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   27-MAR-2024, entry version 212.
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};
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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; 80.
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   GlyCosmos; Q9Y6R4; 2 sites, 1 glycan.
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; 9606-ENSP00000375986; -.
DR   PeptideAtlas; Q9Y6R4; -.
DR   ProteomicsDB; 86777; -. [Q9Y6R4-1]
DR   ProteomicsDB; 86778; -. [Q9Y6R4-2]
DR   Pumba; Q9Y6R4; -.
DR   Antibodypedia; 2064; 379 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   AGR; HGNC:6856; -.
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; SCNRFMS; -.
DR   OrthoDB; 5391541at2759; -.
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; 20 hits in 1208 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 209 other cell types or tissues.
DR   ExpressionAtlas; Q9Y6R4; baseline and differential.
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:0016310; P:phosphorylation; IEA:UniProtKB-KW.
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:0010468; P:regulation of gene expression; IEA:Ensembl.
DR   GO; GO:0010225; P:response to UV-C; IMP:UniProtKB.
DR   CDD; cd06626; STKc_MEKK4; 1.
DR   Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1.
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   PANTHER; PTHR48016; MAP KINASE KINASE KINASE SSK2-RELATED-RELATED; 1.
DR   PANTHER; PTHR48016:SF32; MITOGEN-ACTIVATED PROTEIN KINASE KINASE KINASE 4; 1.
DR   Pfam; PF19431; MEKK4_N; 1.
DR   Pfam; PF00069; Pkinase; 1.
DR   SMART; SM00220; S_TKc; 1.
DR   SUPFAM; SSF101447; Formin homology 2 domain (FH2 domain); 1.
DR   SUPFAM; SSF56112; Protein kinase-like (PK-like); 1.
DR   PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR   PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR   PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
DR   Genevisible; Q9Y6R4; HS.
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;
FT                   AAI43736/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
//