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Protein

Mitogen-activated protein kinase 3

Gene

Mapk3

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: -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.2 Publications

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: MGI
  • identical protein binding Source: MGI
  • MAP kinase activity Source: MGI
  • MAP kinase kinase activity Source: MGI
  • phosphatase binding Source: MGI
  • phosphotyrosine residue binding Source: MGI
  • protein kinase activity Source: MGI
  • protein serine/threonine kinase activity Source: Reactome
  • scaffold protein binding Source: MGI

GO - Biological processi

  • animal organ morphogenesis Source: MGI
  • apoptotic process Source: UniProtKB-KW
  • arachidonic acid metabolic process Source: Ensembl
  • Bergmann glial cell differentiation Source: MGI
  • BMP signaling pathway Source: MGI
  • cardiac neural crest cell development involved in heart development Source: MGI
  • cartilage development Source: MGI
  • caveolin-mediated endocytosis Source: UniProtKB
  • cell cycle Source: UniProtKB-KW
  • cellular response to amino acid starvation Source: MGI
  • cellular response to cadmium ion Source: MGI
  • cellular response to DNA damage stimulus Source: MGI
  • cellular response to dopamine Source: MGI
  • cellular response to mechanical stimulus Source: Ensembl
  • cellular response to reactive oxygen species Source: MGI
  • cellular response to tumor necrosis factor Source: MGI
  • DNA damage induced protein phosphorylation Source: MGI
  • ERK1 and ERK2 cascade Source: CAFA
  • face development Source: MGI
  • interleukin-1-mediated signaling pathway Source: MGI
  • intracellular signal transduction Source: MGI
  • lipopolysaccharide-mediated signaling pathway Source: MGI
  • lung morphogenesis Source: MGI
  • MAPK cascade Source: MGI
  • negative regulation of apolipoprotein binding Source: BHF-UCL
  • neural crest cell development Source: MGI
  • outer ear morphogenesis Source: MGI
  • peptidyl-serine phosphorylation Source: MGI
  • peptidyl-tyrosine autophosphorylation Source: MGI
  • phosphorylation Source: MGI
  • positive regulation of cyclase activity Source: MGI
  • positive regulation of cytokine secretion involved in immune response Source: CAFA
  • positive regulation of ERK1 and ERK2 cascade Source: MGI
  • positive regulation of gene expression Source: MGI
  • positive regulation of histone acetylation Source: MGI
  • positive regulation of histone phosphorylation Source: MGI
  • positive regulation of macrophage chemotaxis Source: CAFA
  • positive regulation of metallopeptidase activity Source: CAFA
  • positive regulation of protein phosphorylation Source: MGI
  • positive regulation of telomerase activity Source: MGI
  • positive regulation of telomere capping Source: MGI
  • positive regulation of telomere maintenance via telomerase Source: MGI
  • positive regulation of transcription by RNA polymerase II Source: MGI
  • positive regulation of translation Source: MGI
  • positive regulation of xenophagy Source: MGI
  • protein-containing complex assembly Source: MGI
  • protein phosphorylation Source: MGI
  • regulation of cellular pH Source: MGI
  • regulation of cytoskeleton organization Source: UniProtKB
  • regulation of DNA binding transcription factor activity Source: UniProtKB
  • regulation of early endosome to late endosome transport Source: UniProtKB
  • regulation of Golgi inheritance Source: UniProtKB
  • regulation of ossification Source: MGI
  • regulation of stress-activated MAPK cascade Source: UniProtKB
  • response to epidermal growth factor Source: UniProtKB
  • response to exogenous dsRNA Source: MGI
  • response to lipopolysaccharide Source: MGI
  • response to toxic substance Source: MGI
  • sensory perception of pain Source: UniProtKB
  • signal transduction Source: MGI
  • stress-activated MAPK cascade Source: MGI
  • thymus development Source: MGI
  • thyroid gland development Source: MGI
  • trachea formation Source: MGI
  • transcription, DNA-templated Source: UniProtKB

Keywordsi

Molecular functionKinase, Serine/threonine-protein kinase, Transferase
Biological processApoptosis, Cell cycle
LigandATP-binding, Nucleotide-binding

Enzyme and pathway databases

ReactomeiR-MMU-110056 MAPK3 (ERK1) activation
R-MMU-112409 RAF-independent MAPK1/3 activation
R-MMU-1295596 Spry regulation of FGF signaling
R-MMU-162658 Golgi Cisternae Pericentriolar Stack Reorganization
R-MMU-198753 ERK/MAPK targets
R-MMU-202670 ERKs are inactivated
R-MMU-2029482 Regulation of actin dynamics for phagocytic cup formation
R-MMU-2559580 Oxidative Stress Induced Senescence
R-MMU-2559582 Senescence-Associated Secretory Phenotype (SASP)
R-MMU-2559585 Oncogene Induced Senescence
R-MMU-2871796 FCERI mediated MAPK activation
R-MMU-3371453 Regulation of HSF1-mediated heat shock response
R-MMU-375165 NCAM signaling for neurite out-growth
R-MMU-445144 Signal transduction by L1
R-MMU-450341 Activation of the AP-1 family of transcription factors
R-MMU-456926 Thrombin signalling through proteinase activated receptors (PARs)
R-MMU-5654726 Negative regulation of FGFR1 signaling
R-MMU-5654727 Negative regulation of FGFR2 signaling
R-MMU-5654732 Negative regulation of FGFR3 signaling
R-MMU-5654733 Negative regulation of FGFR4 signaling
R-MMU-5663213 RHO GTPases Activate WASPs and WAVEs
R-MMU-5673001 RAF/MAP kinase cascade
R-MMU-5674135 MAP2K and MAPK activation
R-MMU-5674499 Negative feedback regulation of MAPK pathway
R-MMU-5675221 Negative regulation of MAPK pathway
R-MMU-6811558 PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling
R-MMU-73728 RNA Polymerase I Promoter Opening
R-MMU-74749 Signal attenuation
R-MMU-881907 Gastrin-CREB signalling pathway via PKC and MAPK
R-MMU-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
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 7

Organism-specific databases

MGIiMGI:1346859 Mapk3

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cytoplasm, Membrane, Nucleus

Pathology & Biotechi

Chemistry databases

ChEMBLiCHEMBL5510

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Initiator methionineiRemoved1 Publication
ChainiPRO_00001862522 – 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
Modified residuei205Phosphotyrosine; by MAP2K1 and MAP2K2Combined sources1
Modified residuei208Phosphothreonine; by autocatalysisBy similarity1

Post-translational modificationi

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).By similarity

Keywords - PTMi

Acetylation, Phosphoprotein

Proteomic databases

EPDiQ63844
MaxQBiQ63844
PaxDbiQ63844
PeptideAtlasiQ63844
PRIDEiQ63844

PTM databases

iPTMnetiQ63844
PhosphoSitePlusiQ63844
SwissPalmiQ63844

Expressioni

Gene expression databases

BgeeiENSMUSG00000063065
CleanExiMM_MAPK3
ExpressionAtlasiQ63844 baseline and differential
GenevisibleiQ63844 MM

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 TPR. Interacts with ADAM15, ARRB2, CANX, DAPK1 (via death domain), HSF4, IER3, MAP2K1/MEK1, NISCH, and SGK1 (By similarity). Interacts with MORG1 (PubMed:15118098). Interacts with PEA15 (PubMed:11702783). Interacts with isoform 1 of MKNK2 and this binding prevents from dephosphorylation and inactivation (PubMed:16162500). Interacts with CDKN2AIP. Interacts with HSF1 (via D domain and preferentially with hyperphosphorylated form); this interaction occurs upon heat shock. Interacts with CAVIN4 (By similarity).By similarity3 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
Klf4Q607933EBI-397682,EBI-3043905

GO - Molecular functioni

  • identical protein binding Source: MGI
  • phosphatase binding Source: MGI
  • phosphotyrosine residue binding Source: MGI
  • scaffold protein binding Source: MGI

Protein-protein interaction databases

BioGridi204970, 17 interactors
CORUMiQ63844
DIPiDIP-31078N
ELMiQ63844
IntActiQ63844, 11 interactors
MINTiQ63844
STRINGi10090.ENSMUSP00000051619

Chemistry databases

BindingDBiQ63844

Structurei

3D structure databases

ProteinModelPortaliQ63844
SMRiQ63844
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

Phylogenomic databases

eggNOGiKOG0660 Eukaryota
ENOG410XNY0 LUCA
GeneTreeiENSGT00910000144035
HOGENOMiHOG000233024
HOVERGENiHBG014652
InParanoidiQ63844
KOiK04371
OrthoDBiEOG091G08QL
PhylomeDBiQ63844
TreeFamiTF105097

Family and domain databases

InterProiView protein in InterPro
IPR011009 Kinase-like_dom_sf
IPR003527 MAP_kinase_CS
IPR008349 MAPK_ERK1/2
IPR000719 Prot_kinase_dom
IPR017441 Protein_kinase_ATP_BS
IPR008271 Ser/Thr_kinase_AS
PfamiView protein in Pfam
PF00069 Pkinase, 1 hit
PRINTSiPR01770 ERK1ERK2MAPK
SMARTiView protein in SMART
SM00220 S_TKc, 1 hit
SUPFAMiSSF56112 SSF56112, 1 hit
PROSITEiView protein in PROSITE
PS01351 MAPK, 1 hit
PS00107 PROTEIN_KINASE_ATP, 1 hit
PS50011 PROTEIN_KINASE_DOM, 1 hit
PS00108 PROTEIN_KINASE_ST, 1 hit

Sequencei

Sequence statusi: Complete.

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

Q63844-1 [UniParc]FASTAAdd to basket

« 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 RFQPGAPEGP
Length:380
Mass (Da):43,066
Last modified:January 23, 2007 - v5
Checksum:i49C14A95B627237F
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti178T → P in CAA45889 (PubMed:8444355).Curated1
Sequence conflicti178T → P no nucleotide entry (PubMed:1459009).Curated1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
BC013754 mRNA Translation: AAH13754.1
BC029712 mRNA Translation: AAH29712.1
S58470 mRNA Translation: AAB19973.1
X64605 mRNA Translation: CAA45889.1
CCDSiCCDS21841.1
PIRiS28184
RefSeqiNP_036082.1, NM_011952.2
UniGeneiMm.8385

Genome annotation databases

EnsembliENSMUST00000057669; ENSMUSP00000051619; ENSMUSG00000063065
GeneIDi26417
KEGGimmu:26417
UCSCiuc009jsm.1 mouse

Similar proteinsi

Entry informationi

Entry nameiMK03_MOUSE
AccessioniPrimary (citable) accession number: Q63844
Secondary accession number(s): Q61531, Q8K0X5, Q91YW5
Entry historyiIntegrated into UniProtKB/Swiss-Prot: November 1, 1997
Last sequence update: January 23, 2007
Last modified: June 20, 2018
This is version 197 of the entry and version 5 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Direct protein sequencing, Reference proteome

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