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P47809

- MP2K4_MOUSE

UniProt

P47809 - MP2K4_MOUSE

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Protein

Dual specificity mitogen-activated protein kinase kinase 4

Gene

Map2k4

Organism
Mus musculus (Mouse)
Status
Reviewed - 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)LengthDescriptionGraphical viewFeature identifierActions
Binding sitei129 – 1291ATP
Active sitei227 – 2271Proton acceptorPROSITE-ProRule annotation

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Nucleotide bindingi106 – 1149ATPPROSITE-ProRule annotation

GO - Molecular functioni

  1. ATP binding Source: UniProtKB-KW
  2. JUN kinase kinase activity Source: Ensembl
  3. protein serine/threonine kinase activity Source: UniProtKB-KW
  4. protein tyrosine kinase activity Source: UniProtKB-KW

GO - Biological processi

  1. activation of JUN kinase activity Source: MGI
  2. apoptotic process Source: UniProtKB-KW
  3. cellular response to mechanical stimulus Source: Ensembl
  4. cellular response to sorbitol Source: Ensembl
  5. JNK cascade Source: MGI
  6. MAPK cascade Source: MGI
  7. positive regulation of DNA replication Source: Ensembl
  8. positive regulation of neuron apoptotic process Source: Ensembl
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.
ReactomeiREACT_188530. FCERI mediated MAPK activation.
REACT_188970. Oxidative Stress Induced Senescence.
REACT_204812. JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1.
REACT_224208. Interleukin-1 signaling.

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
ProteomesiUP000000589: Chromosome 11

Organism-specific databases

MGIiMGI:1346869. Map2k4.

Subcellular locationi

Cytoplasm 1 Publication. Nucleus 1 Publication

GO - Cellular componenti

  1. cytosol Source: Reactome
  2. dendrite cytoplasm Source: Ensembl
  3. nucleus Source: UniProtKB-KW
  4. perikaryon Source: Ensembl
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)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi129 – 1291K → R: Loss of ATP-binding. 1 Publication

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Initiator methioninei1 – 11RemovedBy similarity
Chaini2 – 397396Dual specificity mitogen-activated protein kinase kinase 4PRO_0000086382Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei2 – 21N-acetylalanineBy similarity
Modified residuei88 – 881PhosphoserineBy similarity
Modified residuei255 – 2551Phosphoserine; by MAP3KBy similarity
Modified residuei259 – 2591Phosphothreonine; by MAP3KBy similarity

Post-translational modificationi

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

Keywords - PTMi

Acetylation, Phosphoprotein

Proteomic databases

MaxQBiP47809.
PaxDbiP47809.
PRIDEiP47809.

PTM databases

PhosphoSiteiP47809.

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

BgeeiP47809.
CleanExiMM_MAP2K4.
ExpressionAtlasiP47809. baseline and differential.
GenevestigatoriP47809.

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 interactions.
DIPiDIP-869N.
IntActiP47809. 3 interactions.
MINTiMINT-4102306.
STRINGi10090.ENSMUSP00000041282.

Structurei

3D structure databases

ProteinModelPortaliP47809.
SMRiP47809. Positions 93-386.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini100 – 366267Protein kinasePROSITE-ProRule annotationAdd
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni35 – 5016D domainBy similarityAdd
BLAST
Regioni362 – 38524DVD domainBy similarityAdd
BLAST

Compositional bias

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Compositional biasi5 – 1713Gly/Ser-richAdd
BLAST

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

eggNOGiCOG0515.
HOGENOMiHOG000234206.
HOVERGENiHBG108518.
InParanoidiP47809.
KOiK04430.
OMAiVMKSNDC.
OrthoDBiEOG7J9VPW.
PhylomeDBiP47809.
TreeFamiTF350701.

Family and domain databases

InterProiIPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR002290. Ser/Thr_dual-sp_kinase.
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_009157.4.
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 .
CCDSi CCDS24844.1.
PIRi S52423.
RefSeqi NP_033183.1. NM_009157.4.
UniGenei Mm.412922.

3D structure databases

ProteinModelPortali P47809.
SMRi P47809. Positions 93-386.
ModBasei Search...
MobiDBi Search...

Protein-protein interaction databases

BioGridi 204952. 7 interactions.
DIPi DIP-869N.
IntActi P47809. 3 interactions.
MINTi MINT-4102306.
STRINGi 10090.ENSMUSP00000041282.

Chemistry

BindingDBi P47809.
ChEMBLi CHEMBL2201.

PTM databases

PhosphoSitei P47809.

Proteomic databases

MaxQBi P47809.
PaxDbi P47809.
PRIDEi P47809.

Protocols and materials databases

DNASUi 26398.
Structural Biology Knowledgebase Search...

Genome annotation databases

Ensembli ENSMUST00000046963 ; ENSMUSP00000041282 ; ENSMUSG00000033352 .
GeneIDi 26398.
KEGGi mmu:26398.
UCSCi uc007jlb.1. mouse.

Organism-specific databases

CTDi 6416.
MGIi MGI:1346869. Map2k4.

Phylogenomic databases

eggNOGi COG0515.
HOGENOMi HOG000234206.
HOVERGENi HBG108518.
InParanoidi P47809.
KOi K04430.
OMAi VMKSNDC.
OrthoDBi EOG7J9VPW.
PhylomeDBi P47809.
TreeFami TF350701.

Enzyme and pathway databases

BRENDAi 2.7.12.2. 3474.
Reactomei REACT_188530. FCERI mediated MAPK activation.
REACT_188970. Oxidative Stress Induced Senescence.
REACT_204812. JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1.
REACT_224208. Interleukin-1 signaling.

Miscellaneous databases

NextBioi 304351.
PROi P47809.
SOURCEi Search...

Gene expression databases

Bgeei P47809.
CleanExi MM_MAP2K4.
ExpressionAtlasi P47809. baseline and differential.
Genevestigatori P47809.

Family and domain databases

InterProi IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR002290. Ser/Thr_dual-sp_kinase.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view ]
Pfami PF00069. Pkinase. 1 hit.
[Graphical view ]
SMARTi SM00220. S_TKc. 1 hit.
[Graphical view ]
SUPFAMi SSF56112. SSF56112. 1 hit.
PROSITEi PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view ]
ProtoNeti Search...

Publicationsi

  1. "Role of SAPK/ERK kinase-1 in the stress-activated pathway regulating transcription factor c-Jun."
    Sanchez I., Hughes R.T., Mayer B.J., Yee K., Woodgett J.R., Avruch J., Kyriakis J.M., Zon L.I.
    Nature 372:794-798(1994) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, MUTAGENESIS OF LYS-129.
    Tissue: Embryo.
  2. Zon L.I.
    Submitted (DEC-1996) to the EMBL/GenBank/DDBJ databases
    Cited for: SEQUENCE REVISION.
  3. "SEK1/MKK4 is required for maintenance of a normal peripheral lymphoid compartment but not for lymphocyte development."
    Swat W., Fujikawa K., Ganiatsas S., Yang D., Xavier R.J., Harris N.L., Davidson L., Ferrini R., Davis R.J., Labow M.A., Flavell R.A., Zon L.I., Alt F.W.
    Immunity 8:625-634(1998) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION.
  4. "The MKK7 gene encodes a group of c-Jun NH2-terminal kinase kinases."
    Tournier C., Whitmarsh A.J., Cavanagh J., Barrett T., Davis R.J.
    Mol. Cell. Biol. 19:1569-1581(1999) [PubMed] [Europe PMC] [Abstract]
    Cited for: ENZYME REGULATION, SUBCELLULAR LOCATION, FUNCTION OF THE MKK/JNK PATHWAY.
  5. "Dynamic expression of SEK1 suggests multiple roles of the gene during embryogenesis and in adult brain of mice."
    Lee J.K., Hwang W.S., Lee Y.D., Han P.L.
    Brain Res. Mol. Brain Res. 66:133-140(1999) [PubMed] [Europe PMC] [Abstract]
    Cited for: TISSUE SPECIFICITY.
  6. "MKK7 is an essential component of the JNK signal transduction pathway activated by proinflammatory cytokines."
    Tournier C., Dong C., Turner T.K., Jones S.N., Flavell R.A., Davis R.J.
    Genes Dev. 15:1419-1426(2001) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION.
  7. "A subdomain of MEKK1 that is critical for binding to MKK4."
    Tu Z., Mooney S.M., Lee F.S.
    Cell. Signal. 15:65-77(2003) [PubMed] [Europe PMC] [Abstract]
    Cited for: PHOSPHORYLATION, INTERACTION WITH MAP3K1/MEKK1.
  8. "Different properties of SEK1 and MKK7 in dual phosphorylation of stress-induced activated protein kinase SAPK/JNK in embryonic stem cells."
    Kishimoto H., Nakagawa K., Watanabe T., Kitagawa D., Momose H., Seo J., Nishitai G., Shimizu N., Ohata S., Tanemura S., Asaka S., Goto T., Fukushi H., Yoshida H., Suzuki A., Sasaki T., Wada T., Penninger J.M., Nishina H., Katada T.
    J. Biol. Chem. 278:16595-16601(2003) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION.
  9. "Targeted deletion of the mitogen-activated protein kinase kinase 4 gene in the nervous system causes severe brain developmental defects and premature death."
    Wang X., Nadarajah B., Robinson A.C., McColl B.W., Jin J.W., Dajas-Bailador F., Boot-Handford R.P., Tournier C.
    Mol. Cell. Biol. 27:7935-7946(2007) [PubMed] [Europe PMC] [Abstract]
    Cited for: DISRUPTION PHENOTYPE.
  10. "Cardiac-specific deletion of mkk4 reveals its role in pathological hypertrophic remodeling but not in physiological cardiac growth."
    Liu W., Zi M., Jin J., Prehar S., Oceandy D., Kimura T.E., Lei M., Neyses L., Weston A.H., Cartwright E.J., Wang X.
    Circ. Res. 104:905-914(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: DISRUPTION PHENOTYPE.
  11. "Differential regulation and properties of MAPKs."
    Raman M., Chen W., Cobb M.H.
    Oncogene 26:3100-3112(2007) [PubMed] [Europe PMC] [Abstract]
    Cited for: REVIEW ON ENZYME REGULATION.
  12. "Diverse physiological functions of MKK4 and MKK7 during early embryogenesis."
    Asaoka Y., Nishina H.
    J. Biochem. 148:393-401(2010) [PubMed] [Europe PMC] [Abstract]
    Cited for: REVIEW ON FUNCTION.
  13. "The bottleneck of JNK signaling: molecular and functional characteristics of MKK4 and MKK7."
    Haeusgen W., Herdegen T., Waetzig V.
    Eur. J. Cell Biol. 90:536-544(2011) [PubMed] [Europe PMC] [Abstract]
    Cited for: REVIEW ON REGULATION, REVIEW ON FUNCTION.
  14. "JLP: a scaffolding protein that tethers JNK/p38MAPK signaling modules and transcription factors."
    Lee C.M., Onesime D., Reddy C.D., Dhanasekaran N., Reddy E.P.
    Proc. Natl. Acad. Sci. U.S.A. 99:14189-14194(2002) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH SPAG9.

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: October 29, 2014
This is version 125 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

External Data

Dasty 3