P27361 (MK03_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended 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

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	379 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence 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.35
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.39
Subunit structure	Binds both upstream activators and downstream substrates in multimolecular complexes. Found in a complex with at least BRAF, HRAS1, 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.37 Ref.39
Subcellular location	Cytoplasm. Nucleus. Note: Autophosphorylation at Thr-207 promotes nuclear localization. Ref.17 Ref.39
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.35 Ref.36 Ref.39 Ref.47
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 process	Apoptosis Cell cycle Host-virus interaction
Cellular component	Cytoplasm Nucleus
Coding sequence diversity	Alternative splicing Polymorphism
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Acetylation Phosphoprotein
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	BMP signaling pathway Inferred from mutant phenotype PubMed 19664780. Source: BHF-UCL 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 MyD88-dependent 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 cartilage development Inferred from electronic annotation. Source: Compara caveolin-mediated endocytosis Traceable author statement Ref.41. Source: UniProtKB cell cycle Inferred from electronic annotation. Source: UniProtKB-KW cellular response to mechanical stimulus Inferred from expression pattern PubMed 19593445. Source: UniProtKB epidermal growth factor receptor signaling pathway Traceable author statement. Source: Reactome fibroblast growth factor receptor signaling pathway 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: Compara negative regulation of apolipoprotein binding Inferred from electronic annotation. Source: Compara neurotrophin TRK receptor signaling pathway Traceable author statement. Source: Reactome organ morphogenesis Inferred from electronic annotation. Source: Compara peptidyl-tyrosine autophosphorylation Inferred from direct assay PubMed 8388392. 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 transcription from RNA polymerase II promoter Inferred from mutant phenotype PubMed 20018936. Source: BHF-UCL regulation of Golgi inheritance Traceable author statement Ref.41. Source: UniProtKB regulation of cytoskeleton organization Traceable author statement Ref.41. Source: UniProtKB regulation of early endosome to late endosome transport Traceable author statement Ref.41. 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.41. Source: UniProtKB response to DNA damage stimulus Inferred from electronic annotation. Source: Compara response to epidermal growth factor stimulus Inferred from direct assay Ref.33. Source: UniProtKB response to exogenous dsRNA Inferred from electronic annotation. Source: Compara sensory perception of pain Inferred from electronic annotation. Source: Compara 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 transcription initiation from RNA polymerase I promoter Traceable author statement. Source: Reactome virus-host interaction Inferred from electronic annotation. Source: UniProtKB-KW
Cellular_component	Golgi apparatus Traceable author statement Ref.41. Source: UniProtKB caveola Traceable author statement Ref.41. Source: UniProtKB cytosol Traceable author statement Ref.41. Source: UniProtKB early endosome Traceable author statement Ref.41. Source: UniProtKB focal adhesion Traceable author statement Ref.41. Source: UniProtKB late endosome Traceable author statement Ref.41. Source: UniProtKB microtubule cytoskeleton Inferred from direct assay. Source: HPA mitochondrion Traceable author statement Ref.41. Source: UniProtKB nucleoplasm Traceable author statement. Source: Reactome pseudopodium Inferred from electronic annotation. Source: Compara
Molecular_function	ATP binding Non-traceable author statement. Source: UniProtKB MAP kinase activity Inferred from direct assay PubMed 8388392. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
DAPK1	P53355	4	EBI-73995,EBI-358616
SCRIB	Q14160	2	EBI-73995,EBI-357345

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 key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Initiator methionine

1

1

Removed Ref.8

Chain

2 – 379

378

Mitogen-activated protein kinase 3

PRO_0000186251

Regions

Domain

42 – 330

289

Protein kinase

Nucleotide binding

48 – 56

9

ATP By similarity

Motif

202 – 204

3

TXY

Sites

Active site

166

1

Proton acceptor By similarity

Binding site

71

1

ATP By similarity

Amino acid modifications

Modified residue

2

1

N-acetylalanine Ref.8

Modified residue

170

1

Phosphoserine Ref.38

Modified residue

198

1

Phosphothreonine Ref.38

Modified residue

202

1

Phosphothreonine; by MAP2K1 and MAP2K2 Ref.34 Ref.42 Ref.46

Modified residue

204

1

Phosphotyrosine; by MAP2K1 and MAP2K2 Ref.34 Ref.36 Ref.42 Ref.46 Ref.47

Modified residue

207

1

Phosphothreonine; by autocatalysis Ref.39

Natural variations

Alternative sequence

259 – 302

44

Missing in isoform 2.

VSP_041906

Alternative sequence

340 – 379

40

PVAEE…VLEAP → VGQSPAAVGLGAGEQGGT in isoform 3.

VSP_041907

Natural variant

323

1

E → K. Ref.48
Corresponds to variant rs55859133 [ dbSNP | Ensembl ].

VAR_042253

Experimental info

Sequence conflict

174

1

I → S in CAA42744. Ref.1

Sequence conflict

174

1

I → S in AAK52329. Ref.2

Secondary structure

1

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379

Helix Strand Turn

Details...

Turn

39 – 41

3

Beta strand

42 – 49

8

Beta strand

55 – 61

7

Turn

62 – 65

4

Beta strand

66 – 73

8

Helix

79 – 94

16

Beta strand

104 – 107

4

Turn

112 – 114

3

Beta strand

118 – 123

6

Beta strand

126 – 128

3

Helix

129 – 135

7

Helix

140 – 159

20

Beta strand

171 – 174

4

Beta strand

180 – 182

3

Helix

193 – 195

3

Helix

208 – 210

3

Helix

214 – 217

4

Helix

225 – 240

16

Helix

252 – 261

10

Turn

266 – 268

3

Helix

275 – 283

9

Helix

292 – 295

4

Helix

301 – 310

10

Turn

315 – 317

3

Helix

321 – 325

5

Helix

328 – 330

3

Turn

331 – 333

3

Helix

336 – 338

3

Helix

352 – 354

3

Helix

357 – 367

11

Helix

369 – 371

3

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified January 23, 2007. Version 4. Checksum: E6020CE413EC41F7	FASTA	379	43,136
	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
	Isoform 2 [UniParc]. Checksum: 54DA760A09F1F2F5	FASTA	335	38,275
	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 LDQLNHILAL DLLDRMLTFN PNKRITVEEA LAHPYLEQYY DPTDEPVAEE 310 320 330 PFTFAMELDD LPKERLKELI FQETARFQPG VLEAP
	Isoform 3 (ERK1b) [UniParc]. Checksum: F2C6D29C623AC072	FASTA	357	40,088
	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 SKALDLLDRM LTFNPNKRIT VEEALAHPYL EQYYDPTDEV GQSPAAVGLG AGEQGGT

References

	« Hide 'large scale' referencesShow '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. , 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. , 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, 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, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[35]	"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.
[36]	"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.
[37]	"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.
[38]	"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 SER-170 AND THR-198, MASS SPECTROMETRY.
[39]	"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: AUTOPHOSPHORYLATION AT THR-207, ENZYME REGULATION, SUBUNIT, SUBCELLULAR LOCATION.
[40]	"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.
[41]	"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.
[42]	"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, MASS SPECTROMETRY. Tissue: Leukemic T-cell.
[43]	"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.
[44]	"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].
[45]	"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.
[46]	"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, MASS SPECTROMETRY.
[47]	"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.
[48]	"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. , 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.

Web resources

Atlas of Genetics and Cytogenetics in Oncology and Haematology

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.

IPI

IPI00018195.

PIR

A48082.

RefSeq

NP_001035145.1. NM_001040056.1.
NP_001103361.1. NM_001109891.1.
NP_002737.2. NM_002746.2.

UniGene

Hs.861.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2ZOQ	X-ray	2.39	A/B	1-379	[»]

ProteinModelPortal

P27361.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-30985N.

IntAct

P27361. 22 interactions.

MINT

MINT-99599.

STRING

9606.ENSP00000263025.

PTM databases

PhosphoSite

P27361.

Polymorphism databases

DMDM

232066.

Proteomic databases

PaxDb

P27361.

PRIDE

P27361.

Protocols and materials databases

DNASU

5595.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000263025; ENSP00000263025; ENSG00000102882.
ENST00000322266; ENSP00000327293; ENSG00000102882.
ENST00000395199; ENSP00000378625; ENSG00000102882.
ENST00000395202; ENSP00000378628; ENSG00000102882.
ENST00000403394; ENSP00000384895; ENSG00000102882.

GeneID

5595.

KEGG

hsa:5595.

UCSC

uc002dwr.3. human.
uc002dwv.4. human.

Organism-specific databases

CTD

5595.

GeneCards

GC16M030125.

HGNC

HGNC:6877. MAPK3.

HPA

CAB002683.
HPA003995.
HPA005700.

MIM

601795. gene.

neXtProt

NX_P27361.

PharmGKB

PA30622.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG0515.

HOGENOM

HOG000233024.

HOVERGEN

HBG014652.

InParanoid

P27361.

KO

K04371.

OMA

KYQPPIM.

OrthoDB

EOG45HRXM.

PhylomeDB

P27361.

Enzyme and pathway databases

BRENDA

2.7.11.24. 2681.

Pathway_Interaction_DB

alphasynuclein_pathway. Alpha-synuclein signaling.
angiopoietinreceptor_pathway. Angiopoietin receptor Tie2-mediated signaling.
arf6downstreampathway. Arf6 downstream pathway.
bcr_5pathway. BCR signaling pathway.
anthraxpathway. Cellular roles of Anthrax toxin.
ceramidepathway. Ceramide signaling pathway.
cd8tcrdownstreampathway. Downstream signaling in naive CD8+ T cells.
endothelinpathway. Endothelins.
ephbfwdpathway. EPHB forward signaling.
fcer1pathway. Fc-epsilon receptor I signaling in mast cells.
fgf_pathway. FGF signaling pathway.
ifngpathway. IFN-gamma pathway.
il2_1pathway. IL2-mediated signaling events.
avb3_integrin_pathway. Integrins in angiogenesis.
trkrpathway. Neurotrophic factor-mediated Trk receptor signaling.
avb3_opn_pathway. Osteopontin-mediated events.
ps1pathway. Presenilin action in Notch and Wnt signaling.
tcrraspathway. Ras signaling in the CD4+ TCR pathway.
smad2_3pathway. Regulation of cytoplasmic and nuclear SMAD2/3 signaling.
telomerasepathway. Regulation of Telomerase.
retinoic_acid_pathway. Retinoic acid receptors-mediated signaling.
nfat_3pathway. Role of Calcineurin-dependent NFAT signaling in lymphocytes.
s1p_s1p1_pathway. S1P1 pathway.
s1p_s1p2_pathway. S1P2 pathway.
s1p_s1p3_pathway. S1P3 pathway.
s1p_s1p4_pathway. S1P4 pathway.
met_pathway. Signaling events activated by Hepatocyte Growth Factor Receptor (c-Met).
prlsignalingeventspathway. Signaling events mediated by PRL.
kitpathway. Signaling events mediated by Stem cell factor receptor (c-Kit).
vegfr1_2_pathway. Signaling events mediated by VEGFR1 and VEGFR2.
ret_pathway. Signaling events regulated by Ret tyrosine kinase.
syndecan_1_pathway. Syndecan-1-mediated signaling events.
syndecan_2_pathway. Syndecan-2-mediated signaling events.
trail_pathway. TRAIL signaling pathway.
mapktrkpathway. Trk receptor signaling mediated by the MAPK pathway.
vegfr1_pathway. VEGFR1 specific signals.
lymphangiogenesis_pathway. VEGFR3 signaling in lymphatic endothelium.

Reactome

REACT_111045. Developmental Biology.
REACT_111102. Signal Transduction.
REACT_115566. Cell Cycle.
REACT_116125. Disease.
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.

SignaLink

P27361.

Gene expression databases

ArrayExpress

P27361.

Bgee

P27361.

CleanEx

HS_MAPK3.

Genevestigator

P27361.

GermOnline

ENSG00000102882. Homo sapiens.

Family and domain databases

InterPro

IPR011009. Kinase-like_dom.
IPR003527. MAP_kinase_CS.
IPR008349. MAPK_ERK1/2.
IPR000719. Prot_kinase_cat_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR002290. Ser/Thr_dual-sp_kinase_dom.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]

Pfam

PF00069. Pkinase. 1 hit.
[Graphical view]

PRINTS

PR01770. ERK1ERK2MAPK.

SMART

SM00220. S_TKc. 1 hit.
[Graphical view]

SUPFAM

SSF56112. Kinase_like. 1 hit.

PROSITE

PS01351. MAPK. 1 hit.
PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

BindingDB

P27361.

ChEMBL

CHEMBL3385.

DrugBank

DB01169. Arsenic trioxide.
DB01064. Isoproterenol.
DB00641. Simvastatin.
DB00605. Sulindac.

EvolutionaryTrace

P27361.

GenomeRNAi

5595.

NextBio

21714.

SOURCE

Search...

Entry information

Entry name

MK03_HUMAN

Accession

Primary (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:	May 29, 2013
This is version 155 of the entry and version 4 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.