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O08648

- M3K4_MOUSE

UniProt

O08648 - M3K4_MOUSE

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Protein

Mitogen-activated protein kinase kinase kinase 4

Gene

Map3k4

Organism
Mus musculus (Mouse)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli

Functioni

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 MAP2K6.2 Publications

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.

Cofactori

Enzyme regulationi

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).By similarity

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Binding sitei1361 – 13611ATP
Active sitei1452 – 14521Proton acceptorPROSITE-ProRule annotation

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Nucleotide bindingi1338 – 13469ATPPROSITE-ProRule annotation

GO - Molecular functioni

  1. ATP binding Source: UniProtKB-KW
  2. MAP kinase kinase kinase activity Source: UniProtKB-EC
  3. metal ion binding Source: UniProtKB-KW
  4. protein kinase activity Source: UniProtKB

GO - Biological processi

  1. chorionic trophoblast cell differentiation Source: MGI
  2. determination of dorsal identity Source: MGI
  3. intracellular signal transduction Source: UniProtKB
  4. male germ-line sex determination Source: MGI
  5. placenta development Source: MGI
  6. positive regulation of JUN kinase activity Source: UniProtKB
  7. positive regulation of p38MAPK cascade Source: Ensembl
  8. regulation of gene expression Source: MGI
  9. response to UV-C Source: Ensembl
Complete GO annotation...

Keywords - Molecular functioni

Kinase, Serine/threonine-protein kinase, Transferase

Keywords - Ligandi

ATP-binding, Magnesium, Metal-binding, Nucleotide-binding

Enzyme and pathway databases

BRENDAi2.7.11.25. 3474.

Names & Taxonomyi

Protein namesi
Recommended 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 namesi
Name:Map3k4
Synonyms:Mekk4
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
ProteomesiUP000000589: Chromosome 17

Organism-specific databases

MGIiMGI:1346875. Map3k4.

Subcellular locationi

Cytoplasmperinuclear region 1 Publication
Note: Localized in perinuclear vesicular-like structures, probably Golgi-associated vesicles.

GO - Cellular componenti

  1. cytoplasm Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi1361 – 13611K → A or R: Loss of kinase activity. 2 Publications

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 15971597Mitogen-activated protein kinase kinase kinase 4PRO_0000086248Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei449 – 4491PhosphoserineBy similarity
Modified residuei451 – 4511PhosphothreonineBy similarity
Modified residuei454 – 4541PhosphoserineBy similarity
Modified residuei492 – 4921Phosphoserine1 Publication

Keywords - PTMi

Phosphoprotein

Proteomic databases

MaxQBiO08648.
PaxDbiO08648.
PRIDEiO08648.

PTM databases

PhosphoSiteiO08648.

Expressioni

Tissue specificityi

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

Gene expression databases

BgeeiO08648.
CleanExiMM_MAP3K4.
ExpressionAtlasiO08648. baseline and differential.
GenevestigatoriO08648.

Interactioni

Subunit structurei

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 AXIN1.3 Publications

Protein-protein interaction databases

BioGridi204960. 2 interactions.
STRINGi10090.ENSMUSP00000086459.

Structurei

3D structure databases

ProteinModelPortaliO08648.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini1332 – 1590259Protein kinasePROSITE-ProRule annotationAdd
BLAST

Compositional bias

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Compositional biasi1178 – 11825Poly-Ala

Sequence similaritiesi

Contains 1 protein kinase domain.PROSITE-ProRule annotation

Phylogenomic databases

eggNOGiCOG0515.
GeneTreeiENSGT00590000083157.
HOGENOMiHOG000139909.
HOVERGENiHBG006304.
InParanoidiO08648.
KOiK04428.
OMAiFVKVCTD.
OrthoDBiEOG7P5T02.
TreeFamiTF105114.

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]

Sequences (2)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing. Align

Isoform A (identifier: O08648-1) [UniParc]FASTAAdd to Basket

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.

« Hide

        10         20         30         40         50
MRDAIAEPVP PPALADTPAA AMEELRPAPP PQPEPDPECC PAARQECMLG
60 70 80 90 100
ESARKSMESD PEDFSDETNT ETLYGTSPPS TPRQMKRLSA KHQRNSAGRP
110 120 130 140 150
ASRSNLKEKM NTPSQSPHKD LGKGVETVEE YSYKQEKKIR ATLRTTERDH
160 170 180 190 200
KKNAQCSFML DSVAGSLPKK SIPDVDLNKP YLSLGCSNAK LPVSMPMPIA
210 220 230 240 250
RTARQTSRTD CPADRLKFFE TLRLLLKLTS VSKKKDREQR GQENTAAFWF
260 270 280 290 300
NRSNELIWLE LQAWHAGRTI NDQDLFLYTA RQAIPDIINE ILTFKVNYGS
310 320 330 340 350
IAFSSNGAGF NGPLVEGQCR TPQETNRVGC SSYHEHLQRQ RVSFEQVKRI
360 370 380 390 400
MELLEYMEAL YPSLQALQKD YERYAAKDFE DRVQALCLWL NITKDLNQKL
410 420 430 440 450
RIMGTVLGIK NLSDIGWPVF EIPSPRPSKG YEPEDEVEDT EVELRELESG
460 470 480 490 500
TEESDEEPTP SPRVPELRLS TDAILDSRSQ GCVSRKLERL ESEEDSIGWG
510 520 530 540 550
TADCGPEASR HCLTSIYRPF VDKALKQMGL RKLILRLHKL MNGSLQRARV
560 570 580 590 600
ALVKDDRPVE FSDFPGPMWG SDYVQLSGTP PSSEQKCSAV SWEELRAMDL
610 620 630 640 650
PSFEPAFLVL CRVLLNVIHE CLKLRLEQRP AGEPSLLSIK QLVRECKEVL
660 670 680 690 700
KGGLLMKQYY QFMLQEVLGG LEKTDCNMDA FEEDLQKMLM VYFDYMRSWI
710 720 730 740 750
QMLQQLPQAS HSLKNLLEEE WNFTKEITHY IRGGEAQAGK LFCDIAGMLL
760 770 780 790 800
KSTGSFLESG LQESCAELWT SADDNGAADE LRRSVIEISR ALKELFHEAR
810 820 830 840 850
ERASKALGFA KMLRKDLEIA AEFVLSASAR ELLDALKAKQ YVKVQIPGLE
860 870 880 890 900
NLHVFVPDSL AEEKKIILQL LNAATGKDCS KDPDDVFMDA FLLLTKHGDR
910 920 930 940 950
ARDSEDGWGT WEARAVKIVP QVETVDTLRS MQVDNLLLVV MESAHLVLQR
960 970 980 990 1000
KAFQQSIEGL MTVRHEQTSS QPIIAKGLQQ LKNDALELCN RISDAIDRVD
1010 1020 1030 1040 1050
HMFTLEFDAE VEESESATLQ QYYREAMIQG YNFGFEYHKE VVRLMSGEFR
1060 1070 1080 1090 1100
QKIGDKYISF AQKWMNYVLT KCESGRGTRP RWATQGFDFL QAIEPAFISA
1110 1120 1130 1140 1150
LPEDDFLSLQ ALMNECIGHV IGKPHSPVTA IHRNSPRPVK VPRCHSDPPN
1160 1170 1180 1190 1200
PHLIIPTPEG FSTRSVPSDA RTHGNSVAAA AAVAAAATTA AGRPGPGGGD
1210 1220 1230 1240 1250
SVPAKPVNTA PDTRGSSVPE NDRLASIAAE LQFRSLSRHS SPTEERDEPA
1260 1270 1280 1290 1300
YPRSDSSGST RRSWELRTLI SQTKDSASKQ GPIEAIQKSV RLFEERRYRE
1310 1320 1330 1340 1350
MRRKNIIGQV CDTPKSYDNV MHVGLRKVTF KWQRGNKIGE GQYGKVYTCI
1360 1370 1380 1390 1400
SVDTGELMAM KEIRFQPNDH KTIKETADEL KIFEGIKHPN LVRYFGVELH
1410 1420 1430 1440 1450
REEMYIFMEY CDEGTLEEVS RLGLQEHVIR LYTKQITVAI NVLHEHGIVH
1460 1470 1480 1490 1500
RDIKGANIFL TSSGLIKLGD FGCSVKLKNN AQTMPGEVNS TLGTAAYMAP
1510 1520 1530 1540 1550
EVITRAKGEG HGRAADIWSL GCVVIEMVTG KRPWHEYEHN FQIMYKVGMG
1560 1570 1580 1590
HKPPIPERLS PEGKAFLSHC LESDPKIRWT ASQLLDHAFV KVCTDEE
Length:1,597
Mass (Da):179,834
Last modified:July 27, 2011 - v2
Checksum:iE9C43EB9A4F056BC
GO
Isoform B (identifier: O08648-2) [UniParc]FASTAAdd to Basket

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

Show »
Length:1,545
Mass (Da):175,069
Checksum:i9D5EA5911CC54998
GO

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti363 – 3642SL → NS in AAC08286. (PubMed:9268631)Curated
Sequence conflicti473 – 4731A → T in AAC53126. (PubMed:9079650)Curated
Sequence conflicti473 – 4731A → T in AAC53127. (PubMed:9079650)Curated
Sequence conflicti1184 – 11841A → R in AAC53126. (PubMed:9079650)Curated

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei1162 – 121352Missing in isoform B. 1 PublicationVSP_004885Add
BLAST

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U85607 mRNA. Translation: AAC53126.1.
U85608 mRNA. Translation: AAC53127.1.
BC058719 mRNA. Translation: AAH58719.1.
U66240 mRNA. Translation: AAC08286.1.
CCDSiCCDS37435.1. [O08648-1]
RefSeqiNP_036078.2. NM_011948.2. [O08648-1]
XP_006523392.1. XM_006523329.1. [O08648-2]
UniGeneiMm.28587.

Genome annotation databases

EnsembliENSMUST00000089058; ENSMUSP00000086459; ENSMUSG00000014426. [O08648-1]
GeneIDi26407.
KEGGimmu:26407.
UCSCiuc008akn.1. mouse. [O08648-1]
uc008ako.1. mouse. [O08648-2]

Keywords - Coding sequence diversityi

Alternative splicing

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U85607 mRNA. Translation: AAC53126.1 .
U85608 mRNA. Translation: AAC53127.1 .
BC058719 mRNA. Translation: AAH58719.1 .
U66240 mRNA. Translation: AAC08286.1 .
CCDSi CCDS37435.1. [O08648-1 ]
RefSeqi NP_036078.2. NM_011948.2. [O08648-1 ]
XP_006523392.1. XM_006523329.1. [O08648-2 ]
UniGenei Mm.28587.

3D structure databases

ProteinModelPortali O08648.
ModBasei Search...
MobiDBi Search...

Protein-protein interaction databases

BioGridi 204960. 2 interactions.
STRINGi 10090.ENSMUSP00000086459.

PTM databases

PhosphoSitei O08648.

Proteomic databases

MaxQBi O08648.
PaxDbi O08648.
PRIDEi O08648.

Protocols and materials databases

Structural Biology Knowledgebase Search...

Genome annotation databases

Ensembli ENSMUST00000089058 ; ENSMUSP00000086459 ; ENSMUSG00000014426 . [O08648-1 ]
GeneIDi 26407.
KEGGi mmu:26407.
UCSCi uc008akn.1. mouse. [O08648-1 ]
uc008ako.1. mouse. [O08648-2 ]

Organism-specific databases

CTDi 4216.
MGIi MGI:1346875. Map3k4.

Phylogenomic databases

eggNOGi COG0515.
GeneTreei ENSGT00590000083157.
HOGENOMi HOG000139909.
HOVERGENi HBG006304.
InParanoidi O08648.
KOi K04428.
OMAi FVKVCTD.
OrthoDBi EOG7P5T02.
TreeFami TF105114.

Enzyme and pathway databases

BRENDAi 2.7.11.25. 3474.

Miscellaneous databases

ChiTaRSi Map3k4. mouse.
NextBioi 304385.
PROi O08648.
SOURCEi Search...

Gene expression databases

Bgeei O08648.
CleanExi MM_MAP3K4.
ExpressionAtlasi O08648. baseline and differential.
Genevestigatori O08648.

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

« Hide 'large scale' publications
  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. Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-492, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    Tissue: Liver.

Entry informationi

Entry nameiM3K4_MOUSE
AccessioniPrimary (citable) accession number: O08648
Secondary accession number(s): O08649, O70124, Q6PDG6
Entry historyi
Integrated into UniProtKB/Swiss-Prot: May 30, 2000
Last sequence update: July 27, 2011
Last modified: November 26, 2014
This is version 129 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