ID   M3K9_HUMAN              Reviewed;        1104 AA.
AC   P80192; A3KN85; Q0D2G7; Q6EH31; Q9H2N5;
DT   01-FEB-1994, integrated into UniProtKB/Swiss-Prot.
DT   17-OCT-2006, sequence version 3.
DT   27-MAR-2024, entry version 206.
DE   RecName: Full=Mitogen-activated protein kinase kinase kinase 9;
DE            EC=2.7.11.25;
DE   AltName: Full=Mixed lineage kinase 1;
GN   Name=MAP3K9; Synonyms=MLK1, PRKE1;
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, ACTIVITY REGULATION,
RP   PHOSPHORYLATION AT THR-304; THR-305; SER-308 AND THR-312, AND MUTAGENESIS
RP   OF LYS-171; THR-304; THR-305; SER-308 AND THR-312.
RX   PubMed=15610029; DOI=10.1021/bi049866y;
RA   Durkin J.T., Holskin B.P., Kopec K.K., Reed M.S., Spais C.M., Steffy B.M.,
RA   Gessner G., Angeles T.S., Pohl J., Ator M.A., Meyer S.L.;
RT   "Phosphoregulation of mixed-lineage kinase 1 activity by multiple
RT   phosphorylation in the activation loop.";
RL   Biochemistry 43:16348-16355(2004).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
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 53-1104 (ISOFORM 2).
RA   McNee J.J., Dower S.K., Guesdon F.;
RT   "cDNA sequence and gene organisation of mixed lineage kinase 1.";
RL   Submitted (APR-2000) to the EMBL/GenBank/DDBJ databases.
RN   [4]
RP   NUCLEOTIDE SEQUENCE [MRNA] OF 142-535, AND TISSUE SPECIFICITY.
RC   TISSUE=Colon epithelium;
RX   PubMed=8477742; DOI=10.1111/j.1432-1033.1993.tb17810.x;
RA   Dorow D.S., Devereux L., Dietzsch E., de Kretser T.;
RT   "Identification of a new family of human epithelial protein kinases
RT   containing two leucine/isoleucine-zipper domains.";
RL   Eur. J. Biochem. 213:701-710(1993).
RN   [5]
RP   ACTIVITY REGULATION, BIOPHYSICOCHEMICAL PROPERTIES, AND PHOSPHORYLATION OF
RP   MAP2K4/MKK4.
RX   PubMed=11325962; DOI=10.1074/jbc.m011601200;
RA   Maroney A.C., Finn J.P., Connors T.J., Durkin J.T., Angeles T., Gessner G.,
RA   Xu Z., Meyer S.L., Savage M.J., Greene L.A., Scott R.W., Vaught J.L.;
RT   "Cep-1347 (KT7515), a semisynthetic inhibitor of the mixed lineage kinase
RT   family.";
RL   J. Biol. Chem. 276:25302-25308(2001).
RN   [6]
RP   FUNCTION IN THE APOPTOSIS PATHWAY.
RX   PubMed=11416147; DOI=10.1128/mcb.21.14.4713-4724.2001;
RA   Xu Z., Maroney A.C., Dobrzanski P., Kukekov N.V., Greene L.A.;
RT   "The MLK family mediates c-Jun N-terminal kinase activation in neuronal
RT   apoptosis.";
RL   Mol. Cell. Biol. 21:4713-4724(2001).
RN   [7]
RP   ACTIVITY REGULATION.
RX   PubMed=11755341; DOI=10.1016/s0960-894x(01)00690-4;
RA   Murakata C., Kaneko M., Gessner G., Angeles T.S., Ator M.A., O'Kane T.M.,
RA   McKenna B.A., Thomas B.A., Mathiasen J.R., Saporito M.S.,
RA   Bozyczko-Coyne D., Hudkins R.L.;
RT   "Mixed lineage kinase activity of indolocarbazole analogues.";
RL   Bioorg. Med. Chem. Lett. 12:147-150(2002).
RN   [8]
RP   POSSIBLE ROLE IN ESOPHAGEAL CANCER.
RX   PubMed=18241037; DOI=10.1002/ijc.23397;
RA   Chen J., Guo L., Peiffer D.A., Zhou L., Chan O.T., Bibikova M.,
RA   Wickham-Garcia E., Lu S.H., Zhan Q., Wang-Rodriguez J., Jiang W., Fan J.B.;
RT   "Genomic profiling of 766 cancer-related genes in archived esophageal
RT   normal and carcinoma tissues.";
RL   Int. J. Cancer 122:2249-2254(2008).
RN   [9]
RP   IDENTIFICATION BY 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   [10]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-533, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=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   [11]
RP   X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 136-406.
RX   PubMed=18714982; DOI=10.1021/jm8005838;
RA   Hudkins R.L., Diebold J.L., Tao M., Josef K.A., Park C.H., Angeles T.S.,
RA   Aimone L.D., Husten J., Ator M.A., Meyer S.L., Holskin B.P., Durkin J.T.,
RA   Fedorov A.A., Fedorov E.V., Almo S.C., Mathiasen J.R., Bozyczko-Coyne D.,
RA   Saporito M.S., Scott R.W., Mallamo J.P.;
RT   "Mixed-lineage kinase 1 and mixed-lineage kinase 3 subtype-selective
RT   dihydronaphthyl[3,4-a]pyrrolo[3,4-c]carbazole-5-ones: optimization, mixed-
RT   lineage kinase 1 crystallography, and oral in vivo activity in 1-methyl-4-
RT   phenyltetrahydropyridine models.";
RL   J. Med. Chem. 51:5680-5689(2008).
RN   [12]
RP   VARIANTS [LARGE SCALE ANALYSIS] VAL-246; CYS-467; GLN-497 AND CYS-646.
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: Serine/threonine kinase which acts as an essential component
CC       of the MAP kinase signal transduction pathway. Plays an important role
CC       in the cascades of cellular responses evoked by changes in the
CC       environment. Once activated, acts as an upstream activator of the
CC       MKK/JNK signal transduction cascade through the phosphorylation of
CC       MAP2K4/MKK4 and MAP2K7/MKK7 which in turn activate the JNKs. The
CC       MKK/JNK signaling pathway regulates stress response via activator
CC       protein-1 (JUN) and GATA4 transcription factors. Also plays a role in
CC       mitochondrial death signaling pathway, including the release cytochrome
CC       c, leading to apoptosis. {ECO:0000269|PubMed:11416147,
CC       ECO:0000269|PubMed:15610029}.
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: Homodimerization via the leucine zipper domains is
CC       required for autophosphorylation of multiple sites in the activation
CC       loop and subsequent activation. Autophosphorylation at Thr-312 is the
CC       key step in activation of MAP3K9/MLK1 and is required for full
CC       phosphorylation. Autophosphorylation at Thr-304 and Ser-308 have been
CC       shown to be of secondary importance in the activation of MAP3K9/MLK1.
CC       CEP-1347 and many indolocarbazole analogs have been shown to act as
CC       inhibitors of MAP3K9/MLK1 activity. {ECO:0000269|PubMed:11325962,
CC       ECO:0000269|PubMed:11755341, ECO:0000269|PubMed:15610029}.
CC   -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC       Kinetic parameters:
CC         KM=62 uM for ATP {ECO:0000269|PubMed:11325962};
CC         KM=7 uM for myelin basic protein (MBP) as substrate
CC         {ECO:0000269|PubMed:11325962};
CC   -!- SUBUNIT: Homodimer. {ECO:0000250}.
CC   -!- INTERACTION:
CC       P80192; P08238: HSP90AB1; NbExp=2; IntAct=EBI-3951604, EBI-352572;
CC       P80192; Q92993: KAT5; NbExp=3; IntAct=EBI-3951604, EBI-399080;
CC       P80192; Q8TAP4-4: LMO3; NbExp=3; IntAct=EBI-3951604, EBI-11742507;
CC       P80192; P17252: PRKCA; NbExp=3; IntAct=EBI-3951604, EBI-1383528;
CC       P80192; Q15047-2: SETDB1; NbExp=3; IntAct=EBI-3951604, EBI-9090795;
CC       P80192; P62258: YWHAE; NbExp=3; IntAct=EBI-3951604, EBI-356498;
CC       P80192; P61981: YWHAG; NbExp=4; IntAct=EBI-3951604, EBI-359832;
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=2;
CC       Name=1;
CC         IsoId=P80192-1; Sequence=Displayed;
CC       Name=2;
CC         IsoId=P80192-4; Sequence=VSP_013765;
CC   -!- TISSUE SPECIFICITY: Expressed in epithelial tumor cell lines of
CC       colonic, breast and esophageal origin. {ECO:0000269|PubMed:8477742}.
CC   -!- PTM: Autophosphorylation on serine and threonine residues within the
CC       activation loop plays a role in enzyme activation. Thr-312 is likely to
CC       be the main autophosphorylation site. Autophosphorylation also occurs
CC       on Thr-304 and Ser-308. {ECO:0000269|PubMed:11325962,
CC       ECO:0000269|PubMed:15610029}.
CC   -!- DISEASE: Note=May play a role in esophageal cancer susceptibility
CC       and/or development.
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=AAI11408.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
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DR   EMBL; AY327900; AAQ23054.1; -; mRNA.
DR   EMBL; BC111407; AAI11408.1; ALT_INIT; mRNA.
DR   EMBL; BC133706; AAI33707.1; -; mRNA.
DR   EMBL; AF251442; AAG44591.1; -; mRNA.
DR   CCDS; CCDS32112.1; -. [P80192-4]
DR   CCDS; CCDS61488.1; -. [P80192-1]
DR   PIR; S32467; JU0229.
DR   RefSeq; NP_001271159.1; NM_001284230.1. [P80192-1]
DR   RefSeq; NP_149132.2; NM_033141.3. [P80192-4]
DR   PDB; 3DTC; X-ray; 2.60 A; A=136-406.
DR   PDB; 4UY9; X-ray; 2.81 A; A/B=135-456.
DR   PDBsum; 3DTC; -.
DR   PDBsum; 4UY9; -.
DR   AlphaFoldDB; P80192; -.
DR   SMR; P80192; -.
DR   BioGRID; 110439; 28.
DR   IntAct; P80192; 30.
DR   STRING; 9606.ENSP00000451263; -.
DR   BindingDB; P80192; -.
DR   ChEMBL; CHEMBL2872; -.
DR   DrugBank; DB08703; 12-(2-hydroxyethyl)-2-(1-methylethoxy)-13,14-dihydronaphtho[2,1-a]pyrrolo[3,4-c]carbazol-5(12H)-one.
DR   DrugBank; DB12010; Fostamatinib.
DR   DrugCentral; P80192; -.
DR   GuidetoPHARMACOLOGY; 2084; -.
DR   iPTMnet; P80192; -.
DR   PhosphoSitePlus; P80192; -.
DR   BioMuta; MAP3K9; -.
DR   DMDM; 116242625; -.
DR   CPTAC; CPTAC-860; -.
DR   CPTAC; CPTAC-861; -.
DR   EPD; P80192; -.
DR   jPOST; P80192; -.
DR   MassIVE; P80192; -.
DR   PaxDb; 9606-ENSP00000451263; -.
DR   PeptideAtlas; P80192; -.
DR   ProteomicsDB; 57671; -. [P80192-1]
DR   ProteomicsDB; 57672; -. [P80192-4]
DR   Antibodypedia; 75; 407 antibodies from 33 providers.
DR   DNASU; 4293; -.
DR   Ensembl; ENST00000554752.7; ENSP00000451612.2; ENSG00000006432.16. [P80192-1]
DR   Ensembl; ENST00000555993.6; ENSP00000451263.2; ENSG00000006432.16. [P80192-4]
DR   GeneID; 4293; -.
DR   KEGG; hsa:4293; -.
DR   MANE-Select; ENST00000554752.7; ENSP00000451612.2; NM_001284230.2; NP_001271159.1.
DR   UCSC; uc001xml.5; human. [P80192-1]
DR   AGR; HGNC:6861; -.
DR   CTD; 4293; -.
DR   DisGeNET; 4293; -.
DR   GeneCards; MAP3K9; -.
DR   HGNC; HGNC:6861; MAP3K9.
DR   HPA; ENSG00000006432; Tissue enhanced (retina).
DR   MIM; 600136; gene.
DR   neXtProt; NX_P80192; -.
DR   OpenTargets; ENSG00000006432; -.
DR   PharmGKB; PA30607; -.
DR   VEuPathDB; HostDB:ENSG00000006432; -.
DR   eggNOG; KOG0192; Eukaryota.
DR   GeneTree; ENSGT00940000158243; -.
DR   InParanoid; P80192; -.
DR   OMA; GCGPYRE; -.
DR   OrthoDB; 876955at2759; -.
DR   PhylomeDB; P80192; -.
DR   TreeFam; TF105118; -.
DR   PathwayCommons; P80192; -.
DR   SABIO-RK; P80192; -.
DR   SignaLink; P80192; -.
DR   SIGNOR; P80192; -.
DR   BioGRID-ORCS; 4293; 8 hits in 1178 CRISPR screens.
DR   ChiTaRS; MAP3K9; human.
DR   EvolutionaryTrace; P80192; -.
DR   GeneWiki; MAP3K9; -.
DR   GenomeRNAi; 4293; -.
DR   Pharos; P80192; Tchem.
DR   PRO; PR:P80192; -.
DR   Proteomes; UP000005640; Chromosome 14.
DR   RNAct; P80192; Protein.
DR   Bgee; ENSG00000006432; Expressed in buccal mucosa cell and 161 other cell types or tissues.
DR   ExpressionAtlas; P80192; baseline and differential.
DR   GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR   GO; GO:0004706; F:JUN kinase kinase kinase activity; ISS:UniProtKB.
DR   GO; GO:0004708; F:MAP kinase kinase activity; NAS:UniProtKB.
DR   GO; GO:0042803; F:protein homodimerization activity; ISS:UniProtKB.
DR   GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR   GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:UniProtKB.
DR   GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
DR   GO; GO:0043065; P:positive regulation of apoptotic process; IEA:Ensembl.
DR   GO; GO:0046777; P:protein autophosphorylation; IDA:UniProtKB.
DR   GO; GO:0006468; P:protein phosphorylation; IDA:UniProtKB.
DR   CDD; cd12059; SH3_MLK1-3; 1.
DR   CDD; cd14145; STKc_MLK1; 1.
DR   Gene3D; 2.30.30.40; SH3 Domains; 1.
DR   Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1.
DR   InterPro; IPR011009; Kinase-like_dom_sf.
DR   InterPro; IPR035779; MLK1-3_SH3.
DR   InterPro; IPR016231; MLK1-4.
DR   InterPro; IPR000719; Prot_kinase_dom.
DR   InterPro; IPR017441; Protein_kinase_ATP_BS.
DR   InterPro; IPR001245; Ser-Thr/Tyr_kinase_cat_dom.
DR   InterPro; IPR008271; Ser/Thr_kinase_AS.
DR   InterPro; IPR036028; SH3-like_dom_sf.
DR   InterPro; IPR001452; SH3_domain.
DR   PANTHER; PTHR23257:SF717; MITOGEN-ACTIVATED PROTEIN KINASE KINASE KINASE; 1.
DR   PANTHER; PTHR23257; SERINE-THREONINE PROTEIN KINASE; 1.
DR   Pfam; PF00069; Pkinase; 1.
DR   Pfam; PF14604; SH3_9; 1.
DR   PIRSF; PIRSF000556; MAPKKK9_11; 1.
DR   PRINTS; PR00452; SH3DOMAIN.
DR   PRINTS; PR00109; TYRKINASE.
DR   SMART; SM00220; S_TKc; 1.
DR   SMART; SM00326; SH3; 1.
DR   SUPFAM; SSF56112; Protein kinase-like (PK-like); 1.
DR   SUPFAM; SSF50044; SH3-domain; 1.
DR   PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR   PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR   PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
DR   PROSITE; PS50002; SH3; 1.
DR   Genevisible; P80192; HS.
PE   1: Evidence at protein level;
KW   3D-structure; Alternative splicing; Apoptosis; ATP-binding; Kinase;
KW   Nucleotide-binding; Phosphoprotein; Reference proteome; Repeat;
KW   Serine/threonine-protein kinase; SH3 domain; Stress response;
KW   Transcription; Transcription regulation; Transferase.
FT   CHAIN           1..1104
FT                   /note="Mitogen-activated protein kinase kinase kinase 9"
FT                   /id="PRO_0000086258"
FT   DOMAIN          52..116
FT                   /note="SH3"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00192"
FT   DOMAIN          144..412
FT                   /note="Protein kinase"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   REGION          12..47
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          430..451
FT                   /note="Leucine-zipper 1"
FT   REGION          465..486
FT                   /note="Leucine-zipper 2"
FT   REGION          532..636
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          675..742
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          781..819
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          890..1038
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        26..41
FT                   /note="Acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        532..552
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        578..595
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        719..739
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        783..801
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        894..915
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        927..941
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        955..969
FT                   /note="Pro residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        971..985
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        1012..1038
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   ACT_SITE        268
FT                   /note="Proton acceptor"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT                   ECO:0000255|PROSITE-ProRule:PRU10027"
FT   BINDING         150..158
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   BINDING         171
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT   MOD_RES         304
FT                   /note="Phosphothreonine; by autocatalysis"
FT                   /evidence="ECO:0000269|PubMed:15610029"
FT   MOD_RES         305
FT                   /note="Phosphothreonine; by autocatalysis"
FT                   /evidence="ECO:0000269|PubMed:15610029"
FT   MOD_RES         308
FT                   /note="Phosphoserine; by autocatalysis"
FT                   /evidence="ECO:0000269|PubMed:15610029"
FT   MOD_RES         312
FT                   /note="Phosphothreonine; by autocatalysis"
FT                   /evidence="ECO:0000269|PubMed:15610029"
FT   MOD_RES         533
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:23186163"
FT   VAR_SEQ         675
FT                   /note="M -> MALLAASWVVPIDIE (in isoform 2)"
FT                   /evidence="ECO:0000303|Ref.3"
FT                   /id="VSP_013765"
FT   VARIANT         246
FT                   /note="A -> V (in a metastatic melanoma sample; somatic
FT                   mutation)"
FT                   /evidence="ECO:0000269|PubMed:17344846"
FT                   /id="VAR_040698"
FT   VARIANT         467
FT                   /note="R -> C (in a gastric adenocarcinoma sample; somatic
FT                   mutation; dbSNP:rs773256562)"
FT                   /evidence="ECO:0000269|PubMed:17344846"
FT                   /id="VAR_040699"
FT   VARIANT         497
FT                   /note="R -> Q (in dbSNP:rs56196343)"
FT                   /evidence="ECO:0000269|PubMed:17344846"
FT                   /id="VAR_040700"
FT   VARIANT         646
FT                   /note="Y -> C (in dbSNP:rs34322726)"
FT                   /evidence="ECO:0000269|PubMed:17344846"
FT                   /id="VAR_040701"
FT   MUTAGEN         171
FT                   /note="K->A: Loss of kinase activity and threonine
FT                   phosphorylation."
FT                   /evidence="ECO:0000269|PubMed:15610029"
FT   MUTAGEN         304
FT                   /note="T->A: Reduces threonine phosphorylation. Impairs JNK
FT                   activation."
FT                   /evidence="ECO:0000269|PubMed:15610029"
FT   MUTAGEN         305
FT                   /note="T->A: Little effect on threonine phosphorylation.
FT                   Mildly impairs JNK activation."
FT                   /evidence="ECO:0000269|PubMed:15610029"
FT   MUTAGEN         308
FT                   /note="S->A: Impairs JNK activation."
FT                   /evidence="ECO:0000269|PubMed:15610029"
FT   MUTAGEN         312
FT                   /note="T->A: Loss of threonine phosphorylation. Strongly
FT                   impairs JNK activation."
FT                   /evidence="ECO:0000269|PubMed:15610029"
FT   CONFLICT        356
FT                   /note="A -> R (in Ref. 4)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        433
FT                   /note="M -> T (in Ref. 1; AAQ23054)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        511..535
FT                   /note="KLKDGNRISLPSDFQHKFTVQASPT -> AQPVLPFPHGHSRCPGGTGSSWG
FT                   GQ (in Ref. 4)"
FT                   /evidence="ECO:0000305"
FT   STRAND          143..153
FT                   /evidence="ECO:0007829|PDB:3DTC"
FT   STRAND          156..163
FT                   /evidence="ECO:0007829|PDB:3DTC"
FT   STRAND          166..172
FT                   /evidence="ECO:0007829|PDB:3DTC"
FT   HELIX           185..197
FT                   /evidence="ECO:0007829|PDB:3DTC"
FT   STRAND          206..210
FT                   /evidence="ECO:0007829|PDB:3DTC"
FT   STRAND          217..221
FT                   /evidence="ECO:0007829|PDB:3DTC"
FT   HELIX           228..232
FT                   /evidence="ECO:0007829|PDB:3DTC"
FT   HELIX           239..258
FT                   /evidence="ECO:0007829|PDB:3DTC"
FT   STRAND          259..262
FT                   /evidence="ECO:0007829|PDB:3DTC"
FT   HELIX           271..273
FT                   /evidence="ECO:0007829|PDB:3DTC"
FT   STRAND          274..278
FT                   /evidence="ECO:0007829|PDB:3DTC"
FT   STRAND          281..283
FT                   /evidence="ECO:0007829|PDB:3DTC"
FT   STRAND          290..292
FT                   /evidence="ECO:0007829|PDB:3DTC"
FT   HELIX           299..301
FT                   /evidence="ECO:0007829|PDB:4UY9"
FT   HELIX           313..315
FT                   /evidence="ECO:0007829|PDB:3DTC"
FT   HELIX           318..323
FT                   /evidence="ECO:0007829|PDB:3DTC"
FT   HELIX           328..344
FT                   /evidence="ECO:0007829|PDB:3DTC"
FT   TURN            348..351
FT                   /evidence="ECO:0007829|PDB:3DTC"
FT   HELIX           354..362
FT                   /evidence="ECO:0007829|PDB:3DTC"
FT   HELIX           376..385
FT                   /evidence="ECO:0007829|PDB:3DTC"
FT   HELIX           390..392
FT                   /evidence="ECO:0007829|PDB:3DTC"
FT   HELIX           396..404
FT                   /evidence="ECO:0007829|PDB:3DTC"
FT   HELIX           410..412
FT                   /evidence="ECO:0007829|PDB:4UY9"
FT   HELIX           418..439
FT                   /evidence="ECO:0007829|PDB:4UY9"
FT   HELIX           441..444
FT                   /evidence="ECO:0007829|PDB:4UY9"
SQ   SEQUENCE   1104 AA;  121895 MW;  0F059C867FCE7276 CRC64;
     MEPSRALLGC LASAAAAAPP GEDGAGAGAE EEEEEEEEAA AAVGPGELGC DAPLPYWTAV
     FEYEAAGEDE LTLRLGDVVE VLSKDSQVSG DEGWWTGQLN QRVGIFPSNY VTPRSAFSSR
     CQPGGEDPSC YPPIQLLEID FAELTLEEII GIGGFGKVYR AFWIGDEVAV KAARHDPDED
     ISQTIENVRQ EAKLFAMLKH PNIIALRGVC LKEPNLCLVM EFARGGPLNR VLSGKRIPPD
     ILVNWAVQIA RGMNYLHDEA IVPIIHRDLK SSNILILQKV ENGDLSNKIL KITDFGLARE
     WHRTTKMSAA GTYAWMAPEV IRASMFSKGS DVWSYGVLLW ELLTGEVPFR GIDGLAVAYG
     VAMNKLALPI PSTCPEPFAK LMEDCWNPDP HSRPSFTNIL DQLTTIEESG FFEMPKDSFH
     CLQDNWKHEI QEMFDQLRAK EKELRTWEEE LTRAALQQKN QEELLRRREQ ELAEREIDIL
     ERELNIIIHQ LCQEKPRVKK RKGKFRKSRL KLKDGNRISL PSDFQHKFTV QASPTMDKRK
     SLINSRSSPP ASPTIIPRLR AIQLTPGESS KTWGRSSVVP KEEGEEEEKR APKKKGRTWG
     PGTLGQKELA SGDEGSPQRR EKANGLSTPS ESPHFHLGLK SLVDGYKQWS SSAPNLVKGP
     RSSPALPGFT SLMEMEDEDS EGPGSGESRL QHSPSQSYLC IPFPRGEDGD GPSSDGIHEE
     PTPVNSATST PQLTPTNSLK RGGAHHRRCE VALLGCGAVL AATGLGFDLL EAGKCQLLPL
     EEPEPPAREE KKRREGLFQR SSRPRRSTSP PSRKLFKKEE PMLLLGDPSA SLTLLSLSSI
     SECNSTRSLL RSDSDEIVVY EMPVSPVEAP PLSPCTHNPL VNVRVERFKR DPNQSLTPTH
     VTLTTPSQPS SHRRTPSDGA LKPETLLASR SPSSNGLSPS PGAGMLKTPS PSRDPGEFPR
     LPDPNVVFPP TPRRWNTQQD STLERPKTLE FLPRPRPSAN RQRLDPWWFV SPSHARSTSP
     ANSSSTETPS NLDSCFASSS STVEERPGLP ALLPFQAGPL PPTERTLLDL DAEGQSQDST
     VPLCRAELNT HRPAPYEIQQ EFWS
//