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Protein

Dual specificity mitogen-activated protein kinase kinase 4

Gene

Map2k4

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. Essential component of the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. With MAP2K7/MKK7, is the one of the only known kinase to directly activate the stress-activated protein kinase/c-Jun N-terminal kinases MAPK8/JNK1, MAPK9/JNK2 and MAPK10/JNK3. MAP2K4/MKK4 and MAP2K7/MKK7 both activate the JNKs by phosphorylation, but they differ in their preference for the phosphorylation site in the Thr-Pro-Tyr motif. MAP2K4 shows preference for phosphorylation of the Tyr residue and MAP2K7/MKK7 for the Thr residue. The phosphorylation of the Thr residue by MAP2K7/MKK7 seems to be the prerequisite for JNK activation at least in response to proinflammatory cytokines, while other stimuli activate both MAP2K4/MKK4 and MAP2K7/MKK7 which synergistically phosphorylate JNKs. MAP2K4 is required for maintaining peripheral lymphoid homeostasis. The MKK/JNK signaling pathway is also involved in mitochondrial death signaling pathway, including the release cytochrome c, leading to apoptosis. Whereas MAP2K7/MKK7 exclusively activates JNKs, MAP2K4/MKK4 additionally activates the p38 MAPKs MAPK11, MAPK12, MAPK13 and MAPK14.5 Publications

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.

Enzyme regulationi

Activated in response to a variety of cellular stresses, including UV and gamma-irradiation, heat shock, hyperosmolarity, T-cell receptor stimulation, peroxide and inflammatory cytokines. Also activated by developmental cues. MAP2K4/MKK4 is activated by the majority of MKKKs, such as MAP3K5/ASK1, MAP3K1/MEKK1, MAP3K7/TAK1, MAP3K10/MLK2, MAP3K11/MLK3, MAP3K12/DLK and MAP3K13/LZK.1 Publication

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei129ATP1
Active sitei227Proton acceptorPROSITE-ProRule annotation1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi106 – 114ATPPROSITE-ProRule annotation9

GO - Molecular functioni

GO - Biological processi

Keywordsi

Molecular functionKinase, Serine/threonine-protein kinase, Transferase, Tyrosine-protein kinase
Biological processApoptosis, Stress response
LigandATP-binding, Nucleotide-binding

Enzyme and pathway databases

BRENDAi2.7.12.2 3474
ReactomeiR-MMU-2559580 Oxidative Stress Induced Senescence
R-MMU-2871796 FCERI mediated MAPK activation
R-MMU-450321 JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1

Names & Taxonomyi

Protein namesi
Recommended name:
Dual specificity mitogen-activated protein kinase kinase 4 (EC:2.7.12.2)
Short name:
MAP kinase kinase 4
Short name:
MAPKK 4
Alternative name(s):
C-JUN N-terminal kinase kinase 1
Short name:
JNK kinase 1
Short name:
JNKK 1
JNK-activating kinase 1
MAPK/ERK kinase 4
Short name:
MEK 4
SAPK/ERK kinase 1
Short name:
SEK1
Gene namesi
Name:Map2k4
Synonyms:Jnkk1, Mek4, Mkk4, Prkmk4, Sek1, Serk1, Skk1
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
Proteomesi

Organism-specific databases

MGIiMGI:1346869 Map2k4

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, Nucleus

Pathology & Biotechi

Disruption phenotypei

Causes irregular alignment of Purkinje cells in the cerebellum and delayed radial migration in the cortex during brain development. The cardiac-specific deletion prevents pathological cardiac hypertrophy.2 Publications

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi129K → R: Loss of ATP-binding. 1 Publication1

Chemistry databases

ChEMBLiCHEMBL2201

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Initiator methionineiRemovedBy similarity
ChainiPRO_00000863822 – 397Dual specificity mitogen-activated protein kinase kinase 4Add BLAST396

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei2N-acetylalanineBy similarity1
Modified residuei56Asymmetric dimethylarginine; alternateCombined sources1
Modified residuei56Omega-N-methylarginine; alternateBy similarity1
Modified residuei88PhosphoserineCombined sources1
Modified residuei255PhosphoserineCombined sources1
Modified residuei259PhosphothreonineCombined sources1

Post-translational modificationi

Activated by phosphorylation on Ser-255 and Thr-259 by MAP kinase kinase kinases (MAP3Ks).By similarity

Keywords - PTMi

Acetylation, Methylation, Phosphoprotein

Proteomic databases

EPDiP47809
PaxDbiP47809
PeptideAtlasiP47809
PRIDEiP47809

PTM databases

iPTMnetiP47809
PhosphoSitePlusiP47809

Expressioni

Tissue specificityi

Strong expression is detected in most of the central nervous system and in liver and thymus during early stages of development. While expression in nervous system increases over time, expression in fetal liver and thymus gradually decreases as embryogenesis proceeds. High level of expression in the central nervous system persists throughout postnatal development and remained at a stable level in adult brain.1 Publication

Gene expression databases

BgeeiENSMUSG00000033352
CleanExiMM_MAP2K4
ExpressionAtlasiP47809 baseline and differential
GenevisibleiP47809 MM

Interactioni

Subunit structurei

Interacts with SPAG9. Interacts (via its D domain) with its substrates MAPK8/JNK1, MAPK9/JNK2, MAPK10/JNK3, MAPK11 and MAPK14 (By similarity). Interacts (via its DVD domain) with MAP3Ks activators like MAP3K1/MEKK1 and MAP3K11/MLK3. Interacts with ARRB1, ARRB2 and MAPK8IP3/JIP3 (By similarity).By similarity

Binary interactionsi

Show more details

Protein-protein interaction databases

BioGridi204952, 8 interactors
CORUMiP47809
DIPiDIP-869N
IntActiP47809, 5 interactors
MINTiP47809
STRINGi10090.ENSMUSP00000041282

Structurei

3D structure databases

ProteinModelPortaliP47809
SMRiP47809
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini100 – 366Protein kinasePROSITE-ProRule annotationAdd BLAST267

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni35 – 50D domainBy similarityAdd BLAST16
Regioni362 – 385DVD domainBy similarityAdd BLAST24

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi5 – 17Gly/Ser-richAdd BLAST13

Domaini

The DVD domain (residues 362-385) contains a conserved docking site and is found in the mammalian MAP kinase kinases (MAP2Ks). The DVD sites bind to their specific upstream MAP kinase kinase kinases (MAP3Ks) and are essential for activation (By similarity).By similarity
The D domain (residues 35-50) contains a conserved docking site and is required for the binding to MAPk substrates.

Sequence similaritiesi

Phylogenomic databases

eggNOGiKOG0984 Eukaryota
ENOG410XT3F LUCA
GeneTreeiENSGT00760000119199
HOGENOMiHOG000234206
HOVERGENiHBG108518
InParanoidiP47809
KOiK04430
OMAiVMKSNDC
OrthoDBiEOG091G0A9H
PhylomeDBiP47809
TreeFamiTF350701

Family and domain databases

InterProiView protein in InterPro
IPR011009 Kinase-like_dom_sf
IPR000719 Prot_kinase_dom
IPR017441 Protein_kinase_ATP_BS
IPR008271 Ser/Thr_kinase_AS
PfamiView protein in Pfam
PF00069 Pkinase, 1 hit
SMARTiView protein in SMART
SM00220 S_TKc, 1 hit
SUPFAMiSSF56112 SSF56112, 1 hit
PROSITEiView protein in PROSITE
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.

P47809-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MAAPSPSGGG GSGGGGGTPG PIGPPASGHP AVSSMQGKRK ALKLNFANPP
60 70 80 90 100
VKSTARFTLN PNTTGVQNPH IERLRTHSIE SSGKLKISPE QHWDFTAEDL
110 120 130 140 150
KDLGEIGRGA YGSVNKMVHK PSGQIMAVKR IRSTVDEKEQ KQLLMDLDVV
160 170 180 190 200
MRSSDCPYIV QFYGALFREG DCWICMELMS TSFDKFYKYV YSVLDDVIPE
210 220 230 240 250
EILGKITLAT VKALNHLKEN LKIIHRDIKP SNILLDRSGN IKLCDFGISG
260 270 280 290 300
QLVDSIAKTR DAGCRPYMAP ERIDPSASRQ GYDVRSDVWS LGITLYELAT
310 320 330 340 350
GRFPYPKWNS VFDQLTQVVK GDPPQLSNSE EREFSPSFIN FVNLCLTKDE
360 370 380 390
SKRPKYKELL KHPFILMYEE RTVEVACYVC KILDQMPATP SSPMYVD
Length:397
Mass (Da):44,114
Last modified:November 1, 1997 - v2
Checksum:iB99C6688184E5B3D
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U18310 mRNA Translation: AAB81554.1
CCDSiCCDS24844.1
PIRiS52423
RefSeqiNP_033183.1, NM_009157.5
UniGeneiMm.412922

Genome annotation databases

EnsembliENSMUST00000046963; ENSMUSP00000041282; ENSMUSG00000033352
GeneIDi26398
KEGGimmu:26398
UCSCiuc007jlb.1 mouse

Entry informationi

Entry nameiMP2K4_MOUSE
AccessioniPrimary (citable) accession number: P47809
Entry historyiIntegrated into UniProtKB/Swiss-Prot: February 1, 1996
Last sequence update: November 1, 1997
Last modified: May 23, 2018
This is version 156 of the entry and version 2 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  3. SIMILARITY comments
    Index of protein domains and families

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