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O08648 (M3K4_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 126. 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·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Mitogen-activated protein kinase kinase kinase 4

EC=2.7.11.25
Alternative name(s):
MAPK/ERK kinase kinase 4
Short name=MEK kinase 4
Short name=MEKK 4
Gene names
Name:Map3k4
Synonyms:Mekk4
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

Sequence length1597 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Component of a protein kinase signal transduction cascade. Activates the CSBP2, P38 and JNK MAPK pathways, but not the ERK pathway. Specifically phosphorylates and activates MAP2K4 and MAP2K6. Ref.1 Ref.5

Catalytic activity

ATP + a protein = ADP + a phosphoprotein.

Cofactor

Magnesium.

Enzyme regulation

N-terminal autoinhibitory domain interacts with the C-terminal kinase domain, inhibiting kinase activity, and preventing interaction with its substrate, MAP2K6. The GADD45 proteins activate the kinase by binding to the N-terminal domain. Activated by phosphorylation on Thr-1494 By similarity.

Subunit structure

Monomer and homodimer. Homodimerization enhances kinase activity. Interacts with TRAF4; this promotes homodimerization. Binds both upstream activators and downstream substrates in multimolecular complexes. Interacts with AXIN1 and DIXDC1; interaction with DIXDC1 prevents interaction with AXIN1. Ref.1 Ref.4 Ref.5

Subcellular location

Cytoplasmperinuclear region. Note: Localized in perinuclear vesicular-like structures, probably Golgi-associated vesicles. Ref.5

Tissue specificity

Widely expressed. High expression was found in skeletal muscle, kidney, testis followed by heart brain and lung. Low expression was found in spleen.

Sequence similarities

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

Contains 1 protein kinase domain.

Ontologies

Keywords
   Cellular componentCytoplasm
   Coding sequence diversityAlternative splicing
   LigandATP-binding
Magnesium
Metal-binding
Nucleotide-binding
   Molecular functionKinase
Serine/threonine-protein kinase
Transferase
   PTMPhosphoprotein
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processchorionic trophoblast cell differentiation

Inferred from mutant phenotype PubMed 19289495. Source: MGI

determination of dorsal identity

Inferred from sequence orthology PubMed 17681137. Source: MGI

intracellular signal transduction

Inferred from direct assay Ref.5. Source: UniProtKB

male germ-line sex determination

Inferred from mutant phenotype PubMed 6855886. Source: MGI

placenta development

Inferred from mutant phenotype PubMed 19289495. Source: MGI

positive regulation of JUN kinase activity

Inferred from direct assay Ref.5. Source: UniProtKB

positive regulation of p38MAPK cascade

Inferred from electronic annotation. Source: Ensembl

regulation of gene expression

Inferred from mutant phenotype PubMed 19289495. Source: MGI

response to UV-C

Inferred from electronic annotation. Source: Ensembl

   Cellular_componentcytoplasm

Inferred from direct assay Ref.5. Source: UniProtKB

perinuclear region of cytoplasm

Inferred from electronic annotation. Source: UniProtKB-SubCell

   Molecular_functionATP binding

Inferred from electronic annotation. Source: UniProtKB-KW

MAP kinase kinase kinase activity

Inferred from electronic annotation. Source: UniProtKB-EC

metal ion binding

Inferred from electronic annotation. Source: UniProtKB-KW

protein binding

Inferred from physical interaction Ref.5. Source: UniProtKB

protein kinase activity

Inferred from direct assay Ref.5. Source: UniProtKB

Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]
Isoform A (identifier: O08648-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
Isoform B (identifier: O08648-2)

The sequence of this isoform differs from the canonical sequence as follows:
     1162-1213: Missing.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 15971597Mitogen-activated protein kinase kinase kinase 4
PRO_0000086248

Regions

Domain1332 – 1590259Protein kinase
Nucleotide binding1338 – 13469ATP By similarity
Compositional bias1178 – 11825Poly-Ala

Sites

Active site14521Proton acceptor By similarity
Binding site13611ATP

Amino acid modifications

Modified residue4491Phosphoserine By similarity
Modified residue4511Phosphothreonine By similarity
Modified residue4541Phosphoserine By similarity
Modified residue4921Phosphoserine Ref.6

Natural variations

Alternative sequence1162 – 121352Missing in isoform B.
VSP_004885

Experimental info

Mutagenesis13611K → A or R: Loss of kinase activity. Ref.1 Ref.5
Sequence conflict363 – 3642SL → NS in AAC08286. Ref.3
Sequence conflict4731A → T in AAC53126. Ref.1
Sequence conflict4731A → T in AAC53127. Ref.1
Sequence conflict11841A → R in AAC53126. Ref.1

Sequences

Sequence LengthMass (Da)Tools
Isoform A [UniParc].

Last modified July 27, 2011. Version 2.
Checksum: E9C43EB9A4F056BC

FASTA1,597179,834
        10         20         30         40         50         60 
MRDAIAEPVP PPALADTPAA AMEELRPAPP PQPEPDPECC PAARQECMLG ESARKSMESD 

        70         80         90        100        110        120 
PEDFSDETNT ETLYGTSPPS TPRQMKRLSA KHQRNSAGRP ASRSNLKEKM NTPSQSPHKD 

       130        140        150        160        170        180 
LGKGVETVEE YSYKQEKKIR ATLRTTERDH KKNAQCSFML DSVAGSLPKK SIPDVDLNKP 

       190        200        210        220        230        240 
YLSLGCSNAK LPVSMPMPIA RTARQTSRTD CPADRLKFFE TLRLLLKLTS VSKKKDREQR 

       250        260        270        280        290        300 
GQENTAAFWF NRSNELIWLE LQAWHAGRTI NDQDLFLYTA RQAIPDIINE ILTFKVNYGS 

       310        320        330        340        350        360 
IAFSSNGAGF NGPLVEGQCR TPQETNRVGC SSYHEHLQRQ RVSFEQVKRI MELLEYMEAL 

       370        380        390        400        410        420 
YPSLQALQKD YERYAAKDFE DRVQALCLWL NITKDLNQKL RIMGTVLGIK NLSDIGWPVF 

       430        440        450        460        470        480 
EIPSPRPSKG YEPEDEVEDT EVELRELESG TEESDEEPTP SPRVPELRLS TDAILDSRSQ 

       490        500        510        520        530        540 
GCVSRKLERL ESEEDSIGWG TADCGPEASR HCLTSIYRPF VDKALKQMGL RKLILRLHKL 

       550        560        570        580        590        600 
MNGSLQRARV ALVKDDRPVE FSDFPGPMWG SDYVQLSGTP PSSEQKCSAV SWEELRAMDL 

       610        620        630        640        650        660 
PSFEPAFLVL CRVLLNVIHE CLKLRLEQRP AGEPSLLSIK QLVRECKEVL KGGLLMKQYY 

       670        680        690        700        710        720 
QFMLQEVLGG LEKTDCNMDA FEEDLQKMLM VYFDYMRSWI QMLQQLPQAS HSLKNLLEEE 

       730        740        750        760        770        780 
WNFTKEITHY IRGGEAQAGK LFCDIAGMLL KSTGSFLESG LQESCAELWT SADDNGAADE 

       790        800        810        820        830        840 
LRRSVIEISR ALKELFHEAR ERASKALGFA KMLRKDLEIA AEFVLSASAR ELLDALKAKQ 

       850        860        870        880        890        900 
YVKVQIPGLE NLHVFVPDSL AEEKKIILQL LNAATGKDCS KDPDDVFMDA FLLLTKHGDR 

       910        920        930        940        950        960 
ARDSEDGWGT WEARAVKIVP QVETVDTLRS MQVDNLLLVV MESAHLVLQR KAFQQSIEGL 

       970        980        990       1000       1010       1020 
MTVRHEQTSS QPIIAKGLQQ LKNDALELCN RISDAIDRVD HMFTLEFDAE VEESESATLQ 

      1030       1040       1050       1060       1070       1080 
QYYREAMIQG YNFGFEYHKE VVRLMSGEFR QKIGDKYISF AQKWMNYVLT KCESGRGTRP 

      1090       1100       1110       1120       1130       1140 
RWATQGFDFL QAIEPAFISA LPEDDFLSLQ ALMNECIGHV IGKPHSPVTA IHRNSPRPVK 

      1150       1160       1170       1180       1190       1200 
VPRCHSDPPN PHLIIPTPEG FSTRSVPSDA RTHGNSVAAA AAVAAAATTA AGRPGPGGGD 

      1210       1220       1230       1240       1250       1260 
SVPAKPVNTA PDTRGSSVPE NDRLASIAAE LQFRSLSRHS SPTEERDEPA YPRSDSSGST 

      1270       1280       1290       1300       1310       1320 
RRSWELRTLI SQTKDSASKQ GPIEAIQKSV RLFEERRYRE MRRKNIIGQV CDTPKSYDNV 

      1330       1340       1350       1360       1370       1380 
MHVGLRKVTF KWQRGNKIGE GQYGKVYTCI SVDTGELMAM KEIRFQPNDH KTIKETADEL 

      1390       1400       1410       1420       1430       1440 
KIFEGIKHPN LVRYFGVELH REEMYIFMEY CDEGTLEEVS RLGLQEHVIR LYTKQITVAI 

      1450       1460       1470       1480       1490       1500 
NVLHEHGIVH RDIKGANIFL TSSGLIKLGD FGCSVKLKNN AQTMPGEVNS TLGTAAYMAP 

      1510       1520       1530       1540       1550       1560 
EVITRAKGEG HGRAADIWSL GCVVIEMVTG KRPWHEYEHN FQIMYKVGMG HKPPIPERLS 

      1570       1580       1590 
PEGKAFLSHC LESDPKIRWT ASQLLDHAFV KVCTDEE 

« Hide

Isoform B [UniParc].

Checksum: 9D5EA5911CC54998
Show »

FASTA1,545175,069

References

« Hide 'large scale' references
[1]"Cloning of a novel mitogen-activated protein kinase kinase kinase, MEKK4, that selectively regulates the c-Jun amino terminal kinase pathway."
Gerwins P., Blank J.L., Johnson G.L.
J. Biol. Chem. 272:8288-8295(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS A AND B), FUNCTION, INTERACTION WITH CDC42, MUTAGENESIS OF LYS-1361.
Tissue: Brain.
[2]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM A).
Strain: C57BL/6.
Tissue: Brain.
[3]"Characterization of the C3 YAC contig from proximal mouse chromosome 17 and analysis of allelic expression of genes flanking the imprinted Igf2r gene."
Schweifer N., Valk P.J., Delwel R., Cox R., Francis F., Meier-Ewert S., Lehrach H., Barlow D.P.
Genomics 43:285-297(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 363-1049.
Strain: C57BL/6.
Tissue: Ectoplacental cone.
[4]"The DIX domain protein coiled-coil-DIX1 inhibits c-Jun N-terminal kinase activation by Axin and dishevelled through distinct mechanisms."
Wong C.K., Luo W., Deng Y., Zou H., Ye Z., Lin S.-C.
J. Biol. Chem. 279:39366-39373(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH AXIN1 AND DIXDC1.
[5]"MEKK4 is an effector of the embryonic TRAF4 for JNK activation."
Abell A.N., Johnson G.L.
J. Biol. Chem. 280:35793-35796(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, SUBCELLULAR LOCATION, MUTAGENESIS OF LYS-1361, INTERACTION WITH TRAF4.
[6]"Large-scale phosphorylation analysis of mouse liver."
Villen J., Beausoleil S.A., Gerber S.A., Gygi S.P.
Proc. Natl. Acad. Sci. U.S.A. 104:1488-1493(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-492, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Liver.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
U85607 mRNA. Translation: AAC53126.1.
U85608 mRNA. Translation: AAC53127.1.
BC058719 mRNA. Translation: AAH58719.1.
U66240 mRNA. Translation: AAC08286.1.
CCDSCCDS37435.1. [O08648-1]
RefSeqNP_036078.2. NM_011948.2. [O08648-1]
XP_006523392.1. XM_006523329.1. [O08648-2]
UniGeneMm.28587.

3D structure databases

ProteinModelPortalO08648.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid204960. 2 interactions.
STRING10090.ENSMUSP00000086459.

PTM databases

PhosphoSiteO08648.

Proteomic databases

MaxQBO08648.
PaxDbO08648.
PRIDEO08648.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000089058; ENSMUSP00000086459; ENSMUSG00000014426. [O08648-1]
GeneID26407.
KEGGmmu:26407.
UCSCuc008akn.1. mouse. [O08648-1]
uc008ako.1. mouse. [O08648-2]

Organism-specific databases

CTD4216.
MGIMGI:1346875. Map3k4.

Phylogenomic databases

eggNOGCOG0515.
GeneTreeENSGT00590000083157.
HOGENOMHOG000139909.
HOVERGENHBG006304.
InParanoidQ6PDG6.
KOK04428.
OMAFVKVCTD.
OrthoDBEOG7P5T02.
TreeFamTF105114.

Enzyme and pathway databases

BRENDA2.7.11.25. 3474.

Gene expression databases

ArrayExpressO08648.
BgeeO08648.
CleanExMM_MAP3K4.
GenevestigatorO08648.

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

ChiTaRSMAP3K4. mouse.
NextBio304385.
PROO08648.
SOURCESearch...

Entry information

Entry nameM3K4_MOUSE
AccessionPrimary (citable) accession number: O08648
Secondary accession number(s): O08649, O70124, Q6PDG6
Entry history
Integrated into UniProtKB/Swiss-Prot: May 30, 2000
Last sequence update: July 27, 2011
Last modified: July 9, 2014
This is version 126 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