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M3K4_MOUSE
ID   M3K4_MOUSE              Reviewed;        1597 AA.
AC   O08648; O08649; O70124; Q6PDG6;
DT   30-MAY-2000, integrated into UniProtKB/Swiss-Prot.
DT   27-JUL-2011, sequence version 2.
DT   03-AUG-2022, entry version 176.
DE   RecName: Full=Mitogen-activated protein kinase kinase kinase 4;
DE            EC=2.7.11.25;
DE   AltName: Full=MAPK/ERK kinase kinase 4;
DE            Short=MEK kinase 4;
DE            Short=MEKK 4;
GN   Name=Map3k4; Synonyms=Mekk4;
OS   Mus musculus (Mouse).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC   Murinae; Mus; Mus.
OX   NCBI_TaxID=10090;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS A AND B), FUNCTION, INTERACTION WITH
RP   CDC42, AND MUTAGENESIS OF LYS-1361.
RC   TISSUE=Brain;
RX   PubMed=9079650; DOI=10.1074/jbc.272.13.8288;
RA   Gerwins P., Blank J.L., Johnson G.L.;
RT   "Cloning of a novel mitogen-activated protein kinase kinase kinase, MEKK4,
RT   that selectively regulates the c-Jun amino terminal kinase pathway.";
RL   J. Biol. Chem. 272:8288-8295(1997).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM A).
RC   STRAIN=C57BL/6J; TISSUE=Brain;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [MRNA] OF 363-1049.
RC   STRAIN=C57BL/6J; TISSUE=Ectoplacental cone;
RX   PubMed=9268631; DOI=10.1006/geno.1997.4816;
RA   Schweifer N., Valk P.J., Delwel R., Cox R., Francis F., Meier-Ewert S.,
RA   Lehrach H., Barlow D.P.;
RT   "Characterization of the C3 YAC contig from proximal mouse chromosome 17
RT   and analysis of allelic expression of genes flanking the imprinted Igf2r
RT   gene.";
RL   Genomics 43:285-297(1997).
RN   [4]
RP   INTERACTION WITH AXIN1 AND DIXDC1.
RX   PubMed=15262978; DOI=10.1074/jbc.m404598200;
RA   Wong C.K., Luo W., Deng Y., Zou H., Ye Z., Lin S.-C.;
RT   "The DIX domain protein coiled-coil-DIX1 inhibits c-Jun N-terminal kinase
RT   activation by Axin and dishevelled through distinct mechanisms.";
RL   J. Biol. Chem. 279:39366-39373(2004).
RN   [5]
RP   FUNCTION, SUBCELLULAR LOCATION, MUTAGENESIS OF LYS-1361, AND INTERACTION
RP   WITH TRAF4.
RX   PubMed=16157600; DOI=10.1074/jbc.c500260200;
RA   Abell A.N., Johnson G.L.;
RT   "MEKK4 is an effector of the embryonic TRAF4 for JNK activation.";
RL   J. Biol. Chem. 280:35793-35796(2005).
RN   [6]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-492, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Liver;
RX   PubMed=17242355; DOI=10.1073/pnas.0609836104;
RA   Villen J., Beausoleil S.A., Gerber S.A., Gygi S.P.;
RT   "Large-scale phosphorylation analysis of mouse liver.";
RL   Proc. Natl. Acad. Sci. U.S.A. 104:1488-1493(2007).
RN   [7]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-77; SER-449; THR-451; SER-454
RP   AND SER-492, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE
RP   ANALYSIS].
RC   TISSUE=Brain, Heart, Kidney, Liver, Lung, Pancreas, Spleen, and Testis;
RX   PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA   Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA   Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT   "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL   Cell 143:1174-1189(2010).
CC   -!- FUNCTION: Component of a protein kinase signal transduction cascade.
CC       Activates the CSBP2, P38 and JNK MAPK pathways, but not the ERK
CC       pathway. Specifically phosphorylates and activates MAP2K4 and MAP2K6.
CC       {ECO:0000269|PubMed:16157600, ECO:0000269|PubMed:9079650}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-
CC         [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA-
CC         COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616,
CC         ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.25;
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-
CC         threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060,
CC         Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013,
CC         ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216;
CC         EC=2.7.11.25;
CC   -!- COFACTOR:
CC       Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC   -!- ACTIVITY REGULATION: N-terminal autoinhibitory domain interacts with
CC       the C-terminal kinase domain, inhibiting kinase activity, and
CC       preventing interaction with its substrate, MAP2K6. The GADD45 proteins
CC       activate the kinase by binding to the N-terminal domain. Activated by
CC       phosphorylation on Thr-1494 (By similarity). {ECO:0000250}.
CC   -!- SUBUNIT: Monomer and homodimer. Homodimerization enhances kinase
CC       activity. Interacts with CDC42 (PubMed:9079650). Interacts with TRAF4;
CC       this promotes homodimerization (PubMed:16157600). Binds both upstream
CC       activators and downstream substrates in multimolecular complexes.
CC       Interacts with AXIN1 and DIXDC1; interaction with DIXDC1 prevents
CC       interaction with AXIN1 (PubMed:15262978). Interacts with GADD45 and
CC       MAP2K6 (By similarity). Interacts with ZFP36; this interaction enhances
CC       the association with SH3KBP1/CIN85. Interacts with SH3KBP1; this
CC       interaction enhances the association with ZFP36 (By similarity).
CC       {ECO:0000250|UniProtKB:Q9Y6R4, ECO:0000269|PubMed:15262978,
CC       ECO:0000269|PubMed:16157600, ECO:0000269|PubMed:9079650}.
CC   -!- SUBCELLULAR LOCATION: Cytoplasm, perinuclear region
CC       {ECO:0000269|PubMed:16157600}. Note=Localized in perinuclear vesicular-
CC       like structures, probably Golgi-associated vesicles.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=2;
CC       Name=A;
CC         IsoId=O08648-1; Sequence=Displayed;
CC       Name=B;
CC         IsoId=O08648-2; Sequence=VSP_004885;
CC   -!- TISSUE SPECIFICITY: Widely expressed. High expression was found in
CC       skeletal muscle, kidney, testis followed by heart brain and lung. Low
CC       expression was found in spleen.
CC   -!- SIMILARITY: Belongs to the protein kinase superfamily. STE Ser/Thr
CC       protein kinase family. MAP kinase kinase kinase subfamily.
CC       {ECO:0000305}.
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DR   EMBL; U85607; AAC53126.1; -; mRNA.
DR   EMBL; U85608; AAC53127.1; -; mRNA.
DR   EMBL; BC058719; AAH58719.1; -; mRNA.
DR   EMBL; U66240; AAC08286.1; -; mRNA.
DR   CCDS; CCDS37435.1; -. [O08648-1]
DR   CCDS; CCDS88991.1; -. [O08648-2]
DR   RefSeq; NP_036078.2; NM_011948.2. [O08648-1]
DR   RefSeq; XP_006523392.1; XM_006523329.3.
DR   AlphaFoldDB; O08648; -.
DR   SMR; O08648; -.
DR   BioGRID; 204960; 10.
DR   CORUM; O08648; -.
DR   STRING; 10090.ENSMUSP00000086459; -.
DR   iPTMnet; O08648; -.
DR   PhosphoSitePlus; O08648; -.
DR   EPD; O08648; -.
DR   jPOST; O08648; -.
DR   MaxQB; O08648; -.
DR   PaxDb; O08648; -.
DR   PeptideAtlas; O08648; -.
DR   PRIDE; O08648; -.
DR   ProteomicsDB; 292137; -. [O08648-1]
DR   ProteomicsDB; 292138; -. [O08648-2]
DR   Antibodypedia; 2064; 336 antibodies from 35 providers.
DR   DNASU; 26407; -.
DR   Ensembl; ENSMUST00000089058; ENSMUSP00000086459; ENSMUSG00000014426. [O08648-1]
DR   Ensembl; ENSMUST00000233755; ENSMUSP00000156730; ENSMUSG00000014426. [O08648-2]
DR   GeneID; 26407; -.
DR   KEGG; mmu:26407; -.
DR   UCSC; uc008akn.1; mouse. [O08648-1]
DR   UCSC; uc008ako.1; mouse. [O08648-2]
DR   CTD; 4216; -.
DR   MGI; MGI:1346875; Map3k4.
DR   VEuPathDB; HostDB:ENSMUSG00000014426; -.
DR   eggNOG; KOG4645; Eukaryota.
DR   GeneTree; ENSGT00880000138034; -.
DR   HOGENOM; CLU_003786_0_0_1; -.
DR   InParanoid; O08648; -.
DR   OMA; EETRICY; -.
DR   OrthoDB; 55144at2759; -.
DR   PhylomeDB; O08648; -.
DR   TreeFam; TF105114; -.
DR   BRENDA; 2.7.11.25; 3474.
DR   BioGRID-ORCS; 26407; 8 hits in 75 CRISPR screens.
DR   ChiTaRS; Map3k4; mouse.
DR   PRO; PR:O08648; -.
DR   Proteomes; UP000000589; Chromosome 17.
DR   RNAct; O08648; protein.
DR   Bgee; ENSMUSG00000014426; Expressed in urogenital fold and 272 other tissues.
DR   ExpressionAtlas; O08648; baseline and differential.
DR   Genevisible; O08648; MM.
DR   GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR   GO; GO:0048471; C:perinuclear region of cytoplasm; IEA:UniProtKB-SubCell.
DR   GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR   GO; GO:0004709; F:MAP kinase kinase kinase activity; ISO:MGI.
DR   GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR   GO; GO:0004672; F:protein kinase activity; IDA:UniProtKB.
DR   GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR   GO; GO:0060718; P:chorionic trophoblast cell differentiation; IMP:MGI.
DR   GO; GO:0048263; P:determination of dorsal identity; ISO:MGI.
DR   GO; GO:0035556; P:intracellular signal transduction; IDA:UniProtKB.
DR   GO; GO:0019100; P:male germ-line sex determination; IMP:MGI.
DR   GO; GO:0000165; P:MAPK cascade; ISO:MGI.
DR   GO; GO:0001890; P:placenta development; IMP:MGI.
DR   GO; GO:0043507; P:positive regulation of JUN kinase activity; IDA:UniProtKB.
DR   GO; GO:1900745; P:positive regulation of p38MAPK cascade; ISO:MGI.
DR   GO; GO:0051973; P:positive regulation of telomerase activity; ISO:MGI.
DR   GO; GO:1904355; P:positive regulation of telomere capping; ISO:MGI.
DR   GO; GO:0032212; P:positive regulation of telomere maintenance via telomerase; ISO:MGI.
DR   GO; GO:0006468; P:protein phosphorylation; IBA:GO_Central.
DR   GO; GO:0010468; P:regulation of gene expression; IMP:MGI.
DR   GO; GO:0010225; P:response to UV-C; ISO:MGI.
DR   InterPro; IPR011009; Kinase-like_dom_sf.
DR   InterPro; IPR045801; MEKK4_N.
DR   InterPro; IPR000719; Prot_kinase_dom.
DR   InterPro; IPR017441; Protein_kinase_ATP_BS.
DR   InterPro; IPR008271; Ser/Thr_kinase_AS.
DR   Pfam; PF19431; MEKK4_N; 1.
DR   Pfam; PF00069; Pkinase; 1.
DR   SMART; SM00220; S_TKc; 1.
DR   SUPFAM; SSF56112; SSF56112; 1.
DR   PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR   PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR   PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
PE   1: Evidence at protein level;
KW   Alternative splicing; ATP-binding; Cytoplasm; Kinase; Magnesium;
KW   Metal-binding; Nucleotide-binding; Phosphoprotein; Reference proteome;
KW   Serine/threonine-protein kinase; Transferase.
FT   CHAIN           1..1597
FT                   /note="Mitogen-activated protein kinase kinase kinase 4"
FT                   /id="PRO_0000086248"
FT   DOMAIN          1332..1590
FT                   /note="Protein kinase"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   REGION          1..129
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          424..465
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          1137..1157
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          1190..1220
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          1233..1263
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        24..38
FT                   /note="Pro residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        68..86
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        95..118
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        434..455
FT                   /note="Acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   ACT_SITE        1452
FT                   /note="Proton acceptor"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT                   ECO:0000255|PROSITE-ProRule:PRU10027"
FT   BINDING         1338..1346
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   BINDING         1361
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT   MOD_RES         77
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:21183079"
FT   MOD_RES         424
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q9Y6R4"
FT   MOD_RES         440
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0000250|UniProtKB:Q9Y6R4"
FT   MOD_RES         449
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:21183079"
FT   MOD_RES         451
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0007744|PubMed:21183079"
FT   MOD_RES         454
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:21183079"
FT   MOD_RES         492
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:17242355,
FT                   ECO:0007744|PubMed:21183079"
FT   MOD_RES         1241
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q9Y6R4"
FT   MOD_RES         1263
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q9Y6R4"
FT   VAR_SEQ         1162..1213
FT                   /note="Missing (in isoform B)"
FT                   /evidence="ECO:0000303|PubMed:9079650"
FT                   /id="VSP_004885"
FT   MUTAGEN         1361
FT                   /note="K->A,R: Loss of kinase activity."
FT                   /evidence="ECO:0000269|PubMed:16157600,
FT                   ECO:0000269|PubMed:9079650"
FT   CONFLICT        363..364
FT                   /note="SL -> NS (in Ref. 3; AAC08286)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        473
FT                   /note="A -> T (in Ref. 1; AAC53126/AAC53127)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        1184
FT                   /note="A -> R (in Ref. 1; AAC53126)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   1597 AA;  179834 MW;  E9C43EB9A4F056BC CRC64;
     MRDAIAEPVP PPALADTPAA AMEELRPAPP PQPEPDPECC PAARQECMLG ESARKSMESD
     PEDFSDETNT ETLYGTSPPS TPRQMKRLSA KHQRNSAGRP ASRSNLKEKM NTPSQSPHKD
     LGKGVETVEE YSYKQEKKIR ATLRTTERDH KKNAQCSFML DSVAGSLPKK SIPDVDLNKP
     YLSLGCSNAK LPVSMPMPIA RTARQTSRTD CPADRLKFFE TLRLLLKLTS VSKKKDREQR
     GQENTAAFWF NRSNELIWLE LQAWHAGRTI NDQDLFLYTA RQAIPDIINE ILTFKVNYGS
     IAFSSNGAGF NGPLVEGQCR TPQETNRVGC SSYHEHLQRQ RVSFEQVKRI MELLEYMEAL
     YPSLQALQKD YERYAAKDFE DRVQALCLWL NITKDLNQKL RIMGTVLGIK NLSDIGWPVF
     EIPSPRPSKG YEPEDEVEDT EVELRELESG TEESDEEPTP SPRVPELRLS TDAILDSRSQ
     GCVSRKLERL ESEEDSIGWG TADCGPEASR HCLTSIYRPF VDKALKQMGL RKLILRLHKL
     MNGSLQRARV ALVKDDRPVE FSDFPGPMWG SDYVQLSGTP PSSEQKCSAV SWEELRAMDL
     PSFEPAFLVL CRVLLNVIHE CLKLRLEQRP AGEPSLLSIK QLVRECKEVL KGGLLMKQYY
     QFMLQEVLGG LEKTDCNMDA FEEDLQKMLM VYFDYMRSWI QMLQQLPQAS HSLKNLLEEE
     WNFTKEITHY IRGGEAQAGK LFCDIAGMLL KSTGSFLESG LQESCAELWT SADDNGAADE
     LRRSVIEISR ALKELFHEAR ERASKALGFA KMLRKDLEIA AEFVLSASAR ELLDALKAKQ
     YVKVQIPGLE NLHVFVPDSL AEEKKIILQL LNAATGKDCS KDPDDVFMDA FLLLTKHGDR
     ARDSEDGWGT WEARAVKIVP QVETVDTLRS MQVDNLLLVV MESAHLVLQR KAFQQSIEGL
     MTVRHEQTSS QPIIAKGLQQ LKNDALELCN RISDAIDRVD HMFTLEFDAE VEESESATLQ
     QYYREAMIQG YNFGFEYHKE VVRLMSGEFR QKIGDKYISF AQKWMNYVLT KCESGRGTRP
     RWATQGFDFL QAIEPAFISA LPEDDFLSLQ ALMNECIGHV IGKPHSPVTA IHRNSPRPVK
     VPRCHSDPPN PHLIIPTPEG FSTRSVPSDA RTHGNSVAAA AAVAAAATTA AGRPGPGGGD
     SVPAKPVNTA PDTRGSSVPE NDRLASIAAE LQFRSLSRHS SPTEERDEPA YPRSDSSGST
     RRSWELRTLI SQTKDSASKQ GPIEAIQKSV RLFEERRYRE MRRKNIIGQV CDTPKSYDNV
     MHVGLRKVTF KWQRGNKIGE GQYGKVYTCI SVDTGELMAM KEIRFQPNDH KTIKETADEL
     KIFEGIKHPN LVRYFGVELH REEMYIFMEY CDEGTLEEVS RLGLQEHVIR LYTKQITVAI
     NVLHEHGIVH RDIKGANIFL TSSGLIKLGD FGCSVKLKNN AQTMPGEVNS TLGTAAYMAP
     EVITRAKGEG HGRAADIWSL GCVVIEMVTG KRPWHEYEHN FQIMYKVGMG HKPPIPERLS
     PEGKAFLSHC LESDPKIRWT ASQLLDHAFV KVCTDEE
 
 
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