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Protein

Mitogen-activated protein kinase 3

Gene

Mapk3

Organism
Rattus norvegicus (Rat)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

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 activityi

ATP + a protein = ADP + a phosphoprotein.

Cofactori

Mg2+By similarity

Enzyme regulationi

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.

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei72ATPPROSITE-ProRule annotation1
Active sitei167Proton acceptorPROSITE-ProRule annotation1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi49 – 57ATPPROSITE-ProRule annotation9

GO - Molecular functioni

  • ATP binding Source: RGD
  • MAP kinase activity Source: UniProtKB
  • protein serine/threonine kinase activity Source: RGD
  • scaffold protein binding Source: BHF-UCL

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Kinase, Serine/threonine-protein kinase, Transferase

Keywords - Biological processi

Apoptosis, Cell cycle

Keywords - Ligandi

ATP-binding, Nucleotide-binding

Enzyme and pathway databases

BRENDAi2.7.11.24. 5301.
ReactomeiR-RNO-110056. MAPK3 (ERK1) activation.
R-RNO-112409. RAF-independent MAPK1/3 activation.
R-RNO-1169408. ISG15 antiviral mechanism.
R-RNO-1295596. Spry regulation of FGF signaling.
R-RNO-162658. Golgi Cisternae Pericentriolar Stack Reorganization.
R-RNO-198753. ERK/MAPK targets.
R-RNO-202670. ERKs are inactivated.
R-RNO-2029482. Regulation of actin dynamics for phagocytic cup formation.
R-RNO-2559580. Oxidative Stress Induced Senescence.
R-RNO-2559582. Senescence-Associated Secretory Phenotype (SASP).
R-RNO-2559585. Oncogene Induced Senescence.
R-RNO-2871796. FCERI mediated MAPK activation.
R-RNO-3371453. Regulation of HSF1-mediated heat shock response.
R-RNO-375165. NCAM signaling for neurite out-growth.
R-RNO-445144. Signal transduction by L1.
R-RNO-450341. Activation of the AP-1 family of transcription factors.
R-RNO-456926. Thrombin signalling through proteinase activated receptors (PARs).
R-RNO-5654726. Negative regulation of FGFR1 signaling.
R-RNO-5654727. Negative regulation of FGFR2 signaling.
R-RNO-5654732. Negative regulation of FGFR3 signaling.
R-RNO-5654733. Negative regulation of FGFR4 signaling.
R-RNO-5663213. RHO GTPases Activate WASPs and WAVEs.
R-RNO-5673001. RAF/MAP kinase cascade.
R-RNO-5674135. MAP2K and MAPK activation.
R-RNO-5674499. Negative feedback regulation of MAPK pathway.
R-RNO-5675221. Negative regulation of MAPK pathway.
R-RNO-6811558. PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling.
R-RNO-73728. RNA Polymerase I Promoter Opening.
R-RNO-74749. Signal attenuation.
R-RNO-881907. Gastrin-CREB signalling pathway via PKC and MAPK.
R-RNO-982772. Growth hormone receptor signaling.

Names & Taxonomyi

Protein namesi
Recommended name:
Mitogen-activated protein kinase 3 (EC:2.7.11.24)
Short name:
MAP kinase 3
Short name:
MAPK 3
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 namesi
Name:Mapk3
Synonyms:Erk1, Prkm3
OrganismiRattus norvegicus (Rat)
Taxonomic identifieri10116 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus
Proteomesi
  • UP000002494 Componenti: Chromosome 1

Organism-specific databases

RGDi3046. Mapk3.

Subcellular locationi

  • Cytoplasm By similarity
  • Nucleus

  • Note: Autophosphorylation at Thr-207 promotes nuclear localization. PEA15-binding redirects the biological outcome of MAPK3 kinase-signaling by sequestering MAPK3 into the cytoplasm.By similarity

GO - Cellular componenti

  • caveola Source: UniProtKB
  • cytoskeleton Source: UniProtKB
  • cytosol Source: UniProtKB
  • early endosome Source: UniProtKB
  • extracellular exosome Source: Ensembl
  • focal adhesion Source: UniProtKB
  • Golgi apparatus Source: UniProtKB
  • late endosome Source: UniProtKB
  • microtubule cytoskeleton Source: Ensembl
  • mitochondrion Source: UniProtKB
  • nuclear envelope Source: Ensembl
  • nucleoplasm Source: UniProtKB
  • nucleus Source: UniProtKB
  • protein complex Source: RGD
  • pseudopodium Source: Ensembl
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Nucleus

Pathology & Biotechi

Chemistry databases

ChEMBLiCHEMBL5809.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Initiator methionineiRemoved1 Publication
ChainiPRO_00001862532 – 380Mitogen-activated protein kinase 3Add BLAST379

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei2N-acetylalanine1 Publication1
Modified residuei199PhosphothreonineBy similarity1
Modified residuei203Phosphothreonine; by MAP2K1 and MAP2K2Combined sources1 Publication1
Modified residuei205Phosphotyrosine; by MAP2K1 and MAP2K2Combined sources1 Publication1
Modified residuei208Phosphothreonine; by autocatalysisBy similarity1
Modified residuei264PhosphoserineBy similarity1
Modified residuei266PhosphoserineBy similarity1
Modified residuei302PhosphoserineBy similarity1

Post-translational modificationi

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.By similarity2 Publications

Keywords - PTMi

Acetylation, Phosphoprotein

Proteomic databases

PaxDbiP21708.
PRIDEiP21708.

PTM databases

iPTMnetiP21708.
PhosphoSitePlusiP21708.

Expressioni

Tissue specificityi

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

Developmental stagei

Increased expression during development.

Gene expression databases

BgeeiENSRNOG00000019601.
GenevisibleiP21708. RN.

Interactioni

Subunit structurei

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). Interacts with CDKN2AIP.By similarity

GO - Molecular functioni

  • scaffold protein binding Source: BHF-UCL

Protein-protein interaction databases

BioGridi248427. 3 interactors.
DIPiDIP-487N.
IntActiP21708. 270 interactors.
MINTiMINT-100073.
STRINGi10116.ENSRNOP00000026627.

Structurei

3D structure databases

ProteinModelPortaliP21708.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini43 – 331Protein kinasePROSITE-ProRule annotationAdd BLAST289

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi203 – 205TXY3

Domaini

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

Sequence similaritiesi

Contains 1 protein kinase domain.PROSITE-ProRule annotation

Phylogenomic databases

eggNOGiKOG0660. Eukaryota.
ENOG410XNY0. LUCA.
GeneTreeiENSGT00550000074298.
HOGENOMiHOG000233024.
HOVERGENiHBG014652.
InParanoidiP21708.
KOiK04371.
OMAiPRYTDLQ.
OrthoDBiEOG091G08QL.
PhylomeDBiP21708.
TreeFamiTF105097.

Family and domain databases

InterProiIPR011009. Kinase-like_dom.
IPR003527. MAP_kinase_CS.
IPR008349. MAPK_ERK1/2.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamiPF00069. Pkinase. 1 hit.
[Graphical view]
PRINTSiPR01770. ERK1ERK2MAPK.
SMARTiSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF56112. SSF56112. 1 hit.
PROSITEiPS01351. MAPK. 1 hit.
PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]

Sequences (2)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: P21708-1) [UniParc]FASTAAdd to basket
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.

« Hide

        10         20         30         40         50
MAAAAAAPGG GGGEPRGTAG VVPVVPGEVE VVKGQPFDVG PRYTQLQYIG
60 70 80 90 100
EGAYGMVSSA YDHVRKTRVA IKKISPFEHQ TYCQRTLREI QILLRFRHEN
110 120 130 140 150
VIGIRDILRA PTLEAMRDVY IVQDLMETDL YKLLKSQQLS NDHICYFLYQ
160 170 180 190 200
ILRGLKYIHS ANVLHRDLKP SNLLINTTCD LKICDFGLAR IADPEHDHTG
210 220 230 240 250
FLTEYVATRW YRAPEIMLNS KGYTKSIDIW SVGCILAEML SNRPIFPGKH
260 270 280 290 300
YLDQLNHILG ILGSPSQEDL NCIINMKARN YLQSLPSKTK VAWAKLFPKS
310 320 330 340 350
DSKALDLLDR MLTFNPNKRI TVEEALAHPY LEQYYDPTDE PVAEEPFTFD
360 370 380
MELDDLPKER LKELIFQETA RFQPGAPEAP
Length:380
Mass (Da):43,081
Last modified:January 23, 2007 - v5
Checksum:i49C4EA95B627237F
GO
Isoform 2 (identifier: P21708-2) [UniParc]FASTAAdd to basket
Also known as: B

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

Show »
Length:406
Mass (Da):45,770
Checksum:i2F40B2DFA5A116B0
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti95R → G in AAA11604 (PubMed:1327976).Curated1
Sequence conflicti95R → G in CAA46318 (PubMed:1327976).Curated1
Sequence conflicti95R → G in AAA63486 (Ref. 4) Curated1
Sequence conflicti95R → G in AAA20009 (PubMed:1716439).Curated1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_004830340E → EVSRPPAAGRGISVPSVRPV PYCLCPQ in isoform 2. 1 Publication1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
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.
PIRiJC1451.
RefSeqiNP_059043.1. NM_017347.2.
UniGeneiRn.2592.

Genome annotation databases

EnsembliENSRNOT00000087625; ENSRNOP00000070784; ENSRNOG00000053583. [P21708-1]
GeneIDi50689.
KEGGirno:50689.
UCSCiRGD:3046. rat. [P21708-1]

Keywords - Coding sequence diversityi

Alternative splicing

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
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.
PIRiJC1451.
RefSeqiNP_059043.1. NM_017347.2.
UniGeneiRn.2592.

3D structure databases

ProteinModelPortaliP21708.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi248427. 3 interactors.
DIPiDIP-487N.
IntActiP21708. 270 interactors.
MINTiMINT-100073.
STRINGi10116.ENSRNOP00000026627.

Chemistry databases

ChEMBLiCHEMBL5809.

PTM databases

iPTMnetiP21708.
PhosphoSitePlusiP21708.

Proteomic databases

PaxDbiP21708.
PRIDEiP21708.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSRNOT00000087625; ENSRNOP00000070784; ENSRNOG00000053583. [P21708-1]
GeneIDi50689.
KEGGirno:50689.
UCSCiRGD:3046. rat. [P21708-1]

Organism-specific databases

CTDi5595.
RGDi3046. Mapk3.

Phylogenomic databases

eggNOGiKOG0660. Eukaryota.
ENOG410XNY0. LUCA.
GeneTreeiENSGT00550000074298.
HOGENOMiHOG000233024.
HOVERGENiHBG014652.
InParanoidiP21708.
KOiK04371.
OMAiPRYTDLQ.
OrthoDBiEOG091G08QL.
PhylomeDBiP21708.
TreeFamiTF105097.

Enzyme and pathway databases

BRENDAi2.7.11.24. 5301.
ReactomeiR-RNO-110056. MAPK3 (ERK1) activation.
R-RNO-112409. RAF-independent MAPK1/3 activation.
R-RNO-1169408. ISG15 antiviral mechanism.
R-RNO-1295596. Spry regulation of FGF signaling.
R-RNO-162658. Golgi Cisternae Pericentriolar Stack Reorganization.
R-RNO-198753. ERK/MAPK targets.
R-RNO-202670. ERKs are inactivated.
R-RNO-2029482. Regulation of actin dynamics for phagocytic cup formation.
R-RNO-2559580. Oxidative Stress Induced Senescence.
R-RNO-2559582. Senescence-Associated Secretory Phenotype (SASP).
R-RNO-2559585. Oncogene Induced Senescence.
R-RNO-2871796. FCERI mediated MAPK activation.
R-RNO-3371453. Regulation of HSF1-mediated heat shock response.
R-RNO-375165. NCAM signaling for neurite out-growth.
R-RNO-445144. Signal transduction by L1.
R-RNO-450341. Activation of the AP-1 family of transcription factors.
R-RNO-456926. Thrombin signalling through proteinase activated receptors (PARs).
R-RNO-5654726. Negative regulation of FGFR1 signaling.
R-RNO-5654727. Negative regulation of FGFR2 signaling.
R-RNO-5654732. Negative regulation of FGFR3 signaling.
R-RNO-5654733. Negative regulation of FGFR4 signaling.
R-RNO-5663213. RHO GTPases Activate WASPs and WAVEs.
R-RNO-5673001. RAF/MAP kinase cascade.
R-RNO-5674135. MAP2K and MAPK activation.
R-RNO-5674499. Negative feedback regulation of MAPK pathway.
R-RNO-5675221. Negative regulation of MAPK pathway.
R-RNO-6811558. PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling.
R-RNO-73728. RNA Polymerase I Promoter Opening.
R-RNO-74749. Signal attenuation.
R-RNO-881907. Gastrin-CREB signalling pathway via PKC and MAPK.
R-RNO-982772. Growth hormone receptor signaling.

Miscellaneous databases

PROiP21708.

Gene expression databases

BgeeiENSRNOG00000019601.
GenevisibleiP21708. RN.

Family and domain databases

InterProiIPR011009. Kinase-like_dom.
IPR003527. MAP_kinase_CS.
IPR008349. MAPK_ERK1/2.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamiPF00069. Pkinase. 1 hit.
[Graphical view]
PRINTSiPR01770. ERK1ERK2MAPK.
SMARTiSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF56112. SSF56112. 1 hit.
PROSITEiPS01351. MAPK. 1 hit.
PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiMK03_RAT
AccessioniPrimary (citable) accession number: P21708
Secondary accession number(s): Q4PIY8, Q62686, Q9JJ13
Entry historyi
Integrated into UniProtKB/Swiss-Prot: May 1, 1991
Last sequence update: January 23, 2007
Last modified: November 30, 2016
This is version 188 of the entry and version 5 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.