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P27361 (MK03_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 168. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (7) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Alt products·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Mitogen-activated protein kinase 3

Short name=MAP kinase 3
Short name=MAPK 3
EC=2.7.11.24
Alternative name(s):
ERT2
Extracellular signal-regulated kinase 1
Short name=ERK-1
Insulin-stimulated MAP2 kinase
MAP kinase isoform p44
Short name=p44-MAPK
Microtubule-associated protein 2 kinase
p44-ERK1
Gene names
Name:MAPK3
Synonyms:ERK1, PRKM3
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length379 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK1/ERK2 and MAPK3/ERK1 are the 2 MAPKs which play an important role in the MAPK/ERK cascade. They participate also in a signaling cascade initiated by activated KIT and KITLG/SCF. Depending on the cellular context, the MAPK/ERK cascade mediates diverse biological functions such as cell growth, adhesion, survival and differentiation through the regulation of transcription, translation, cytoskeletal rearrangements. The MAPK/ERK cascade plays also a role in initiation and regulation of meiosis, mitosis, and postmitotic functions in differentiated cells by phosphorylating a number of transcription factors. About 160 substrates have already been discovered for ERKs. Many of these substrates are localized in the nucleus, and seem to participate in the regulation of transcription upon stimulation. However, other substrates are found in the cytosol as well as in other cellular organelles, and those are responsible for processes such as translation, mitosis and apoptosis. Moreover, the MAPK/ERK cascade is also involved in the regulation of the endosomal dynamics, including lysosome processing and endosome cycling through the perinuclear recycling compartment (PNRC); as well as in the fragmentation of the Golgi apparatus during mitosis. The substrates include transcription factors (such as ATF2, BCL6, ELK1, ERF, FOS, HSF4 or SPZ1), cytoskeletal elements (such as CANX, CTTN, GJA1, MAP2, MAPT, PXN, SORBS3 or STMN1), regulators of apoptosis (such as BAD, BTG2, CASP9, DAPK1, IER3, MCL1 or PPARG), regulators of translation (such as EIF4EBP1) and a variety of other signaling-related molecules (like ARHGEF2, FRS2 or GRB10). Protein kinases (such as RAF1, RPS6KA1/RSK1, RPS6KA3/RSK2, RPS6KA2/RSK3, RPS6KA6/RSK4, SYK, MKNK1/MNK1, MKNK2/MNK2, RPS6KA5/MSK1, RPS6KA4/MSK2, MAPKAPK3 or MAPKAPK5) and phosphatases (such as DUSP1, DUSP4, DUSP6 or DUSP16) are other substrates which enable the propagation the MAPK/ERK signal to additional cytosolic and nuclear targets, thereby extending the specificity of the cascade. Ref.11 Ref.13 Ref.14 Ref.15 Ref.18 Ref.19 Ref.22 Ref.24 Ref.25 Ref.26 Ref.28 Ref.36

Catalytic activity

ATP + a protein = ADP + a phosphoprotein.

Cofactor

Magnesium By similarity.

Enzyme regulation

Phosphorylated by MAP2K1/MEK1 and MAP2K2/MEK2 on Thr-202 and Tyr-204 in response to external stimuli like insulin or NGF. Both phosphorylations are required for activity. This phosphorylation causes dramatic conformational changes, which enable full activation and interaction of MAPK1/ERK2 with its substrates. Dephosphorylated and inactivated by DUSP3, DUSP6 and DUSP9. Ref.19 Ref.40

Subunit structure

Binds both upstream activators and downstream substrates in multimolecular complexes. Found in a complex with at least BRAF, HRAS, MAP2K1/MEK1, MAPK3 and RGS14 By similarity. Binds to HIV-1 Nef through its SH3 domain. This interaction inhibits its tyrosine-kinase activity. Interacts with ADAM15, ARRB2, CANX, DAPK1 (via death domain), HSF4, IER3, MAP2K1/MEK1, MORG1, NISCH, and SGK1. Interacts with PEA15 and MKNK2 By similarity. MKNK2 isoform 1 binding prevents from dephosphorylation and inactivation By similarity. Interacts with TPR. Ref.12 Ref.15 Ref.17 Ref.19 Ref.20 Ref.23 Ref.28 Ref.30 Ref.31 Ref.33 Ref.38 Ref.40

Subcellular location

Cytoplasm. Nucleus. Note: Autophosphorylation at Thr-207 promotes nuclear localization. Ref.17 Ref.40

Domain

The TXY motif contains the threonine and tyrosine residues whose phosphorylation activates the MAP kinases. Ref.17

Post-translational modification

Phosphorylated upon KIT and FLT3 signaling By similarity. Dually phosphorylated on Thr-202 and Tyr-204, which activates the enzyme. Ligand-activated ALK induces tyrosine phosphorylation. Dephosphorylated by PTPRJ at Tyr-204. Ref.16 Ref.29 Ref.36 Ref.37 Ref.40 Ref.50

Sequence similarities

Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. MAP kinase subfamily.

Contains 1 protein kinase domain.

Ontologies

Keywords
   Biological processApoptosis
Cell cycle
Host-virus interaction
   Cellular componentCytoplasm
Nucleus
   Coding sequence diversityAlternative splicing
Polymorphism
   LigandATP-binding
Nucleotide-binding
   Molecular functionKinase
Serine/threonine-protein kinase
Transferase
   PTMAcetylation
Phosphoprotein
   Technical term3D-structure
Complete proteome
Direct protein sequencing
Reference proteome
Gene Ontology (GO)
   Biological_processBMP signaling pathway

Inferred from mutant phenotype PubMed 19664780. Source: BHF-UCL

DNA damage induced protein phosphorylation

Inferred from direct assay PubMed 17560175. Source: UniProtKB

Fc-epsilon receptor signaling pathway

Traceable author statement. Source: Reactome

Fc-gamma receptor signaling pathway involved in phagocytosis

Traceable author statement. Source: Reactome

JAK-STAT cascade involved in growth hormone signaling pathway

Traceable author statement. Source: Reactome

MAPK cascade

Non-traceable author statement PubMed 20018936. Source: BHF-UCL

MyD88-dependent toll-like receptor signaling pathway

Traceable author statement. Source: Reactome

MyD88-independent toll-like receptor signaling pathway

Traceable author statement. Source: Reactome

Ras protein signal transduction

Traceable author statement. Source: Reactome

TRIF-dependent toll-like receptor signaling pathway

Traceable author statement. Source: Reactome

activation of MAPK activity

Traceable author statement. Source: Reactome

activation of MAPKK activity

Traceable author statement. Source: Reactome

apoptotic process

Inferred from electronic annotation. Source: UniProtKB-KW

axon guidance

Traceable author statement. Source: Reactome

blood coagulation

Traceable author statement. Source: Reactome

cartilage development

Inferred from electronic annotation. Source: Ensembl

caveolin-mediated endocytosis

Traceable author statement Ref.42. Source: UniProtKB

cell cycle

Inferred from electronic annotation. Source: UniProtKB-KW

cellular response to mechanical stimulus

Inferred from expression pattern PubMed 19593445. Source: UniProtKB

cytokine-mediated signaling pathway

Traceable author statement. Source: Reactome

epidermal growth factor receptor signaling pathway

Traceable author statement. Source: Reactome

fibroblast growth factor receptor signaling pathway

Traceable author statement. Source: Reactome

gene expression

Traceable author statement. Source: Reactome

innate immune response

Traceable author statement. Source: Reactome

insulin receptor signaling pathway

Traceable author statement. Source: Reactome

interleukin-1-mediated signaling pathway

Inferred from mutant phenotype PubMed 20018936. Source: BHF-UCL

lipopolysaccharide-mediated signaling pathway

Inferred from electronic annotation. Source: Ensembl

negative regulation of apolipoprotein binding

Inferred from electronic annotation. Source: Ensembl

neurotrophin TRK receptor signaling pathway

Traceable author statement. Source: Reactome

organ morphogenesis

Inferred from electronic annotation. Source: Ensembl

peptidyl-tyrosine autophosphorylation

Inferred from direct assay PubMed 8388392. Source: UniProtKB

phosphorylation

Inferred from direct assay PubMed 15950189. Source: UniProtKB

platelet activation

Traceable author statement. Source: Reactome

positive regulation of ERK1 and ERK2 cascade

Inferred from mutant phenotype PubMed 19664780. Source: BHF-UCL

positive regulation of histone acetylation

Inferred from mutant phenotype PubMed 20018936. Source: BHF-UCL

positive regulation of histone phosphorylation

Inferred from mutant phenotype PubMed 20018936. Source: BHF-UCL

positive regulation of protein phosphorylation

Inferred from mutant phenotype PubMed 19664780. Source: BHF-UCL

positive regulation of transcription from RNA polymerase II promoter

Inferred from mutant phenotype PubMed 20018936. Source: BHF-UCL

protein phosphorylation

Inferred from direct assay Ref.1. Source: UniProtKB

regulation of Golgi inheritance

Traceable author statement Ref.42. Source: UniProtKB

regulation of cytoskeleton organization

Traceable author statement Ref.42. Source: UniProtKB

regulation of early endosome to late endosome transport

Traceable author statement Ref.42. Source: UniProtKB

regulation of sequence-specific DNA binding transcription factor activity

Traceable author statement. Source: Reactome

regulation of stress-activated MAPK cascade

Traceable author statement Ref.42. Source: UniProtKB

response to epidermal growth factor

Inferred from direct assay Ref.33. Source: UniProtKB

response to exogenous dsRNA

Inferred from electronic annotation. Source: Ensembl

sensory perception of pain

Inferred from electronic annotation. Source: Ensembl

small GTPase mediated signal transduction

Traceable author statement. Source: Reactome

stress-activated MAPK cascade

Traceable author statement. Source: Reactome

toll-like receptor 10 signaling pathway

Traceable author statement. Source: Reactome

toll-like receptor 2 signaling pathway

Traceable author statement. Source: Reactome

toll-like receptor 3 signaling pathway

Traceable author statement. Source: Reactome

toll-like receptor 4 signaling pathway

Traceable author statement. Source: Reactome

toll-like receptor 5 signaling pathway

Traceable author statement. Source: Reactome

toll-like receptor 9 signaling pathway

Traceable author statement. Source: Reactome

toll-like receptor TLR1:TLR2 signaling pathway

Traceable author statement. Source: Reactome

toll-like receptor TLR6:TLR2 signaling pathway

Traceable author statement. Source: Reactome

toll-like receptor signaling pathway

Traceable author statement. Source: Reactome

transcription from RNA polymerase I promoter

Traceable author statement. Source: Reactome

transcription initiation from RNA polymerase I promoter

Traceable author statement. Source: Reactome

viral process

Inferred from electronic annotation. Source: UniProtKB-KW

   Cellular_componentGolgi apparatus

Traceable author statement Ref.42. Source: UniProtKB

caveola

Traceable author statement Ref.42. Source: UniProtKB

cytoskeleton

Traceable author statement Ref.42. Source: UniProtKB

cytosol

Traceable author statement Ref.42. Source: UniProtKB

early endosome

Traceable author statement Ref.42. Source: UniProtKB

focal adhesion

Traceable author statement Ref.42. Source: UniProtKB

late endosome

Traceable author statement Ref.42. Source: UniProtKB

microtubule cytoskeleton

Inferred from direct assay. Source: HPA

mitochondrion

Traceable author statement Ref.42. Source: UniProtKB

nucleoplasm

Traceable author statement. Source: Reactome

nucleus

Traceable author statement Ref.42. Source: UniProtKB

pseudopodium

Inferred from electronic annotation. Source: Ensembl

   Molecular_functionATP binding

Inferred from electronic annotation. Source: UniProtKB-KW

MAP kinase activity

Inferred from direct assay PubMed 8388392. Source: UniProtKB

phosphatase binding

Inferred from physical interaction Ref.37. Source: UniProtKB

protein binding

Inferred from physical interaction PubMed 15950189Ref.33. Source: UniProtKB

Complete GO annotation...

Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: P27361-1)

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.
Isoform 2 (identifier: P27361-2)

The sequence of this isoform differs from the canonical sequence as follows:
     259-302: Missing.
Isoform 3 (identifier: P27361-3)

Also known as: ERK1b;

The sequence of this isoform differs from the canonical sequence as follows:
     340-379: PVAEEPFTFAMELDDLPKERLKELIFQETARFQPGVLEAP → VGQSPAAVGLGAGEQGGT

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Initiator methionine11Removed Ref.8
Chain2 – 379378Mitogen-activated protein kinase 3
PRO_0000186251

Regions

Domain42 – 330289Protein kinase
Nucleotide binding48 – 569ATP By similarity
Motif202 – 2043TXY

Sites

Active site1661Proton acceptor By similarity
Binding site711ATP By similarity

Amino acid modifications

Modified residue21N-acetylalanine Ref.8 Ref.35 Ref.48 Ref.49
Modified residue1701Phosphoserine
Modified residue1981Phosphothreonine Ref.39
Modified residue2021Phosphothreonine; by MAP2K1 and MAP2K2 Ref.34 Ref.43 Ref.47
Modified residue2041Phosphotyrosine; by MAP2K1 and MAP2K2 Ref.34 Ref.37 Ref.43 Ref.47 Ref.50
Modified residue2071Phosphothreonine; by autocatalysis Ref.40

Natural variations

Alternative sequence259 – 30244Missing in isoform 2.
VSP_041906
Alternative sequence340 – 37940PVAEE…VLEAP → VGQSPAAVGLGAGEQGGT in isoform 3.
VSP_041907
Natural variant3231E → K. Ref.51
Corresponds to variant rs55859133 [ dbSNP | Ensembl ].
VAR_042253

Experimental info

Sequence conflict1741I → S in CAA42744. Ref.1
Sequence conflict1741I → S in AAK52329. Ref.2

Secondary structure

.......................................................... 379
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 [UniParc].

Last modified January 23, 2007. Version 4.
Checksum: E6020CE413EC41F7

FASTA37943,136
        10         20         30         40         50         60 
MAAAAAQGGG GGEPRRTEGV GPGVPGEVEM VKGQPFDVGP RYTQLQYIGE GAYGMVSSAY 

        70         80         90        100        110        120 
DHVRKTRVAI KKISPFEHQT YCQRTLREIQ ILLRFRHENV IGIRDILRAS TLEAMRDVYI 

       130        140        150        160        170        180 
VQDLMETDLY KLLKSQQLSN DHICYFLYQI LRGLKYIHSA NVLHRDLKPS NLLINTTCDL 

       190        200        210        220        230        240 
KICDFGLARI ADPEHDHTGF LTEYVATRWY RAPEIMLNSK GYTKSIDIWS VGCILAEMLS 

       250        260        270        280        290        300 
NRPIFPGKHY LDQLNHILGI LGSPSQEDLN CIINMKARNY LQSLPSKTKV AWAKLFPKSD 

       310        320        330        340        350        360 
SKALDLLDRM LTFNPNKRIT VEEALAHPYL EQYYDPTDEP VAEEPFTFAM ELDDLPKERL 

       370 
KELIFQETAR FQPGVLEAP 

« Hide

Isoform 2 [UniParc].

Checksum: 54DA760A09F1F2F5
Show »

FASTA33538,275
Isoform 3 (ERK1b) [UniParc].

Checksum: F2C6D29C623AC072
Show »

FASTA35740,088

References

« Hide 'large scale' references
[1]"Molecular cloning, expression, and characterization of the human mitogen-activated protein kinase p44erk1."
Charest D.L., Jirik F., Harder K., Pelech S.L., Mordret G.
Mol. Cell. Biol. 13:4679-4690(1993) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
Tissue: Hepatoma.
[2]"Properties of human ERK1b."
Aebersold D.M., Yung Y., Seger R.
Submitted (APR-2001) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3).
[3]"Identification of dominant negative Erk1/2 variants in cancer cells."
Cheng H., Ren S., Qiu R., Wang M., Feng Y.H.
Submitted (FEB-2006) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
[4]SeattleSNPs variation discovery resource
Submitted (DEC-2007) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[5]"The sequence and analysis of duplication-rich human chromosome 16."
Martin J., Han C., Gordon L.A., Terry A., Prabhakar S., She X., Xie G., Hellsten U., Chan Y.M., Altherr M., Couronne O., Aerts A., Bajorek E., Black S., Blumer H., Branscomb E., Brown N.C., Bruno W.J. expand/collapse author list , Buckingham J.M., Callen D.F., Campbell C.S., Campbell M.L., Campbell E.W., Caoile C., Challacombe J.F., Chasteen L.A., Chertkov O., Chi H.C., Christensen M., Clark L.M., Cohn J.D., Denys M., Detter J.C., Dickson M., Dimitrijevic-Bussod M., Escobar J., Fawcett J.J., Flowers D., Fotopulos D., Glavina T., Gomez M., Gonzales E., Goodstein D., Goodwin L.A., Grady D.L., Grigoriev I., Groza M., Hammon N., Hawkins T., Haydu L., Hildebrand C.E., Huang W., Israni S., Jett J., Jewett P.B., Kadner K., Kimball H., Kobayashi A., Krawczyk M.-C., Leyba T., Longmire J.L., Lopez F., Lou Y., Lowry S., Ludeman T., Manohar C.F., Mark G.A., McMurray K.L., Meincke L.J., Morgan J., Moyzis R.K., Mundt M.O., Munk A.C., Nandkeshwar R.D., Pitluck S., Pollard M., Predki P., Parson-Quintana B., Ramirez L., Rash S., Retterer J., Ricke D.O., Robinson D.L., Rodriguez A., Salamov A., Saunders E.H., Scott D., Shough T., Stallings R.L., Stalvey M., Sutherland R.D., Tapia R., Tesmer J.G., Thayer N., Thompson L.S., Tice H., Torney D.C., Tran-Gyamfi M., Tsai M., Ulanovsky L.E., Ustaszewska A., Vo N., White P.S., Williams A.L., Wills P.L., Wu J.-R., Wu K., Yang J., DeJong P., Bruce D., Doggett N.A., Deaven L., Schmutz J., Grimwood J., Richardson P., Rokhsar D.S., Eichler E.E., Gilna P., Lucas S.M., Myers R.M., Rubin E.M., Pennacchio L.A.
Nature 432:988-994(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[6]Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. expand/collapse author list , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C.
Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[7]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
Tissue: Lymph.
[8]Bienvenut W.V., Dhillon A.S., Kolch W.
Submitted (FEB-2008) to UniProtKB
Cited for: PROTEIN SEQUENCE OF 2-15; 33-41; 88-94; 117-131; 212-220; 279-287; 303-318 AND 360-370, CLEAVAGE OF INITIATOR METHIONINE, ACETYLATION AT ALA-2, IDENTIFICATION BY MASS SPECTROMETRY.
Tissue: Hepatoma.
[9]"Extracellular signal-regulated kinases in T cells: characterization of human ERK1 and ERK2 cDNAs."
Owaki H., Makar R., Boulton T.G., Cobb M.H., Geppert T.D.
Biochem. Biophys. Res. Commun. 182:1416-1422(1992) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 14-379 (ISOFORM 1).
[10]"Heterogeneous expression of four MAP kinase isoforms in human tissues."
Gonzalez F.A., Raden D.L., Rigby M.R., Davis R.J.
FEBS Lett. 304:170-178(1992) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 25-379 (ISOFORM 1).
[11]"Serine 25 of oncoprotein 18 is a major cytosolic target for the mitogen-activated protein kinase."
Marklund U., Brattsand G., Shingler V., Gullberg M.
J. Biol. Chem. 268:15039-15047(1993) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN PHOSPHORYLATION OF STMN1.
[12]"Human immunodeficiency virus type 1 Nef binds directly to LCK and mitogen-activated protein kinase, inhibiting kinase activity."
Greenway A.L., Azad A., Mills J., McPhee D.A.
J. Virol. 70:6701-6708(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH HIV-1 NEF.
[13]"MNK1, a new MAP kinase-activated protein kinase, isolated by a novel expression screening method for identifying protein kinase substrates."
Fukunaga R., Hunter T.
EMBO J. 16:1921-1933(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN PHOSPHORYLATION OF MKNK1/MNK1.
[14]"MAPKAPK5, a novel mitogen-activated protein kinase (MAPK)-activated protein kinase, is a substrate of the extracellular-regulated kinase (ERK) and p38 kinase."
Ni H., Wang X.S., Diener K., Yao Z.
Biochem. Biophys. Res. Commun. 243:492-496(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN PHOSPHORYLATION OF MAPKAPK5.
[15]"Phosphorylation by CK2 and MAPK enhances calnexin association with ribosomes."
Chevet E., Wong H.N., Gerber D., Cochet C., Fazel A., Cameron P.H., Gushue J.N., Thomas D.Y., Bergeron J.J.
EMBO J. 18:3655-3666(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN PHOSPHORYLATION OF CANX, INTERACTION WITH CANX.
[16]"Extracellular regulated kinases (ERK) 1 and ERK2 are authentic substrates for the dual-specificity protein-tyrosine phosphatase VHR. A novel role in down-regulating the ERK pathway."
Todd J.L., Tanner K.G., Denu J.M.
J. Biol. Chem. 274:13271-13280(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: DEPHOSPHORYLATION BY DUSP3.
[17]"Identification of a cytoplasmic-retention sequence in ERK2."
Rubinfeld H., Hanoch T., Seger R.
J. Biol. Chem. 274:30349-30352(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: SUBCELLULAR LOCATION, INTERACTION WITH MAP2K1/MEK1, DOMAIN.
[18]"Reduced MAP kinase phosphatase-1 degradation after p42/p44MAPK-dependent phosphorylation."
Brondello J.M., Pouyssegur J., McKenzie F.R.
Science 286:2514-2517(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN PHOSPHORYLATION OF DUSP1.
[19]"IEX-1: a new ERK substrate involved in both ERK survival activity and ERK activation."
Garcia J., Ye Y., Arranz V., Letourneux C., Pezeron G., Porteu F.
EMBO J. 21:5151-5163(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN PHOSPHORYLATION OF IER3, INTERACTION WITH IER3, ENZYME REGULATION.
[20]"Insulin receptor substrate 4 associates with the protein IRAS."
Sano H., Liu S.C.H., Lane W.S., Piletz J.E., Lienhard G.E.
J. Biol. Chem. 277:19439-19447(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH NISCH.
[21]"Signal transduction via the stem cell factor receptor/c-Kit."
Ronnstrand L.
Cell. Mol. Life Sci. 61:2535-2548(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW ON ROLE IN KIT SIGNALING.
[22]"Phosphorylation of Grb10 by mitogen-activated protein kinase: identification of Ser150 and Ser476 of human Grb10zeta as major phosphorylation sites."
Langlais P., Wang C., Dong L.Q., Carroll C.A., Weintraub S.T., Liu F.
Biochemistry 44:8890-8897(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN PHOSPHORYLATION OF GRB10.
[23]"Bidirectional signals transduced by DAPK-ERK interaction promote the apoptotic effect of DAPK."
Chen C.H., Wang W.J., Kuo J.C., Tsai H.C., Lin J.R., Chang Z.F., Chen R.H.
EMBO J. 24:294-304(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH DAPK1.
[24]"Growth factors can activate ATF2 via a two-step mechanism: phosphorylation of Thr71 through the Ras-MEK-ERK pathway and of Thr69 through RalGDS-Src-p38."
Ouwens D.M., de Ruiter N.D., van der Zon G.C., Carter A.P., Schouten J., van der Burgt C., Kooistra K., Bos J.L., Maassen J.A., van Dam H.
EMBO J. 21:3782-3793(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN PHOSPHORYLATION OF ATF2.
[25]"EGFR and FGFR signaling through FRS2 is subject to negative feedback control by ERK1/2."
Wu Y., Chen Z., Ullrich A.
Biol. Chem. 384:1215-1226(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN PHOSPHORYLATION OF FRS2.
[26]"Phosphorylation of serine 147 of tis21/BTG2/pc3 by p-Erk1/2 induces Pin-1 binding in cytoplasm and cell death."
Hong J.W., Ryu M.S., Lim I.K.
J. Biol. Chem. 280:21256-21263(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN PHOSPHORYLATION OF BTG2.
[27]"Global, in vivo, and site-specific phosphorylation dynamics in signaling networks."
Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M.
Cell 127:635-648(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Cervix carcinoma.
[28]"Association and regulation of heat shock transcription factor 4b with both extracellular signal-regulated kinase mitogen-activated protein kinase and dual-specificity tyrosine phosphatase DUSP26."
Hu Y., Mivechi N.F.
Mol. Cell. Biol. 26:3282-3294(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH HSF4.
[29]"ALK activation induces Shc and FRS2 recruitment: Signaling and phenotypic outcomes in PC12 cells differentiation."
Degoutin J., Vigny M., Gouzi J.Y.
FEBS Lett. 581:727-734(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION.
[30]"Mutations of beta-arrestin 2 that limit self-association also interfere with interactions with the beta2-adrenoceptor and the ERK1/2 MAPKs: implications for beta2-adrenoceptor signalling via the ERK1/2 MAPKs."
Xu T.-R., Baillie G.S., Bhari N., Houslay T.M., Pitt A.M., Adams D.R., Kolch W., Houslay M.D., Milligan G.
Biochem. J. 413:51-60(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH ARRB2.
[31]"Distinct functions of natural ADAM-15 cytoplasmic domain variants in human mammary carcinoma."
Zhong J.L., Poghosyan Z., Pennington C.J., Scott X., Handsley M.M., Warn A., Gavrilovic J., Honert K., Kruger A., Span P.N., Sweep F.C., Edwards D.R.
Mol. Cancer Res. 6:383-394(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH ADAM15.
[32]"Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle."
Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., Greff Z., Keri G., Stemmann O., Mann M.
Mol. Cell 31:438-448(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Cervix carcinoma.
[33]"Extracellular signal-regulated kinase 2 (ERK2) phosphorylation sites and docking domain on the nuclear pore complex protein Tpr cooperatively regulate ERK2-Tpr interaction."
Vomastek T., Iwanicki M.P., Burack W.R., Tiwari D., Kumar D., Parsons J.T., Weber M.J., Nandicoori V.K.
Mol. Cell. Biol. 28:6954-6966(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH TPR.
[34]"A quantitative atlas of mitotic phosphorylation."
Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P.
Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-202 AND TYR-204, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Cervix carcinoma.
[35]"Lys-N and trypsin cover complementary parts of the phosphoproteome in a refined SCX-based approach."
Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.
Anal. Chem. 81:4493-4501(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[36]"The D816V mutation of c-Kit circumvents a requirement for Src family kinases in c-Kit signal transduction."
Sun J., Pedersen M., Ronnstrand L.
J. Biol. Chem. 284:11039-11047(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN KIT SIGNALING PATHWAY, PHOSPHORYLATION.
[37]"Tumor suppressor density-enhanced phosphatase-1 (DEP-1) inhibits the RAS pathway by direct dephosphorylation of ERK1/2 kinases."
Sacco F., Tinti M., Palma A., Ferrari E., Nardozza A.P., Hooft van Huijsduijnen R., Takahashi T., Castagnoli L., Cesareni G.
J. Biol. Chem. 284:22048-22058(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION AT TYR-204, DEPHOSPHORYLATION BY PTPRJ AT TYR-204.
[38]"Protein kinase SGK1 enhances MEK/ERK complex formation through the phosphorylation of ERK2: implication for the positive regulatory role of SGK1 on the ERK function during liver regeneration."
Won M., Park K.A., Byun H.S., Kim Y.R., Choi B.L., Hong J.H., Park J., Seok J.H., Lee Y.H., Cho C.H., Song I.S., Kim Y.K., Shen H.M., Hur G.M.
J. Hepatol. 51:67-76(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH SGK1.
[39]"Large-scale proteomics analysis of the human kinome."
Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G., Mann M., Daub H.
Mol. Cell. Proteomics 8:1751-1764(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-198, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[40]"A new type of ERK1/2 autophosphorylation causes cardiac hypertrophy."
Lorenz K., Schmitt J.P., Schmitteckert E.M., Lohse M.J.
Nat. Med. 15:75-83(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION AT THR-207, ENZYME REGULATION, SUBUNIT, SUBCELLULAR LOCATION.
[41]"The extracellular signal-regulated kinase: multiple substrates regulate diverse cellular functions."
Yoon S., Seger R.
Growth Factors 24:21-44(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW ON FUNCTION.
[42]"The ERK signaling cascade--views from different subcellular compartments."
Yao Z., Seger R.
BioFactors 35:407-416(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW ON FUNCTION, REVIEW ON SUBCELLULAR LOCATION.
[43]"Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions."
Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., Rodionov V., Han D.K.
Sci. Signal. 2:RA46-RA46(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-202 AND TYR-204, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Leukemic T-cell.
[44]"Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis."
Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.
Sci. Signal. 3:RA3-RA3(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Cervix carcinoma.
[45]"Initial characterization of the human central proteome."
Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.
BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[46]"The ERK cascade: distinct functions within various subcellular organelles."
Wortzel I., Seger R.
Genes Cancer 2:195-209(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW ON ENZYME REGULATION, REVIEW ON FUNCTION.
[47]"System-wide temporal characterization of the proteome and phosphoproteome of human embryonic stem cell differentiation."
Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.
Sci. Signal. 4:RS3-RS3(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-202 AND TYR-204, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[48]"Comparative large-scale characterisation of plant vs. mammal proteins reveals similar and idiosyncratic N-alpha acetylation features."
Bienvenut W.V., Sumpton D., Martinez A., Lilla S., Espagne C., Meinnel T., Giglione C.
Mol. Cell. Proteomics 11:M111.015131-M111.015131(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[49]"N-terminal acetylome analyses and functional insights of the N-terminal acetyltransferase NatB."
Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A., Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E., Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R.
Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[50]"Crystal structure of human mono-phosphorylated ERK1 at Tyr204."
Kinoshita T., Yoshida I., Nakae S., Okita K., Gouda M., Matsubara M., Yokota K., Ishiguro H., Tada T.
Biochem. Biophys. Res. Commun. 377:1123-1127(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.39 ANGSTROMS), PHOSPHORYLATION AT TYR-204.
[51]"Patterns of somatic mutation in human cancer genomes."
Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G. expand/collapse author list , Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.
Nature 446:153-158(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT [LARGE SCALE ANALYSIS] LYS-323.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
X60188 mRNA. Translation: CAA42744.1.
AY033607 mRNA. Translation: AAK52329.1.
DQ399291 mRNA. Translation: ABD60302.1.
EU332853 Genomic DNA. Translation: ABY87542.1.
AC012645 Genomic DNA. No translation available.
CH471238 Genomic DNA. Translation: EAW79912.1.
CH471238 Genomic DNA. Translation: EAW79915.1.
BC013992 mRNA. Translation: AAH13992.1.
M84490 mRNA. Translation: AAA36142.1.
Z11696 mRNA. Translation: CAA77754.1.
CCDSCCDS10672.1. [P27361-1]
CCDS42148.1. [P27361-2]
CCDS42149.1. [P27361-3]
PIRA48082.
RefSeqNP_001035145.1. NM_001040056.2. [P27361-3]
NP_001103361.1. NM_001109891.1. [P27361-2]
NP_002737.2. NM_002746.2. [P27361-1]
UniGeneHs.861.

3D structure databases

PDBe
RCSB-PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
2ZOQX-ray2.39A/B1-379[»]
ProteinModelPortalP27361.
SMRP27361. Positions 24-375.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid111581. 114 interactions.
DIPDIP-30985N.
IntActP27361. 50 interactions.
MINTMINT-99599.
STRING9606.ENSP00000263025.

Chemistry

BindingDBP27361.
ChEMBLCHEMBL1907606.
DrugBankDB01169. Arsenic trioxide.
DB01064. Isoproterenol.
DB00641. Simvastatin.
DB00605. Sulindac.
GuidetoPHARMACOLOGY1494.

PTM databases

PhosphoSiteP27361.

Polymorphism databases

DMDM232066.

Proteomic databases

MaxQBP27361.
PaxDbP27361.
PRIDEP27361.

Protocols and materials databases

DNASU5595.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000263025; ENSP00000263025; ENSG00000102882. [P27361-1]
ENST00000322266; ENSP00000327293; ENSG00000102882. [P27361-2]
ENST00000395199; ENSP00000378625; ENSG00000102882. [P27361-3]
ENST00000395202; ENSP00000378628; ENSG00000102882. [P27361-2]
ENST00000403394; ENSP00000384895; ENSG00000102882. [P27361-3]
GeneID5595.
KEGGhsa:5595.
UCSCuc002dwr.3. human. [P27361-1]
uc002dwt.3. human. [P27361-3]
uc002dwv.4. human. [P27361-2]

Organism-specific databases

CTD5595.
GeneCardsGC16M030125.
HGNCHGNC:6877. MAPK3.
HPACAB002683.
HPA003995.
HPA005700.
MIM601795. gene.
neXtProtNX_P27361.
PharmGKBPA30622.
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG0515.
HOGENOMHOG000233024.
HOVERGENHBG014652.
InParanoidP27361.
KOK04371.
OMAAEMLSNK.
OrthoDBEOG7M3J0K.
PhylomeDBP27361.
TreeFamTF105097.

Enzyme and pathway databases

BRENDA2.7.11.24. 2681.
ReactomeREACT_111045. Developmental Biology.
REACT_111102. Signal Transduction.
REACT_115566. Cell Cycle.
REACT_116125. Disease.
REACT_120956. Cellular responses to stress.
REACT_1788. Transcription.
REACT_21300. Mitotic M-M/G1 phases.
REACT_604. Hemostasis.
REACT_6782. TRAF6 Mediated Induction of proinflammatory cytokines.
REACT_6900. Immune System.
REACT_71. Gene Expression.
SignaLinkP27361.

Gene expression databases

ArrayExpressP27361.
BgeeP27361.
CleanExHS_MAPK3.
GenevestigatorP27361.

Family and domain databases

InterProIPR011009. Kinase-like_dom.
IPR003527. MAP_kinase_CS.
IPR008349. MAPK_ERK1/2.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR002290. Ser/Thr_dual-sp_kinase_dom.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamPF00069. Pkinase. 1 hit.
[Graphical view]
PRINTSPR01770. ERK1ERK2MAPK.
SMARTSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMSSF56112. SSF56112. 1 hit.
PROSITEPS01351. MAPK. 1 hit.
PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

EvolutionaryTraceP27361.
GeneWikiMAPK3.
GenomeRNAi5595.
NextBio21714.
PROP27361.
SOURCESearch...

Entry information

Entry nameMK03_HUMAN
AccessionPrimary (citable) accession number: P27361
Secondary accession number(s): A8CZ58, B0LPG3, Q8NHX1
Entry history
Integrated into UniProtKB/Swiss-Prot: August 1, 1992
Last sequence update: January 23, 2007
Last modified: July 9, 2014
This is version 168 of the entry and version 4 of the sequence. [Complete history]
Entry statusReviewed (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.

Relevant documents

SIMILARITY comments

Index of protein domains and families

Human and mouse protein kinases

Human and mouse protein kinases: classification and index

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 16

Human chromosome 16: entries, gene names and cross-references to MIM