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P21708 (MK03_RAT) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 161. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (1) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Alt products·Sequence annotation·Sequences·References·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
MNK1
Microtubule-associated protein 2 kinase
p44-ERK1
Gene names
Name:Mapk3
Synonyms:Erk1, Prkm3
OrganismRattus norvegicus (Rat) [Reference proteome]
Taxonomic identifier10116 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus

Protein attributes

Sequence length380 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.

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. Dephosphorylated 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, HRAS, MAP2K1/MEK1, MAPK3 and RGS14. Interacts with ADAM15, ARRB2, CANX, DAPK1 (via death domain), HSF4, IER3, MAP2K1/MEK1, MORG1, NISCH, PEA15, SGK1 and MKNK2 By similarity. MKNK2 isoform 1 binding prevents from dephosphorylation and inactivation. Interacts with TPR By similarity. Ref.12

Subcellular location

Cytoplasm By similarity. 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 By similarity.

Isoform 2: Nucleus.

Tissue specificity

Highest levels within the nervous system, expressed in different tissues, mostly in intestine, placenta and lung.

Developmental stage

Increased expression during development.

Domain

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

Post-translational modification

Phosphorylated upon FLT3 and KIT signaling. Ligand-activated ALK induces tyrosine phosphorylation By similarity. Dephosphorylated by PTPRJ at Tyr-205 By similarity. Dually phosphorylated on Thr-203 and Tyr-205, which activates the enzyme. Ref.3 Ref.9 Ref.10

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
   Cellular componentCytoplasm
Nucleus
   Coding sequence diversityAlternative splicing
   LigandATP-binding
Nucleotide-binding
   Molecular functionKinase
Serine/threonine-protein kinase
Transferase
   PTMAcetylation
Phosphoprotein
   Technical termComplete proteome
Direct protein sequencing
Reference proteome
Gene Ontology (GO)
   Biological_processMAPK cascade

Inferred from mutant phenotype PubMed 17310240. Source: RGD

MAPK import into nucleus

Inferred from direct assay PubMed 12097495. Source: RGD

apoptotic process

Inferred from electronic annotation. Source: UniProtKB-KW

arachidonic acid metabolic process

Inferred from expression pattern PubMed 15027896. Source: RGD

caveolin-mediated endocytosis

Traceable author statement Ref.14. Source: UniProtKB

cell cycle

Inferred from electronic annotation. Source: UniProtKB-KW

intracellular signal transduction

Inferred from direct assay PubMed 12072413. Source: RGD

positive regulation of transcription, DNA-templated

Inferred from expression pattern PubMed 12097495. Source: RGD

positive regulation of translation

Inferred from mutant phenotype PubMed 15027896. Source: RGD

protein complex assembly

Inferred from mutant phenotype PubMed 7889942. Source: UniProtKB

protein phosphorylation

Inferred from direct assay PubMed 15027896. Source: RGD

regulation of Golgi inheritance

Traceable author statement Ref.14. Source: UniProtKB

regulation of cytoskeleton organization

Traceable author statement Ref.14. Source: UniProtKB

regulation of early endosome to late endosome transport

Traceable author statement Ref.14. Source: UniProtKB

regulation of stress-activated MAPK cascade

Traceable author statement Ref.14. Source: UniProtKB

response to epidermal growth factor

Inferred from sequence or structural similarity. Source: UniProtKB

response to toxic substance

Inferred from direct assay PubMed 17651772. Source: RGD

   Cellular_componentGolgi apparatus

Traceable author statement Ref.14. Source: UniProtKB

caveola

Traceable author statement Ref.14. Source: UniProtKB

cytoskeleton

Traceable author statement Ref.14. Source: UniProtKB

cytosol

Traceable author statement Ref.14. Source: UniProtKB

early endosome

Traceable author statement Ref.14. Source: UniProtKB

focal adhesion

Traceable author statement Ref.14. Source: UniProtKB

late endosome

Traceable author statement Ref.14. Source: UniProtKB

mitochondrion

Traceable author statement Ref.14. Source: UniProtKB

nucleoplasm

Inferred from direct assay PubMed 7889942. Source: UniProtKB

nucleus

Traceable author statement Ref.14. Source: UniProtKB

protein complex

Inferred from direct assay PubMed 15781236. Source: RGD

   Molecular_functionATP binding

Inferred from direct assay PubMed 15027896. Source: RGD

MAP kinase activity

Inferred from direct assay PubMed 7889942. Source: UniProtKB

protein serine/threonine kinase activity

Inferred by curator PubMed 15027896. Source: RGD

Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: P21708-1)

Also known as: A;

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: P21708-2)

Also known as: B;

The sequence of this isoform differs from the canonical sequence as follows:
     340-340: E → EVSRPPAAGRGISVPSVRPVPYCLCPQ

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Initiator methionine11Removed Ref.3
Chain2 – 380379Mitogen-activated protein kinase 3
PRO_0000186253

Regions

Domain43 – 331289Protein kinase
Nucleotide binding49 – 579ATP By similarity
Motif203 – 2053TXY

Sites

Active site1671Proton acceptor By similarity
Binding site721ATP By similarity

Amino acid modifications

Modified residue21N-acetylalanine Ref.3
Modified residue1711Phosphoserine By similarity
Modified residue1991Phosphothreonine By similarity
Modified residue2031Phosphothreonine; by MAP2K1 and MAP2K2 Ref.3 Ref.11
Modified residue2051Phosphotyrosine; by MAP2K1 and MAP2K2 Ref.3 Ref.11
Modified residue2081Phosphothreonine; by autocatalysis By similarity

Natural variations

Alternative sequence3401E → EVSRPPAAGRGISVPSVRPV PYCLCPQ in isoform 2.
VSP_004830

Experimental info

Sequence conflict951R → G in AAA11604. Ref.1
Sequence conflict951R → G in CAA46318. Ref.1
Sequence conflict951R → G in AAA63486. Ref.4
Sequence conflict951R → G in AAA20009. Ref.7

Sequences

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

Last modified January 23, 2007. Version 5.
Checksum: 49C4EA95B627237F

FASTA38043,081
        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 RFQPGAPEAP 

« Hide

Isoform 2 (B) [UniParc].

Checksum: 2F40B2DFA5A116B0
Show »

FASTA40645,770

References

« Hide 'large scale' references
[1]"Sequence of a rat cDNA encoding the ERK1-MAP kinase."
Marquardt B., Stabel S.
Gene 120:297-299(1992) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
Strain: Sprague-Dawley.
Tissue: Brain.
[2]"ERK1b, a 46-kDa ERK isoform that is differentially regulated by MEK."
Yung Y., Yao Z., Hanoch T., Seger R.
J. Biol. Chem. 275:15799-15808(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
[3]Bienvenut W.V., von Kriegsheim A.F., Kolch W.
Submitted (AUG-2006) to UniProtKB
Cited for: PROTEIN SEQUENCE OF 2-65; 96-132; 157-209; 213-221; 280-357 AND 361-380 (ISOFORM 2), CLEAVAGE OF INITIATOR METHIONINE, ACETYLATION AT ALA-2, PHOSPHORYLATION AT THR-203 AND TYR-205, IDENTIFICATION BY MASS SPECTROMETRY.
Tissue: Pheochromocytoma.
[4]Maisonpierre P.C., le Beau M.M., Espinosa R. III, Ip N.Y., Belluscio L., la Monte S.M., Squinto S., Furth M.E., Yancopoulos G.D.
Submitted (JUL-1991) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 7-380 (ISOFORM 1).
[5]Lubec G., Afjehi-Sadat L., Kang S.U.
Submitted (JUL-2007) to UniProtKB
Cited for: PROTEIN SEQUENCE OF 73-84 AND 183-190, IDENTIFICATION BY MASS SPECTROMETRY.
Strain: Sprague-Dawley.
Tissue: Brain and Spinal cord.
[6]"An insulin-stimulated protein kinase similar to yeast kinases involved in cell cycle control."
Boulton T.G., Yancopoulos G.D., Gregory J.S., Slaughter C., Moomaw C., Hsu J., Cobb M.H.
Science 249:64-67(1990) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 14-380 (ISOFORM 1), PARTIAL PROTEIN SEQUENCE.
[7]"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] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 14-380 (ISOFORM 1).
Tissue: Brain cortex.
[8]"Purification and properties of extracellular signal-regulated kinase 1, an insulin-stimulated microtubule-associated protein 2 kinase."
Boulton T.G., Gregory J.S., Cobb M.H.
Biochemistry 30:278-286(1991) [PubMed] [Europe PMC] [Abstract]
Cited for: PROTEIN SEQUENCE OF 43-64 AND 167-185, CHARACTERIZATION.
[9]"Microtubule-associated protein 2 kinases, ERK1 and ERK2, undergo autophosphorylation on both tyrosine and threonine residues: implications for their mechanism of activation."
Seger R., Ahn N.G., Boulton T.G., Yancopoulos G.D., Panayotatos N., Radziejewska E., Ericsson L., Bratlien R.L., Cobb M.H., Krebs E.G.
Proc. Natl. Acad. Sci. U.S.A. 88:6142-6146(1991) [PubMed] [Europe PMC] [Abstract]
Cited for: AUTOPHOSPHORYLATION.
[10]"PHAS-I as a link between mitogen-activated protein kinase and translation initiation."
Lin T.-A., Kong X., Haystead T.A.J., Pause A., Belsham G.J., Sonenberg N., Lawrence J.C. Jr.
Science 266:653-656(1994) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION OF EIF4EBP1.
[11]"Quantitative phosphoproteomics of vasopressin-sensitive renal cells: regulation of aquaporin-2 phosphorylation at two sites."
Hoffert J.D., Pisitkun T., Wang G., Shen R.-F., Knepper M.A.
Proc. Natl. Acad. Sci. U.S.A. 103:7159-7164(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-203 AND TYR-205, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[12]"Regulator of G-protein signaling 14 (RGS14) is a selective H-Ras effector."
Willard F.S., Willard M.D., Kimple A.J., Soundararajan M., Oestreich E.A., Li X., Sowa N.A., Kimple R.J., Doyle D.A., Der C.J., Zylka M.J., Snider W.D., Siderovski D.P.
PLoS ONE 4:E4884-E4884(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION IN A COMPLEX WITH BRAF; HRAS; MAP2K1 AND RGS14.
[13]"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.
[14]"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.
[15]"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.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
S46779 mRNA. Translation: AAA11604.1.
X65198 mRNA. Translation: CAA46318.1.
AF155236 mRNA. Translation: AAF71666.1.
M61177 mRNA. Translation: AAA63486.1.
M38194 mRNA. Translation: AAA41123.1.
U12008 mRNA. Translation: AAA20009.1.
PIRJC1451.
RefSeqNP_059043.1. NM_017347.2.
UniGeneRn.2592.

3D structure databases

ProteinModelPortalP21708.
SMRP21708. Positions 33-375.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid248427. 3 interactions.
DIPDIP-487N.
IntActP21708. 268 interactions.
MINTMINT-100073.

Chemistry

ChEMBLCHEMBL5809.

PTM databases

PhosphoSiteP21708.

Proteomic databases

PaxDbP21708.
PRIDEP21708.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSRNOT00000026627; ENSRNOP00000026627; ENSRNOG00000019601. [P21708-1]
GeneID50689.
KEGGrno:50689.
UCSCRGD:3046. rat. [P21708-1]

Organism-specific databases

CTD5595.
RGD3046. Mapk3.

Phylogenomic databases

eggNOGCOG0515.
GeneTreeENSGT00550000074298.
HOGENOMHOG000233024.
HOVERGENHBG014652.
InParanoidP21708.
KOK04371.
OMARARHIDN.
OrthoDBEOG7M3J0K.
PhylomeDBP21708.
TreeFamTF105097.

Enzyme and pathway databases

BRENDA2.7.11.24. 5301.

Gene expression databases

GenevestigatorP21708.

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]
PANTHERPTHR24055:SF111. PTHR24055:SF111. 1 hit.
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

NextBio610550.
PROP21708.

Entry information

Entry nameMK03_RAT
AccessionPrimary (citable) accession number: P21708
Secondary accession number(s): Q4PIY8, Q62686, Q9JJ13
Entry history
Integrated into UniProtKB/Swiss-Prot: May 1, 1991
Last sequence update: January 23, 2007
Last modified: April 16, 2014
This is version 161 of the entry and version 5 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families