O08648 (M3K4_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

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 names

Name:	Map3k4
Synonyms:	Mekk4

Organism

Mus musculus (Mouse) [Reference proteome]

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length	1597 AA.
Sequence status	Complete.
Protein existence	Evidence 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	Cytoplasm › perinuclear 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 component	Cytoplasm
Coding sequence diversity	Alternative splicing
Ligand	ATP-binding Magnesium Metal-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Phosphoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	MAPK cascade Inferred from electronic annotation. Source: GOC activation of MAPKK activity Inferred from electronic annotation. Source: GOC chorionic trophoblast cell differentiation Inferred from mutant phenotype PubMed 19289495. Source: MGI determination of dorsal identity Inferred from sequence orthology PubMed 17681137. Source: MGI 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 regulation of gene expression Inferred from mutant phenotype PubMed 19289495. Source: MGI
Cellular_component	cytoplasm Inferred from direct assay Ref.5. Source: UniProtKB perinuclear region of cytoplasm Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW MAP kinase kinase kinase activity Inferred from electronic annotation. Source: EC metal ion binding Inferred from electronic annotation. Source: UniProtKB-KW 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 key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 1597	1597	Mitogen-activated protein kinase kinase kinase 4		PRO_0000086248
Regions
	Domain	1332 – 1590	259	Protein kinase
	Nucleotide binding	1338 – 1346	9	ATP By similarity
	Compositional bias	1178 – 1182	5	Poly-Ala
Sites
	Active site	1452	1	Proton acceptor By similarity
	Binding site	1361	1	ATP
Amino acid modifications
	Modified residue	449	1	Phosphoserine By similarity
	Modified residue	451	1	Phosphothreonine By similarity
	Modified residue	454	1	Phosphoserine By similarity
	Modified residue	492	1	Phosphoserine Ref.6
Natural variations
	Alternative sequence	1162 – 1213	52	Missing in isoform B.		VSP_004885
Experimental info
	Mutagenesis	1361	1	K → A or R: Loss of kinase activity. Ref.1 Ref.5
	Sequence conflict	363 – 364	2	SL → NS in AAC08286. Ref.3
	Sequence conflict	473	1	A → T in AAC53126. Ref.1
	Sequence conflict	473	1	A → T in AAC53127. Ref.1
	Sequence conflict	1184	1	A → R in AAC53126. Ref.1

Sequences

	Sequence		Length	Mass (Da)
	Isoform A [UniParc]. Last modified July 27, 2011. Version 2. Checksum: E9C43EB9A4F056BC	FASTA	1,597	179,834
	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
	Isoform B [UniParc]. Checksum: 9D5EA5911CC54998	FASTA	1,545	175,069
	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 FRGSSVPEND RLASIAAELQ FRSLSRHSSP TEERDEPAYP 1210 1220 1230 1240 1250 1260 RSDSSGSTRR SWELRTLISQ TKDSASKQGP IEAIQKSVRL FEERRYREMR RKNIIGQVCD 1270 1280 1290 1300 1310 1320 TPKSYDNVMH VGLRKVTFKW QRGNKIGEGQ YGKVYTCISV DTGELMAMKE IRFQPNDHKT 1330 1340 1350 1360 1370 1380 IKETADELKI FEGIKHPNLV RYFGVELHRE EMYIFMEYCD EGTLEEVSRL GLQEHVIRLY 1390 1400 1410 1420 1430 1440 TKQITVAINV LHEHGIVHRD IKGANIFLTS SGLIKLGDFG CSVKLKNNAQ TMPGEVNSTL 1450 1460 1470 1480 1490 1500 GTAAYMAPEV ITRAKGEGHG RAADIWSLGC VVIEMVTGKR PWHEYEHNFQ IMYKVGMGHK 1510 1520 1530 1540 PPIPERLSPE GKAFLSHCLE SDPKIRWTAS QLLDHAFVKV CTDEE

References

	« Hide 'large scale' referencesShow '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, MASS SPECTROMETRY. 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.
IPI	IPI00623304. IPI00875136.
RefSeq	NP_036078.2. NM_011948.2.
UniGene	Mm.28587.
3D structure databases
ProteinModelPortal	O08648.
ModBase	Search...
Protein-protein interaction databases
STRING	10090.ENSMUSP00000086459.
PTM databases
PhosphoSite	O08648.
Proteomic databases
PaxDb	O08648.
PRIDE	O08648.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSMUST00000089058; ENSMUSP00000086459; ENSMUSG00000014426.
GeneID	26407.
KEGG	mmu:26407.
UCSC	uc008ako.1. mouse.
Organism-specific databases
CTD	4216.
MGI	MGI:1346875. Map3k4.
Phylogenomic databases
eggNOG	COG0515.
GeneTree	ENSGT00590000083157.
HOGENOM	HOG000139909.
HOVERGEN	HBG006304.
InParanoid	Q6PDG6.
KO	K04428.
OMA	SDPPNPH.
OrthoDB	EOG46MBHQ.
Enzyme and pathway databases
BRENDA	2.7.11.25. 3474.
Gene expression databases
ArrayExpress	O08648.
Bgee	O08648.
CleanEx	MM_MAP3K4.
Genevestigator	O08648.
GermOnline	ENSMUSG00000014426. Mus musculus.
Family and domain databases
InterPro	IPR011009. Kinase-like_dom. IPR000719. Prot_kinase_cat_dom. IPR017441. Protein_kinase_ATP_BS. IPR002290. Ser/Thr_dual-sp_kinase_dom. IPR008271. Ser/Thr_kinase_AS. [Graphical view]
Pfam	PF00069. Pkinase. 1 hit. [Graphical view]
SMART	SM00220. S_TKc. 1 hit. [Graphical view]
SUPFAM	SSF56112. Kinase_like. 1 hit.
PROSITE	PS00107. PROTEIN_KINASE_ATP. 1 hit. PS50011. PROTEIN_KINASE_DOM. 1 hit. PS00108. PROTEIN_KINASE_ST. 1 hit. [Graphical view]
ProtoNet	Search...
Other
ChiTaRS	MAP3K4. mouse.
NextBio	304385.
SOURCE	Search...

Entry information

Entry name

M3K4_MOUSE

Accession

Primary (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:	April 3, 2013
This is version 114 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program