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Protein

Dual specificity mitogen-activated protein kinase kinase 4

Gene

Map2k4

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-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

Complete GO annotation...

Keywords - Molecular functioni

Kinase, Serine/threonine-protein kinase, Transferase, Tyrosine-protein kinase

Keywords - Biological processi

Apoptosis, Stress response

Keywords - Ligandi

ATP-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 lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 11

Organism-specific databases

MGIiMGI:1346869. Map2k4.

Subcellular locationi

GO - Cellular componenti

Complete GO annotation...

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

WithEntry#Exp.IntActNotes
Map3k1P533492EBI-447934,EBI-447913
Mapk8ip3Q9ESN9-23EBI-447934,EBI-9549291

Protein-protein interaction databases

BioGridi204952. 7 interactors.
DIPiDIP-869N.
IntActiP47809. 4 interactors.
MINTiMINT-4102306.
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

Contains 1 protein kinase domain.PROSITE-ProRule annotation

Phylogenomic databases

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

Family and domain databases

InterProiIPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamiPF00069. Pkinase. 1 hit.
[Graphical view]
SMARTiSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF56112. SSF56112. 1 hit.
PROSITEiPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]

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.

Cross-referencesi

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.

3D structure databases

ProteinModelPortaliP47809.
SMRiP47809.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi204952. 7 interactors.
DIPiDIP-869N.
IntActiP47809. 4 interactors.
MINTiMINT-4102306.
STRINGi10090.ENSMUSP00000041282.

Chemistry databases

ChEMBLiCHEMBL2201.

PTM databases

iPTMnetiP47809.
PhosphoSitePlusiP47809.

Proteomic databases

EPDiP47809.
PaxDbiP47809.
PeptideAtlasiP47809.
PRIDEiP47809.

Protocols and materials databases

DNASUi26398.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

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

Organism-specific databases

CTDi6416.
MGIiMGI:1346869. Map2k4.

Phylogenomic databases

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

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.

Miscellaneous databases

PROiP47809.
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000033352.
CleanExiMM_MAP2K4.
ExpressionAtlasiP47809. baseline and differential.
GenevisibleiP47809. MM.

Family and domain databases

InterProiIPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamiPF00069. Pkinase. 1 hit.
[Graphical view]
SMARTiSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF56112. SSF56112. 1 hit.
PROSITEiPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiMP2K4_MOUSE
AccessioniPrimary (citable) accession number: P47809
Entry historyi
Integrated into UniProtKB/Swiss-Prot: February 1, 1996
Last sequence update: November 1, 1997
Last modified: November 2, 2016
This is version 144 of the entry and version 2 of the sequence. [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

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.