M3K4_HUMAN
ID M3K4_HUMAN Reviewed; 1608 AA.
AC Q9Y6R4; A6H8W0; B7ZLD3; B9EG75; Q5VTT8; Q5VTT9; Q92612; Q9H408;
DT 30-MAY-2000, integrated into UniProtKB/Swiss-Prot.
DT 18-MAY-2010, sequence version 2.
DT 03-AUG-2022, entry version 203.
DE RecName: Full=Mitogen-activated protein kinase kinase kinase 4;
DE EC=2.7.11.25;
DE AltName: Full=MAP three kinase 1;
DE AltName: Full=MAPK/ERK kinase kinase 4;
DE Short=MEK kinase 4;
DE Short=MEKK 4;
GN Name=MAP3K4; Synonyms=KIAA0213, MAPKKK4, MEKK4, MTK1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, TISSUE SPECIFICITY,
RP ALTERNATIVE SPLICING, AND MUTAGENESIS OF LYS-1372.
RC TISSUE=Fetal liver, and Skeletal muscle;
RX PubMed=9305639; DOI=10.1093/emboj/16.16.4973;
RA Takekawa M., Posas F., Saito H.;
RT "A human homolog of the yeast Ssk2/Ssk22 MAP kinase kinase kinases, MTK1,
RT mediates stress-induced activation of the p38 and JNK pathways.";
RL EMBO J. 16:4973-4982(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Bone marrow;
RX PubMed=9039502; DOI=10.1093/dnares/3.5.321;
RA Nagase T., Seki N., Ishikawa K., Ohira M., Kawarabayasi Y., Ohara O.,
RA Tanaka A., Kotani H., Miyajima N., Nomura N.;
RT "Prediction of the coding sequences of unidentified human genes. VI. The
RT coding sequences of 80 new genes (KIAA0201-KIAA0280) deduced by analysis of
RT cDNA clones from cell line KG-1 and brain.";
RL DNA Res. 3:321-329(1996).
RN [3]
RP SEQUENCE REVISION.
RA Ohara O., Nagase T., Kikuno R., Nomura N.;
RL Submitted (JAN-2003) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=14574404; DOI=10.1038/nature02055;
RA Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L.,
RA Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E., Gilbert J.G.R.,
RA Clamp M.E., Bethel G., Milne S., Ainscough R., Almeida J.P., Ambrose K.D.,
RA Andrews T.D., Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J.,
RA Banerjee R., Barker D.J., Barlow K.F., Bates K., Beare D.M., Beasley H.,
RA Beasley O., Bird C.P., Blakey S.E., Bray-Allen S., Brook J., Brown A.J.,
RA Brown J.Y., Burford D.C., Burrill W., Burton J., Carder C., Carter N.P.,
RA Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V.,
RA Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J.,
RA Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E., Ellington A.E.,
RA Evans K.A., Faulkner L., Francis M.D., Frankish A., Frankland J.,
RA French L., Garner P., Garnett J., Ghori M.J., Gilby L.M., Gillson C.J.,
RA Glithero R.J., Grafham D.V., Grant M., Gribble S., Griffiths C.,
RA Griffiths M.N.D., Hall R., Halls K.S., Hammond S., Harley J.L., Hart E.A.,
RA Heath P.D., Heathcott R., Holmes S.J., Howden P.J., Howe K.L., Howell G.R.,
RA Huckle E., Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M.,
RA Joy A.A., Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K.,
RA Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R.,
RA Lloyd D.M., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M.,
RA Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K., McMurray A.,
RA Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T., Novik K.L.,
RA Oliver K., Overton-Larty E.K., Parker A., Patel R., Pearce A.V., Peck A.I.,
RA Phillimore B.J.C.T., Phillips S., Plumb R.W., Porter K.M., Ramsey Y.,
RA Ranby S.A., Rice C.M., Ross M.T., Searle S.M., Sehra H.K., Sheridan E.,
RA Skuce C.D., Smith S., Smith M., Spraggon L., Squares S.L., Steward C.A.,
RA Sycamore N., Tamlyn-Hall G., Tester J., Theaker A.J., Thomas D.W.,
RA Thorpe A., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M.,
RA West A.P., White S.S., Whitehead S.L., Whittaker H., Wild A., Willey D.J.,
RA Wilmer T.E., Wood J.M., Wray P.W., Wyatt J.C., Young L., Younger R.M.,
RA Bentley D.R., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Dunham I.,
RA Rogers J., Beck S.;
RT "The DNA sequence and analysis of human chromosome 6.";
RL Nature 425:805-811(2003).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2), AND VARIANT
RP HIS-157.
RC TISSUE=Cerebellum;
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 [7]
RP FUNCTION, ACTIVITY REGULATION, INTERACTION WITH GADD45 AND MAP2K6, AND
RP MUTAGENESIS OF LYS-1372.
RX PubMed=12052864; DOI=10.1128/mcb.22.13.4544-4555.2002;
RA Mita H., Tsutsui J., Takekawa M., Witten E.A., Saito H.;
RT "Regulation of MTK1/MEKK4 kinase activity by its N-terminal autoinhibitory
RT domain and GADD45 binding.";
RL Mol. Cell. Biol. 22:4544-4555(2002).
RN [8]
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 [9]
RP INTERACTION 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 [10]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a
RT refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-499, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19369195; DOI=10.1074/mcp.m800588-mcp200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [12]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [13]
RP INTERACTION WITH SH3KBP1 AND ZFP36.
RX PubMed=20221403; DOI=10.1371/journal.pone.0009588;
RA Kedar V.P., Darby M.K., Williams J.G., Blackshear P.J.;
RT "Phosphorylation of human tristetraprolin in response to its interaction
RT with the Cbl interacting protein CIN85.";
RL PLoS ONE 5:E9588-E9588(2010).
RN [14]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [15]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-456; SER-457; THR-458 AND
RP SER-461, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T.,
RA Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.;
RT "System-wide temporal characterization of the proteome and phosphoproteome
RT of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [16]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-431; THR-447; SER-481;
RP SER-499; SER-1252 AND SER-1274, AND IDENTIFICATION BY MASS SPECTROMETRY
RP [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma, and Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [17]
RP VARIANTS [LARGE SCALE ANALYSIS] THR-294; ILE-335; HIS-566; HIS-584;
RP PRO-906; GLN-1413 AND VAL-1492.
RX PubMed=17344846; DOI=10.1038/nature05610;
RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G.,
RA Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S.,
RA Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G.,
RA Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K.,
RA Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D.,
RA Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R.,
RA Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A.,
RA Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F.,
RA Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F.,
RA Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G.,
RA Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R.,
RA Futreal P.A., Stratton M.R.;
RT "Patterns of somatic mutation in human cancer genomes.";
RL Nature 446:153-158(2007).
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:12052864, ECO:0000269|PubMed:9305639}.
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-1505. {ECO:0000269|PubMed:12052864}.
CC -!- SUBUNIT: Monomer and homodimer. Homodimerization enhances kinase
CC activity. Interacts with TRAF4; this promotes homodimerization
CC (PubMed:16157600). Binds both upstream activators and downstream
CC substrates in multimolecular complexes. Interacts with AXIN1 and
CC DIXDC1; interaction with DIXDC1 prevents interaction with AXIN1
CC (PubMed:15262978). Interacts with GADD45 and MAP2K6 (PubMed:12052864).
CC Interacts with ZFP36; this interaction enhances the association with
CC SH3KBP1/CIN85 (PubMed:20221403). Interacts with SH3KBP1; this
CC interaction enhances the association with ZFP36 (PubMed:20221403).
CC Interacts with CDC42 (By similarity). {ECO:0000250|UniProtKB:O08648,
CC ECO:0000269|PubMed:12052864, ECO:0000269|PubMed:15262978,
CC ECO:0000269|PubMed:16157600, ECO:0000269|PubMed:20221403}.
CC -!- INTERACTION:
CC Q9Y6R4; O75369: FLNB; NbExp=2; IntAct=EBI-448104, EBI-352089;
CC Q9Y6R4; O75293: GADD45B; NbExp=2; IntAct=EBI-448104, EBI-448187;
CC Q9Y6R4; Q96B97: SH3KBP1; NbExp=5; IntAct=EBI-448104, EBI-346595;
CC Q9Y6R4; P0CG48: UBC; NbExp=2; IntAct=EBI-448104, EBI-3390054;
CC -!- SUBCELLULAR LOCATION: Cytoplasm, perinuclear region {ECO:0000250}.
CC Note=Localized in perinuclear vesicular-like structures, probably
CC Golgi-associated vesicles. {ECO:0000250}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1; Synonyms=A;
CC IsoId=Q9Y6R4-1; Sequence=Displayed;
CC Name=2; Synonyms=B;
CC IsoId=Q9Y6R4-2; Sequence=VSP_004884;
CC -!- TISSUE SPECIFICITY: Expressed at high levels in heart, placenta,
CC skeletal muscle and pancreas, and at lower levels in other tissues.
CC {ECO:0000269|PubMed:9305639}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. STE Ser/Thr
CC protein kinase family. MAP kinase kinase kinase subfamily.
CC {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAA13204.2; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; AF002715; AAB68804.1; -; mRNA.
DR EMBL; D86968; BAA13204.2; ALT_INIT; mRNA.
DR EMBL; AL109942; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL139393; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL591045; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL596452; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471051; EAW47587.1; -; Genomic_DNA.
DR EMBL; BC136276; AAI36277.1; -; mRNA.
DR EMBL; BC143735; AAI43736.1; -; mRNA.
DR EMBL; BC146770; AAI46771.1; -; mRNA.
DR CCDS; CCDS34565.1; -. [Q9Y6R4-1]
DR CCDS; CCDS34566.1; -. [Q9Y6R4-2]
DR PIR; T03022; T03022.
DR RefSeq; NP_001278887.1; NM_001291958.1.
DR RefSeq; NP_001288001.1; NM_001301072.1.
DR RefSeq; NP_005913.2; NM_005922.3. [Q9Y6R4-1]
DR RefSeq; NP_006715.2; NM_006724.3. [Q9Y6R4-2]
DR AlphaFoldDB; Q9Y6R4; -.
DR SMR; Q9Y6R4; -.
DR BioGRID; 110380; 70.
DR CORUM; Q9Y6R4; -.
DR IntAct; Q9Y6R4; 22.
DR MINT; Q9Y6R4; -.
DR STRING; 9606.ENSP00000375986; -.
DR BindingDB; Q9Y6R4; -.
DR ChEMBL; CHEMBL4853; -.
DR DrugBank; DB12010; Fostamatinib.
DR DrugCentral; Q9Y6R4; -.
DR CarbonylDB; Q9Y6R4; -.
DR GlyGen; Q9Y6R4; 2 sites, 1 O-linked glycan (2 sites).
DR iPTMnet; Q9Y6R4; -.
DR PhosphoSitePlus; Q9Y6R4; -.
DR BioMuta; MAP3K4; -.
DR DMDM; 296434576; -.
DR CPTAC; CPTAC-847; -.
DR CPTAC; CPTAC-848; -.
DR EPD; Q9Y6R4; -.
DR jPOST; Q9Y6R4; -.
DR MassIVE; Q9Y6R4; -.
DR MaxQB; Q9Y6R4; -.
DR PaxDb; Q9Y6R4; -.
DR PeptideAtlas; Q9Y6R4; -.
DR PRIDE; Q9Y6R4; -.
DR ProteomicsDB; 86777; -. [Q9Y6R4-1]
DR ProteomicsDB; 86778; -. [Q9Y6R4-2]
DR Antibodypedia; 2064; 336 antibodies from 35 providers.
DR DNASU; 4216; -.
DR Ensembl; ENST00000366919.6; ENSP00000355886.2; ENSG00000085511.20. [Q9Y6R4-2]
DR Ensembl; ENST00000392142.9; ENSP00000375986.4; ENSG00000085511.20. [Q9Y6R4-1]
DR GeneID; 4216; -.
DR KEGG; hsa:4216; -.
DR MANE-Select; ENST00000392142.9; ENSP00000375986.4; NM_005922.4; NP_005913.3.
DR UCSC; uc003qtn.4; human. [Q9Y6R4-1]
DR CTD; 4216; -.
DR DisGeNET; 4216; -.
DR GeneCards; MAP3K4; -.
DR HGNC; HGNC:6856; MAP3K4.
DR HPA; ENSG00000085511; Low tissue specificity.
DR MIM; 602425; gene.
DR neXtProt; NX_Q9Y6R4; -.
DR OpenTargets; ENSG00000085511; -.
DR PharmGKB; PA30600; -.
DR VEuPathDB; HostDB:ENSG00000085511; -.
DR eggNOG; KOG4645; Eukaryota.
DR GeneTree; ENSGT00880000138034; -.
DR InParanoid; Q9Y6R4; -.
DR OMA; EETRICY; -.
DR OrthoDB; 55144at2759; -.
DR PhylomeDB; Q9Y6R4; -.
DR TreeFam; TF105114; -.
DR BRENDA; 2.7.12.2; 2681.
DR PathwayCommons; Q9Y6R4; -.
DR SignaLink; Q9Y6R4; -.
DR SIGNOR; Q9Y6R4; -.
DR BioGRID-ORCS; 4216; 19 hits in 1127 CRISPR screens.
DR ChiTaRS; MAP3K4; human.
DR GeneWiki; MAP3K4; -.
DR GenomeRNAi; 4216; -.
DR Pharos; Q9Y6R4; Tbio.
DR PRO; PR:Q9Y6R4; -.
DR Proteomes; UP000005640; Chromosome 6.
DR RNAct; Q9Y6R4; protein.
DR Bgee; ENSG00000085511; Expressed in middle temporal gyrus and 207 other tissues.
DR ExpressionAtlas; Q9Y6R4; baseline and differential.
DR Genevisible; Q9Y6R4; HS.
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; IDA:UniProtKB.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0060718; P:chorionic trophoblast cell differentiation; IEA:Ensembl.
DR GO; GO:0035556; P:intracellular signal transduction; ISS:UniProtKB.
DR GO; GO:0019100; P:male germ-line sex determination; IEA:Ensembl.
DR GO; GO:0000165; P:MAPK cascade; IDA:UniProtKB.
DR GO; GO:0001890; P:placenta development; IEA:Ensembl.
DR GO; GO:0043507; P:positive regulation of JUN kinase activity; IDA:UniProtKB.
DR GO; GO:1900745; P:positive regulation of p38MAPK cascade; IDA:UniProtKB.
DR GO; GO:0051973; P:positive regulation of telomerase activity; IMP:BHF-UCL.
DR GO; GO:1904355; P:positive regulation of telomere capping; IMP:BHF-UCL.
DR GO; GO:0032212; P:positive regulation of telomere maintenance via telomerase; IMP:BHF-UCL.
DR GO; GO:0006468; P:protein phosphorylation; IBA:GO_Central.
DR GO; GO:0010468; P:regulation of gene expression; IEA:Ensembl.
DR GO; GO:0010225; P:response to UV-C; IMP:UniProtKB.
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..1608
FT /note="Mitogen-activated protein kinase kinase kinase 4"
FT /id="PRO_0000086247"
FT DOMAIN 1343..1601
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 1..136
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 429..478
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1157..1190
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1202..1231
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1244..1274
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 21..41
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 75..93
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 101..128
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 443..462
FT /note="Acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1210..1226
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 1463
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10027"
FT BINDING 1349..1357
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 1372
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOD_RES 84
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O08648"
FT MOD_RES 431
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 447
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 456
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21406692"
FT MOD_RES 457
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21406692"
FT MOD_RES 458
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:21406692"
FT MOD_RES 461
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21406692"
FT MOD_RES 481
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 499
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:19369195,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 1252
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 1274
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT VAR_SEQ 1175..1224
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334,
FT ECO:0000303|PubMed:9039502"
FT /id="VSP_004884"
FT VARIANT 157
FT /note="R -> H (in dbSNP:rs4559074)"
FT /evidence="ECO:0000269|PubMed:15489334"
FT /id="VAR_059767"
FT VARIANT 294
FT /note="I -> T (in dbSNP:rs35842248)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040686"
FT VARIANT 335
FT /note="V -> I (in dbSNP:rs35730939)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040687"
FT VARIANT 566
FT /note="R -> H (in dbSNP:rs55765351)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040688"
FT VARIANT 584
FT /note="Q -> H (in dbSNP:rs34018542)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040689"
FT VARIANT 906
FT /note="H -> P (in dbSNP:rs35533223)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040690"
FT VARIANT 1413
FT /note="E -> Q (in an ovarian serous carcinoma sample;
FT somatic mutation)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040691"
FT VARIANT 1492
FT /note="A -> V (in dbSNP:rs41267837)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040692"
FT MUTAGEN 1372
FT /note="K->R: Loss of activity."
FT /evidence="ECO:0000269|PubMed:12052864,
FT ECO:0000269|PubMed:9305639"
FT CONFLICT 35
FT /note="P -> PP (in Ref. 6; AAI36277)"
FT /evidence="ECO:0000305"
FT CONFLICT 500
FT /note="E -> D (in Ref. 6; AAI46771)"
FT /evidence="ECO:0000305"
FT CONFLICT 791
FT /note="R -> I (in Ref. 1; AAB68804)"
FT /evidence="ECO:0000305"
FT CONFLICT 1190
FT /note="Missing (in Ref. 5; EAW47587 and 6; AAI43736/
FT AAI36277)"
FT /evidence="ECO:0000305"
FT CONFLICT 1199
FT /note="Missing (in Ref. 1; AAB68804)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 1608 AA; 181685 MW; C22294914945EA91 CRC64;
MREAAAALVP PPAFAVTPAA AMEEPPPPPP PPPPPPEPET ESEPECCLAA RQEGTLGDSA
CKSPESDLED FSDETNTENL YGTSPPSTPR QMKRMSTKHQ RNNVGRPASR SNLKEKMNAP
NQPPHKDTGK TVENVEEYSY KQEKKIRAAL RTTERDRKKN VQCSFMLDSV GGSLPKKSIP
DVDLNKPYLS LGCSNAKLPV SVPMPIARPA RQTSRTDCPA DRLKFFETLR LLLKLTSVSK
KKDREQRGQE NTSGFWLNRS NELIWLELQA WHAGRTINDQ DFFLYTARQA IPDIINEILT
FKVDYGSFAF VRDRAGFNGT SVEGQCKATP GTKIVGYSTH HEHLQRQRVS FEQVKRIMEL
LEYIEALYPS LQALQKDYEK YAAKDFQDRV QALCLWLNIT KDLNQKLRIM GTVLGIKNLS
DIGWPVFEIP SPRPSKGNEP EYEGDDTEGE LKELESSTDE SEEEQISDPR VPEIRQPIDN
SFDIQSRDCI SKKLERLESE DDSLGWGAPD WSTEAGFSRH CLTSIYRPFV DKALKQMGLR
KLILRLHKLM DGSLQRARIA LVKNDRPVEF SEFPDPMWGS DYVQLSRTPP SSEEKCSAVS
WEELKAMDLP SFEPAFLVLC RVLLNVIHEC LKLRLEQRPA GEPSLLSIKQ LVRECKEVLK
GGLLMKQYYQ FMLQEVLEDL EKPDCNIDAF EEDLHKMLMV YFDYMRSWIQ MLQQLPQASH
SLKNLLEEEW NFTKEITHYI RGGEAQAGKL FCDIAGMLLK STGSFLEFGL QESCAEFWTS
ADDSSASDEI RRSVIEISRA LKELFHEARE RASKALGFAK MLRKDLEIAA EFRLSAPVRD
LLDVLKSKQY VKVQIPGLEN LQMFVPDTLA EEKSIILQLL NAAAGKDCSK DSDDVLIDAY
LLLTKHGDRA RDSEDSWGTW EAQPVKVVPQ VETVDTLRSM QVDNLLLVVM QSAHLTIQRK
AFQQSIEGLM TLCQEQTSSQ PVIAKALQQL KNDALELCNR ISNAIDRVDH MFTSEFDAEV
DESESVTLQQ YYREAMIQGY NFGFEYHKEV VRLMSGEFRQ KIGDKYISFA RKWMNYVLTK
CESGRGTRPR WATQGFDFLQ AIEPAFISAL PEDDFLSLQA LMNECIGHVI GKPHSPVTGL
YLAIHRNSPR PMKVPRCHSD PPNPHLIIPT PEGFSTRSMP SDARSHGSPA AAAAAAAAAV
AASRPSPSGG DSVLPKSISS AHDTRGSSVP ENDRLASIAA ELQFRSLSRH SSPTEERDEP
AYPRGDSSGS TRRSWELRTL ISQSKDTASK LGPIEAIQKS VRLFEEKRYR EMRRKNIIGQ
VCDTPKSYDN VMHVGLRKVT FKWQRGNKIG EGQYGKVYTC ISVDTGELMA MKEIRFQPND
HKTIKETADE LKIFEGIKHP NLVRYFGVEL HREEMYIFME YCDEGTLEEV SRLGLQEHVI
RLYSKQITIA INVLHEHGIV HRDIKGANIF LTSSGLIKLG DFGCSVKLKN NAQTMPGEVN
STLGTAAYMA PEVITRAKGE GHGRAADIWS LGCVVIEMVT GKRPWHEYEH NFQIMYKVGM
GHKPPIPERL SPEGKDFLSH CLESDPKMRW TASQLLDHSF VKVCTDEE
