p>This subsection of the ‘Entry information’ section shows the date of integration of the entry into UniProtKB, the date of the last sequence update and the date of the last annotation modification (‘Last modified’). The version number for both the entry and the <a href="http://www.uniprot.org/help/canonical_and_isoforms">canonical sequence</a> are also displayed.<p><a href='/help/entry_history' target='_top'>More...</a></p>Entry historyiIntegrated into UniProtKB/Swiss-Prot: November 1, 1986
Last sequence update: November 1, 1986
Last modified: February 13, 2019
This is version 231 of the entry and version 1 of the sequence. See complete history.
<p>This subsection of the ‘Entry information’ section indicates whether the entry has been manually annotated and reviewed by UniProtKB curators or not, in other words, if the entry belongs to the Swiss-Prot section of UniProtKB (<strong>reviewed</strong>) or to the computer-annotated TrEMBL section (<strong>unreviewed</strong>).<p><a href='/help/entry_status' target='_top'>More...</a></p>Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

<p>This section contains any relevant information that doesn’t fit in any other defined sections<p><a href='/help/miscellaneous_section' target='_top'>More...</a></p>Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  2. SIMILARITY comments
    Index of protein domains and families
  3. Human chromosome 3
    Human chromosome 3: entries, gene names and cross-references to MIM
  4. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  5. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  6. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  7. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
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