Q63844 (MK03_MOUSE) 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
MNK1
Microtubule-associated protein 2 kinase
Mitogen-activated protein kinase 1
Short name=MAP kinase 1
Short name=MAPK 1
p44-ERK1

Gene names

Name:	Mapk3
Synonyms:	Erk1, Prkm3

Organism

Mus musculus (Mouse)

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length	380 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 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 additionnal cytosolic and nuclear targets, thereby extending the specificity of the cascade. Ref.11 Ref.12
Catalytic activity	ATP + a protein = ADP + a phosphoprotein.
Cofactor	Magnesium By similarity.
Enzyme regulation	Phosphorylated by MAP2K1/MEK1 and MAP2K2/MEK2 on Thr-203 and Tyr-205 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. Dephospphorylated and inactivated by DUSP3, DUSP6 and DUSP9.
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. Interacts with ADAM15, ARRB2, CANX, DAPK1 (via death domain), HSF4, IER3, MAP2K1/MEK1, NISCH, and SGK1 By similarity. Interacts with MORG1, PEA15 and MKNK2. MKNK2 isoform 1 binding prevents from dephosphorylation and inactivation. Ref.11 Ref.13 Ref.15
Subcellular location	Cytoplasm. Nucleus. Note: Autophosphorylation at Thr-207 promotes nuclear localization By similarity. PEA15-binding redirects the biological outcome of MAPK3 kinase-signaling by sequestering MAPK3 into the cytoplasm. Ref.11 Ref.12
Domain	The TXY motif contains the threonine and tyrosine residues whose phosphorylation activates the MAP kinases.
Post-translational modification	Dually phosphorylated on Thr-203 and Tyr-205, which activates the enzyme. Ligand-activated ALK induces tyrosine phosphorylation By similarity. Dephosphorylated by PTPRJ at Tyr-205 By similarity. Autophosphorylated on threonine and tyrosine residues in vitro. Phosphorylated upon FLT3 and KIT signaling By similarity. Ref.9 Ref.10 Ref.12 Ref.14 Ref.16 Ref.17 Ref.18 Ref.19 Ref.20
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
Cellular component	Cytoplasm Nucleus
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Acetylation Phosphoprotein
Technical term	Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological process	cartilage development Inferred from direct assay. Source: MGI cell cycle Inferred from electronic annotation. Source: UniProtKB-KW lipopolysaccharide-mediated signaling pathway Inferred from direct assay. Source: MGI negative regulation of apolipoprotein binding Inferred from mutant phenotype. Source: BHF-UCL organ morphogenesis Inferred from direct assay. Source: MGI regulation of sequence-specific DNA binding transcription factor activity Inferred from mutant phenotype. Source: UniProtKB response to DNA damage stimulus Inferred from direct assay. Source: MGI response to exogenous dsRNA Inferred from direct assay. Source: MGI sensory perception of pain Inferred from mutant phenotype. Source: UniProtKB transcription, DNA-dependent Inferred from mutant phenotype. Source: UniProtKB
Cellular component	nucleoplasm Traceable author statement. Source: Reactome pseudopodium Inferred from direct assay. Source: UniProtKB
Molecular function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW MAP kinase activity Inferred from direct assay. Source: MGI phosphotyrosine binding Inferred from mutant phenotype. Source: MGI
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Initiator methionine	1	1	Removed Ref.2
	Chain	2 – 380	379	Mitogen-activated protein kinase 3		PRO_0000186252
Regions
	Domain	43 – 331	289	Protein kinase
	Nucleotide binding	49 – 57	9	ATP By similarity
	Motif	203 – 205	3	TXY
Sites
	Active site	167	1	Proton acceptor By similarity
	Binding site	72	1	ATP By similarity
Amino acid modifications
	Modified residue	2	1	N-acetylalanine Ref.2
	Modified residue	171	1	Phosphoserine By similarity
	Modified residue	199	1	Phosphothreonine By similarity
	Modified residue	203	1	Phosphothreonine; by MAP2K1 and MAP2K2 Ref.16 Ref.17 Ref.18 Ref.19
	Modified residue	205	1	Phosphotyrosine; by MAP2K1 and MAP2K2 Ref.16 Ref.17 Ref.18 Ref.19
	Modified residue	208	1	Phosphothreonine; by autocatalysis By similarity
Experimental info
	Sequence conflict	178	1	T → P in CAA45889. Ref.7
	Sequence conflict	178	1	T → P no nucleotide entry Ref.8

Sequences

	Sequence		Length	Mass (Da)
	Q63844 [UniParc]. Last modified January 23, 2007. Version 5. Checksum: 49C14A95B627237F	FASTA	380	43,066
	10 20 30 40 50 60 MAAAAAAPGG GGGEPRGTAG VVPVVPGEVE VVKGQPFDVG PRYTQLQYIG EGAYGMVSSA 70 80 90 100 110 120 YDHVRKTRVA IKKISPFEHQ TYCQRTLREI QILLRFRHEN VIGIRDILRA PTLEAMRDVY 130 140 150 160 170 180 IVQDLMETDL YKLLKSQQLS NDHICYFLYQ ILRGLKYIHS ANVLHRDLKP SNLLINTTCD 190 200 210 220 230 240 LKICDFGLAR IADPEHDHTG FLTEYVATRW YRAPEIMLNS KGYTKSIDIW SVGCILAEML 250 260 270 280 290 300 SNRPIFPGKH YLDQLNHILG ILGSPSQEDL NCIINMKARN YLQSLPSKTK VAWAKLFPKS 310 320 330 340 350 360 DSKALDLLDR MLTFNPNKRI TVEEALAHPY LEQYYDPTDE PVAEEPFTFD MELDDLPKER 370 380 LKELIFQETA RFQPGAPEGP

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"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: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Strain: FVB/N. Tissue: Kidney and Mammary tumor.
[2]	Bienvenut W.V., Serrels B., Brunton V.G., Frame M.C. Submitted (FEB-2008) to UniProtKB Cited for: PROTEIN SEQUENCE OF 2-65; 89-105; 110-132; 157-209; 213-221; 280-288; 304-319 AND 361-371, CLEAVAGE OF INITIATOR METHIONINE, ACETYLATION AT ALA-2, MASS SPECTROMETRY. Tissue: Embryonic fibroblast.
[3]	"Molecular cloning of a mouse extracellular signal regulated kinase (erk-1)." Tanner B., Mueckler M. Biochim. Biophys. Acta 1171:319-320(1993) [PubMed: 8424957] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 4-380.
[4]	"Mouse Erk-1 gene product is a serine/threonine protein kinase that has the potential to phosphorylate tyrosine." Crews C.M., Alessandrini A.A., Erikson R.L. Proc. Natl. Acad. Sci. U.S.A. 88:8845-8849(1991) [PubMed: 1717989] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 10-19. Tissue: Pre-B cell.
[5]	"Molecular analysis of microtubule-associated protein-2 kinase cDNA from mouse and rat brain." de Miguel C., Kligman D., Patel J., Detera-Wadleigh S.D. DNA Cell Biol. 10:505-514(1991) [PubMed: 1716439] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 77-380. Tissue: Fetal brain.
[6]	Lubec G., Klug S. Submitted (MAR-2007) to UniProtKB Cited for: PROTEIN SEQUENCE OF 136-153 AND 191-209, MASS SPECTROMETRY. Tissue: Hippocampus.
[7]	"Novel CDC2-related protein kinases produced in murine hematopoietic stem cells." Ershler M.A., Nagorskaya T.V., Visser J.W.M., Belyavsky A.V. Gene 124:305-306(1993) [PubMed: 8444355] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 171-209. Strain: CBA. Tissue: Bone marrow.
[8]	"Identification of new protein kinase genes, similar to kinases of the cdc2 family and expressed in murine hematopoietic stem cells." Ershler M.A., Nagorskaya T.V., Visser J.W.M., Belyavsky A.V. Dokl. Akad. Nauk SSSR 324:893-897(1992) [PubMed: 1459009] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 171-205.
[9]	"Flt3 signaling involves tyrosyl-phosphorylation of SHP-2 and SHIP and their association with Grb2 and Shc in Baf3/Flt3 cells." Zhang S., Mantel C., Broxmeyer H.E. J. Leukoc. Biol. 65:372-380(1999) [PubMed: 10080542] [Abstract] Cited for: PHOSPHORYLATION IN RESPONSE TO FLT3 SIGNALING.
[10]	"Flt3 mutations from patients with acute myeloid leukemia induce transformation of 32D cells mediated by the Ras and STAT5 pathways." Mizuki M., Fenski R., Halfter H., Matsumura I., Schmidt R., Muller C., Gruning W., Kratz-Albers K., Serve S., Steur C., Buchner T., Kienast J., Kanakura Y., Berdel W.E., Serve H. Blood 96:3907-3914(2000) [PubMed: 11090077] [Abstract] Cited for: PHOSPHORYLATION IN RESPONSE TO FLT3 SIGNALING.
[11]	"PEA-15 mediates cytoplasmic sequestration of ERK MAP kinase." Formstecher E., Ramos J.W., Fauquet M., Calderwood D.A., Hsieh J.C., Canton B., Nguyen X.T., Barnier J.V., Camonis J., Ginsberg M.H., Chneiweiss H. Dev. Cell 1:239-250(2001) [PubMed: 11702783] [Abstract] Cited for: INTERACTION WITH PEA15, SUBCELLULAR LOCATION, FUNCTION OF THE MAPK ERK CASCADE.
[12]	"Molecular interpretation of ERK signal duration by immediate early gene products." Murphy L.O., Smith S., Chen R.H., Fingar D.C., Blenis J. Nat. Cell Biol. 4:556-564(2002) [PubMed: 12134156] [Abstract] Cited for: FUNCTION IN PHOSPHORYLATION OF FOS, SUBCELLULAR LOCATION.
[13]	"Modular construction of a signaling scaffold: MORG1 interacts with components of the ERK cascade and links ERK signaling to specific agonists." Vomastek T., Schaeffer H.-J., Tarcsafalvi A., Smolkin M.E., Bissonette E.A., Weber M.J. Proc. Natl. Acad. Sci. U.S.A. 101:6981-6986(2004) [PubMed: 15118098] [Abstract] Cited for: INTERACTION WITH MORG1.
[14]	"bHLH-zip transcription factor Spz1 mediates mitogen-activated protein kinase cell proliferation, transformation, and tumorigenesis." Hsu S.-H., Hsieh-Li H.-M., Huang H.-Y., Huang P.-H., Li H. Cancer Res. 65:4041-4050(2005) [PubMed: 15899793] [Abstract] Cited for: PHOSPHORYLATION OF SPZ1.
[15]	"Features of the catalytic domains and C termini of the MAPK signal-integrating kinases Mnk1 and Mnk2 determine their differing activities and regulatory properties." Parra J.L., Buxade M., Proud C.G. J. Biol. Chem. 280:37623-37633(2005) [PubMed: 16162500] [Abstract] Cited for: INTERACTION WITH MKNK2.
[16]	"Quantitative time-resolved phosphoproteomic analysis of mast cell signaling." Cao L., Yu K., Banh C., Nguyen V., Ritz A., Raphael B.J., Kawakami Y., Kawakami T., Salomon A.R. J. Immunol. 179:5864-5876(2007) [PubMed: 17947660] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-203 AND TYR-205, MASS SPECTROMETRY. Tissue: Mast cell.
[17]	"Large-scale identification and evolution indexing of tyrosine phosphorylation sites from murine brain." Ballif B.A., Carey G.R., Sunyaev S.R., Gygi S.P. J. Proteome Res. 7:311-318(2008) [PubMed: 18034455] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-203 AND TYR-205, MASS SPECTROMETRY. Tissue: Brain.
[18]	"Solid tumor proteome and phosphoproteome analysis by high resolution mass spectrometry." Zanivan S., Gnad F., Wickstroem S.A., Geiger T., Macek B., Cox J., Faessler R., Mann M. J. Proteome Res. 7:5314-5326(2008) [PubMed: 19367708] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-203 AND TYR-205, MASS SPECTROMETRY. Tissue: Melanoma.
[19]	"Large scale localization of protein phosphorylation by use of electron capture dissociation mass spectrometry." Sweet S.M., Bailey C.M., Cunningham D.L., Heath J.K., Cooper H.J. Mol. Cell. Proteomics 8:904-912(2009) [PubMed: 19131326] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-203 AND TYR-205, MASS SPECTROMETRY. Tissue: Embryonic fibroblast.
[20]	"Protein-tyrosine phosphatase DEP-1 controls receptor tyrosine kinase FLT3 signaling." Arora D., Stopp S., Bohmer S.A., Schons J., Godfrey R., Masson K., Razumovskaya E., Ronnstrand L., Tanzer S., Bauer R., Bohmer F.D., Muller J.P. J. Biol. Chem. 286:10918-10929(2011) [PubMed: 21262971] [Abstract] Cited for: PHOSPHORYLATION IN RESPONSE TO FLT3 SIGNALING.
[21]	"The extracellular signal-regulated kinase: multiple substrates regulate diverse cellular functions." Yoon S., Seger R. Growth Factors 24:21-44(2006) [PubMed: 16393692] [Abstract] Cited for: REVIEW ON FUNCTION.
[22]	"The ERK signaling cascade--views from different subcellular compartments." Yao Z., Seger R. BioFactors 35:407-416(2009) [PubMed: 19565474] [Abstract] Cited for: REVIEW ON FUNCTION, REVIEW ON SUBCELLULAR LOCATION.
[23]	"The ERK cascade: distinct functions within various subcellular organelles." Wortzel I., Seger R. Genes Cancer 2:195-209(2011) [PubMed: 21779493] [Abstract] Cited for: REVIEW ON ENZYME REGULATION, REVIEW ON FUNCTION.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	BC013754 mRNA. Translation: AAH13754.1. BC029712 mRNA. Translation: AAH29712.1. S58470 mRNA. Translation: AAB19973.1. X64605 mRNA. Translation: CAA45889.1.
IPI	IPI00230277.
PIR	S28184.
RefSeq	NP_036082.1. NM_011952.2.
UniGene	Mm.8385.
3D structure databases
ProteinModelPortal	Q63844.
SMR	Q63844. Positions 25-375.
ModBase	Search...
Protein-protein interaction databases
IntAct	Q63844. 4 interactions.
STRING	Q63844.
PTM databases
PhosphoSite	Q63844.
Proteomic databases
PRIDE	Q63844.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSMUST00000057669; ENSMUSP00000051619; ENSMUSG00000063065.
GeneID	26417.
KEGG	mmu:26417.
NMPDR	fig|10090.3.peg.17639.
Organism-specific databases
CTD	5595.
MGI	MGI:1346859. Mapk3.
Phylogenomic databases
eggNOG	roNOG04134.
GeneTree	ENSGT00550000074298.
HOVERGEN	HBG014652.
OrthoDB	EOG45HRXM.
PhylomeDB	Q63844.
Enzyme and pathway databases
Reactome	REACT_115202. Signal Transduction. REACT_98458. Immune System.
Gene expression databases
ArrayExpress	Q63844.
Bgee	Q63844.
CleanEx	MM_MAPK3.
Genevestigator	Q63844.
GermOnline	ENSMUSG00000063065. Mus musculus.
Family and domain databases
InterPro	IPR008349. Erk_1_2_MAPK. IPR011009. Kinase-like_dom. IPR003527. MAP_kinase_CS. IPR000719. Prot_kinase_cat_dom. IPR017441. Protein_kinase_ATP_BS. IPR017442. Se/Thr_kinase-like_dom. IPR008271. Ser/Thr_kinase_AS. IPR002290. Ser/Thr_kinase_dom. [Graphical view]
KO	K04371.
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
NextBio	304429.
SOURCE	Search...

Entry information

Entry name

MK03_MOUSE

Accession

Primary (citable) accession number: Q63844
Secondary accession number(s): Q61531, Q8K0X5, Q91YW5

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 1, 1997
Last sequence update:	January 23, 2007
Last modified:	January 25, 2012
This is version 126 of the entry and version 5 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program