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P47809 (MP2K4_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 122. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (3) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Dual specificity mitogen-activated protein kinase kinase 4

Short name=MAP kinase kinase 4
Short name=MAPKK 4
EC=2.7.12.2
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 names
Name:Map2k4
Synonyms:Jnkk1, Mek4, Mkk4, Prkmk4, Sek1, Serk1, Skk1
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

Sequence length397 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

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. Ref.1 Ref.3 Ref.4 Ref.6 Ref.8

Catalytic activity

ATP + a protein = ADP + a phosphoprotein.

Enzyme regulation

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. Ref.4

Subunit structure

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. Ref.7 Ref.14

Subcellular location

Cytoplasm. Nucleus Ref.4.

Tissue specificity

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. Ref.5

Domain

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.

The D domain (residues 35-50) contains a conserved docking site and is required for the binding to MAPk substrates.

Post-translational modification

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

Disruption phenotype

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. Ref.9 Ref.10

Sequence similarities

Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase subfamily.

Contains 1 protein kinase domain.

Ontologies

Keywords
   Biological processApoptosis
Stress response
   Cellular componentCytoplasm
Nucleus
   LigandATP-binding
Nucleotide-binding
   Molecular functionKinase
Serine/threonine-protein kinase
Transferase
Tyrosine-protein kinase
   PTMAcetylation
Phosphoprotein
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processJNK cascade

Inferred from sequence orthology PubMed 17681137. Source: MGI

MAPK cascade

Inferred from physical interaction PubMed 12556533. Source: MGI

activation of JUN kinase activity

Inferred from sequence orthology PubMed 17681137. Source: MGI

apoptotic process

Inferred from electronic annotation. Source: UniProtKB-KW

cellular response to mechanical stimulus

Inferred from electronic annotation. Source: Ensembl

cellular response to sorbitol

Inferred from electronic annotation. Source: Ensembl

positive regulation of DNA replication

Inferred from electronic annotation. Source: Ensembl

positive regulation of neuron apoptotic process

Inferred from electronic annotation. Source: Ensembl

   Cellular_componentcytosol

Traceable author statement. Source: Reactome

dendrite cytoplasm

Inferred from electronic annotation. Source: Ensembl

nucleus

Inferred from electronic annotation. Source: UniProtKB-SubCell

perikaryon

Inferred from electronic annotation. Source: Ensembl

   Molecular_functionATP binding

Inferred from electronic annotation. Source: UniProtKB-KW

JUN kinase kinase activity

Inferred from electronic annotation. Source: Ensembl

protein binding

Inferred from physical interaction PubMed 10523642. Source: BHF-UCL

protein serine/threonine kinase activity

Inferred from electronic annotation. Source: UniProtKB-KW

protein tyrosine kinase activity

Inferred from electronic annotation. Source: UniProtKB-KW

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Initiator methionine11Removed By similarity
Chain2 – 397396Dual specificity mitogen-activated protein kinase kinase 4
PRO_0000086382

Regions

Domain100 – 366267Protein kinase
Nucleotide binding106 – 1149ATP By similarity
Region35 – 5016D domain By similarity
Region362 – 38524DVD domain By similarity
Compositional bias5 – 1713Gly/Ser-rich

Sites

Active site2271Proton acceptor By similarity
Binding site1291ATP

Amino acid modifications

Modified residue21N-acetylalanine By similarity
Modified residue881Phosphoserine By similarity
Modified residue2551Phosphoserine; by MAP3K By similarity
Modified residue2591Phosphothreonine; by MAP3K By similarity

Experimental info

Mutagenesis1291K → R: Loss of ATP-binding. Ref.1

Sequences

Sequence LengthMass (Da)Tools
P47809 [UniParc].

Last modified November 1, 1997. Version 2.
Checksum: B99C6688184E5B3D

FASTA39744,114
        10         20         30         40         50         60 
MAAPSPSGGG GSGGGGGTPG PIGPPASGHP AVSSMQGKRK ALKLNFANPP VKSTARFTLN 

        70         80         90        100        110        120 
PNTTGVQNPH IERLRTHSIE SSGKLKISPE QHWDFTAEDL KDLGEIGRGA YGSVNKMVHK 

       130        140        150        160        170        180 
PSGQIMAVKR IRSTVDEKEQ KQLLMDLDVV MRSSDCPYIV QFYGALFREG DCWICMELMS 

       190        200        210        220        230        240 
TSFDKFYKYV YSVLDDVIPE EILGKITLAT VKALNHLKEN LKIIHRDIKP SNILLDRSGN 

       250        260        270        280        290        300 
IKLCDFGISG QLVDSIAKTR DAGCRPYMAP ERIDPSASRQ GYDVRSDVWS LGITLYELAT 

       310        320        330        340        350        360 
GRFPYPKWNS VFDQLTQVVK GDPPQLSNSE EREFSPSFIN FVNLCLTKDE SKRPKYKELL 

       370        380        390 
KHPFILMYEE RTVEVACYVC KILDQMPATP SSPMYVD 

« Hide

References

[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.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
U18310 mRNA. Translation: AAB81554.1.
CCDSCCDS24844.1.
PIRS52423.
RefSeqNP_033183.1. NM_009157.4.
UniGeneMm.412922.

3D structure databases

ProteinModelPortalP47809.
SMRP47809. Positions 93-386.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid204952. 7 interactions.
DIPDIP-869N.
IntActP47809. 2 interactions.
MINTMINT-4102306.
STRING10090.ENSMUSP00000041282.

Chemistry

BindingDBP47809.
ChEMBLCHEMBL2201.

PTM databases

PhosphoSiteP47809.

Proteomic databases

MaxQBP47809.
PaxDbP47809.
PRIDEP47809.

Protocols and materials databases

DNASU26398.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000046963; ENSMUSP00000041282; ENSMUSG00000033352.
GeneID26398.
KEGGmmu:26398.
UCSCuc007jlb.1. mouse.

Organism-specific databases

CTD6416.
MGIMGI:1346869. Map2k4.

Phylogenomic databases

eggNOGCOG0515.
HOGENOMHOG000234206.
HOVERGENHBG108518.
InParanoidP47809.
KOK04430.
OMAVMKSNDC.
OrthoDBEOG7J9VPW.
PhylomeDBP47809.
TreeFamTF350701.

Enzyme and pathway databases

BRENDA2.7.12.2. 3474.

Gene expression databases

ArrayExpressP47809.
BgeeP47809.
CleanExMM_MAP2K4.
GenevestigatorP47809.

Family and domain databases

InterProIPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR002290. Ser/Thr_dual-sp_kinase_dom.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamPF00069. Pkinase. 1 hit.
[Graphical view]
SMARTSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMSSF56112. SSF56112. 1 hit.
PROSITEPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

NextBio304351.
PROP47809.
SOURCESearch...

Entry information

Entry nameMP2K4_MOUSE
AccessionPrimary (citable) accession number: P47809
Entry history
Integrated into UniProtKB/Swiss-Prot: February 1, 1996
Last sequence update: November 1, 1997
Last modified: July 9, 2014
This is version 122 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

Human and mouse protein kinases

Human and mouse protein kinases: classification and index

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot