(data stored in ACNUC8465 zone)

SWISSPROT: MP2K6_HUMAN

ID   MP2K6_HUMAN             Reviewed;         334 AA.
AC   P52564;
DT   01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
DT   01-OCT-1996, sequence version 1.
DT   11-DEC-2019, entry version 196.
DE   RecName: Full=Dual specificity mitogen-activated protein kinase kinase 6;
DE            Short=MAP kinase kinase 6;
DE            Short=MAPKK 6;
DE            EC=2.7.12.2;
DE   AltName: Full=MAPK/ERK kinase 6;
DE            Short=MEK 6;
DE   AltName: Full=Stress-activated protein kinase kinase 3;
DE            Short=SAPK kinase 3;
DE            Short=SAPKK-3;
DE            Short=SAPKK3;
GN   Name=MAP2K6; Synonyms=MEK6, MKK6, PRKMK6, SKK3;
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), MUTAGENESIS, AND FUNCTION.
RC   TISSUE=Skeletal muscle;
RX   PubMed=8622669; DOI=10.1128/mcb.16.3.1247;
RA   Raingeaud J., Whitmarsh A.J., Barrett T., Derijard B., Davis R.J.;
RT   "MKK3- and MKK6-regulated gene expression is mediated by the p38 mitogen-
RT   activated protein kinase signal transduction pathway.";
RL   Mol. Cell. Biol. 16:1247-1255(1996).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, AND ACTIVITY REGULATION.
RC   TISSUE=T-cell;
RX   PubMed=8626699; DOI=10.1074/jbc.271.19.11427;
RA   Stein B., Brady H., Yang M.X., Young D.B., Barbosa M.S.;
RT   "Cloning and characterization of MEK6, a novel member of the mitogen-
RT   activated protein kinase kinase cascade.";
RL   J. Biol. Chem. 271:11427-11433(1996).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), TISSUE SPECIFICITY, AND
RP   MUTAGENESIS.
RC   TISSUE=Placenta;
RX   PubMed=8621675; DOI=10.1074/jbc.271.6.2886;
RA   Han J., Lee J.-D., Jiang Y., Li Z., Feng L., Ulevitch R.J.;
RT   "Characterization of the structure and function of a novel MAP kinase
RT   kinase (MKK6).";
RL   J. Biol. Chem. 271:2886-2891(1996).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), PHOSPHORYLATION, ACTIVITY
RP   REGULATION, AND FUNCTION.
RX   PubMed=8663074; DOI=10.1074/jbc.271.23.13675;
RA   Moriguchi T., Kuroyanagi N., Yamaguchi K., Gotoh Y., Irie K., Kano T.,
RA   Shirakabe K., Muro Y., Shibuya H., Matsumoto K., Nishida E., Hagiwara M.;
RT   "A novel kinase cascade mediated by mitogen-activated protein kinase kinase
RT   6 and MKK3.";
RL   J. Biol. Chem. 271:13675-13679(1996).
RN   [5]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX   PubMed=8861944; DOI=10.1002/j.1460-2075.1996.tb00790.x;
RA   Cuenda A., Alonso G., Morrice N., Jones M., Meier R., Cohen P.,
RA   Nebreda A.R.;
RT   "Purification and cDNA cloning of SAPKK3, the major activator of RK/p38 in
RT   stress- and cytokine-stimulated monocytes and epithelial cells.";
RL   EMBO J. 15:4156-4164(1996).
RN   [6]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC   TISSUE=Urinary bladder;
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 IN ACTIVATION OF MAPK13.
RX   PubMed=9218798; DOI=10.1093/emboj/16.12.3563;
RA   Goedert M., Cuenda A., Craxton M., Jakes R., Cohen P.;
RT   "Activation of the novel stress-activated protein kinase SAPK4 by cytokines
RT   and cellular stresses is mediated by SKK3 (MKK6); comparison of its
RT   substrate specificity with that of other SAP kinases.";
RL   EMBO J. 16:3563-3571(1997).
RN   [8]
RP   SUBCELLULAR LOCATION.
RX   PubMed=9768359; DOI=10.1016/s0960-9822(98)70442-7;
RA   Ben-Levy R., Hooper S., Wilson R., Paterson H.F., Marshall C.J.;
RT   "Nuclear export of the stress-activated protein kinase p38 mediated by its
RT   substrate MAPKAP kinase-2.";
RL   Curr. Biol. 8:1049-1057(1998).
RN   [9]
RP   PHOSPHORYLATION BY MAP3K4.
RX   PubMed=9841871; DOI=10.1042/bj3360599;
RA   Chan-Hui P.Y., Weaver R.;
RT   "Human mitogen-activated protein kinase kinase kinase mediates the stress-
RT   induced activation of mitogen-activated protein kinase cascades.";
RL   Biochem. J. 336:599-609(1998).
RN   [10]
RP   PHOSPHORYLATION BY MAP3K2/MEKK2 AND MAP3K3/MEK3.
RX   PubMed=10347227; DOI=10.1074/jbc.274.23.16604;
RA   Deacon K., Blank J.L.;
RT   "MEK kinase 3 directly activates MKK6 and MKK7, specific activators of the
RT   p38 and c-Jun NH2-terminal kinases.";
RL   J. Biol. Chem. 274:16604-16610(1999).
RN   [11]
RP   INTERACTION WITH TAOK2, AND PHOSPHORYLATION BY TAOK2.
RX   PubMed=10497253; DOI=10.1074/jbc.274.40.28803;
RA   Chen Z., Hutchison M., Cobb M.H.;
RT   "Isolation of the protein kinase TAO2 and identification of its mitogen-
RT   activated protein kinase/extracellular signal-regulated kinase kinase
RT   binding domain.";
RL   J. Biol. Chem. 274:28803-28807(1999).
RN   [12]
RP   PHOSPHORYLATION BY MAP3K7/TAK1.
RX   PubMed=10094049; DOI=10.1038/18465;
RA   Ninomiya-Tsuji J., Kishimoto K., Hiyama A., Inoue J., Cao Z., Matsumoto K.;
RT   "The kinase TAK1 can activate the NIK-I kappaB as well as the MAP kinase
RT   cascade in the IL-1 signalling pathway.";
RL   Nature 398:252-256(1999).
RN   [13]
RP   CLEAVAGE BY ANTHRAX LETHAL FACTOR.
RX   PubMed=11104681; DOI=10.1042/bj3520739;
RA   Vitale G., Bernardi L., Napolitani G., Mock M., Montecucco C.;
RT   "Susceptibility of mitogen-activated protein kinase kinase family members
RT   to proteolysis by anthrax lethal factor.";
RL   Biochem. J. 352:739-745(2000).
RN   [14]
RP   FUNCTION.
RX   PubMed=10961885;
RA   Visconti R., Gadina M., Chiariello M., Chen E.H., Stancato L.F.,
RA   Gutkind J.S., O'Shea J.J.;
RT   "Importance of the MKK6/p38 pathway for interleukin-12-induced STAT4 serine
RT   phosphorylation and transcriptional activity.";
RL   Blood 96:1844-1852(2000).
RN   [15]
RP   FUNCTION.
RX   PubMed=11727828; DOI=10.1515/bc.2001.178;
RA   Bode J.G., Ludwig S., Freitas C.A., Schaper F., Ruhl M., Melmed S.,
RA   Heinrich P.C., Haussinger D.;
RT   "The MKK6/p38 mitogen-activated protein kinase pathway is capable of
RT   inducing SOCS3 gene expression and inhibits IL-6-induced transcription.";
RL   Biol. Chem. 382:1447-1453(2001).
RN   [16]
RP   PHOSPHORYLATION BY MAP3K5/ASK1.
RX   PubMed=11689443; DOI=10.1093/emboj/20.21.6028;
RA   Morita K., Saitoh M., Tobiume K., Matsuura H., Enomoto S., Nishitoh H.,
RA   Ichijo H.;
RT   "Negative feedback regulation of ASK1 by protein phosphatase 5 (PP5) in
RT   response to oxidative stress.";
RL   EMBO J. 20:6028-6036(2001).
RN   [17]
RP   PHOSPHORYLATION BY TAOK2.
RX   PubMed=11279118; DOI=10.1074/jbc.m100681200;
RA   Chen Z., Cobb M.H.;
RT   "Regulation of stress-responsive mitogen-activated protein (MAP) kinase
RT   pathways by TAO2.";
RL   J. Biol. Chem. 276:16070-16075(2001).
RN   [18]
RP   PHOSPHORYLATION BY MAP3K7/TAK1.
RX   PubMed=11460167; DOI=10.1038/35085597;
RA   Wang C., Deng L., Hong M., Akkaraju G.R., Inoue J., Chen Z.J.;
RT   "TAK1 is a ubiquitin-dependent kinase of MKK and IKK.";
RL   Nature 412:346-351(2001).
RN   [19]
RP   INTERACTION WITH EIF2AK2, AND PHOSPHORYLATION.
RX   PubMed=15229216; DOI=10.1074/jbc.m406554200;
RA   Silva A.M., Whitmore M., Xu Z., Jiang Z., Li X., Williams B.R.;
RT   "Protein kinase R (PKR) interacts with and activates mitogen-activated
RT   protein kinase kinase 6 (MKK6) in response to double-stranded RNA
RT   stimulation.";
RL   J. Biol. Chem. 279:37670-37676(2004).
RN   [20]
RP   INTERACTION WITH DCTN1, AND MICROTUBULE-BINDING.
RX   PubMed=15375157; DOI=10.1074/jbc.c400333200;
RA   Cheung P.Y., Zhang Y., Long J., Lin S., Zhang M., Jiang Y., Wu Z.;
RT   "p150(Glued), Dynein, and microtubules are specifically required for
RT   activation of MKK3/6 and p38 MAPKs.";
RL   J. Biol. Chem. 279:45308-45311(2004).
RN   [21]
RP   FUNCTION IN PHOSPHORYLATION OF PAK6.
RX   PubMed=15550393; DOI=10.1074/jbc.m406701200;
RA   Kaur R., Liu X., Gjoerup O., Zhang A., Yuan X., Balk S.P., Schneider M.C.,
RA   Lu M.L.;
RT   "Activation of p21-activated kinase 6 by MAP kinase kinase 6 and p38 MAP
RT   kinase.";
RL   J. Biol. Chem. 280:3323-3330(2005).
RN   [22]
RP   DOMAIN.
RX   PubMed=15866172; DOI=10.1016/j.molcel.2005.04.001;
RA   Takekawa M., Tatebayashi K., Saito H.;
RT   "Conserved docking site is essential for activation of mammalian MAP kinase
RT   kinases by specific MAP kinase kinase kinases.";
RL   Mol. Cell 18:295-306(2005).
RN   [23]
RP   ACETYLATION AT SER-207 AND THR-211, PHOSPHORYLATION AT SER-207 AND THR-211,
RP   INACTIVATION BY YERSINIA YOPJ, AND IDENTIFICATION BY MASS SPECTROMETRY.
RX   PubMed=16728640; DOI=10.1126/science.1126867;
RA   Mukherjee S., Keitany G., Li Y., Wang Y., Ball H.L., Goldsmith E.J.,
RA   Orth K.;
RT   "Yersinia YopJ acetylates and inhibits kinase activation by blocking
RT   phosphorylation.";
RL   Science 312:1211-1214(2006).
RN   [24]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma;
RX   PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA   Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA   Elledge S.J., Gygi S.P.;
RT   "A quantitative atlas of mitotic phosphorylation.";
RL   Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN   [25]
RP   PHOSPHORYLATION BY MAP3K5/ASK1, ACTIVITY REGULATION, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY.
RX   PubMed=20364819; DOI=10.1021/bi100010j;
RA   Sturchler E., Feurstein D., McDonald P., Duckett D.;
RT   "Mechanism of oxidative stress-induced ASK1-catalyzed MKK6
RT   phosphorylation.";
RL   Biochemistry 49:4094-4102(2010).
RN   [26]
RP   FUNCTION.
RX   PubMed=20869211; DOI=10.1016/j.jdermsci.2010.08.006;
RA   Kim M.Y., Choi T.Y., Kim J.H., Lee J.H., Kim J.G., Sohn K.C., Yoon K.S.,
RA   Kim C.D., Lee J.H., Yoon T.J.;
RT   "MKK6 increases the melanocyte dendricity through the regulation of Rho
RT   family GTPases.";
RL   J. Dermatol. Sci. 60:114-119(2010).
RN   [27]
RP   REVIEW ON ACTIVITY REGULATION, AND REVIEW ON FUNCTION.
RX   PubMed=9779990; DOI=10.1038/sj.onc.1202251;
RA   Dhanasekaran N., Premkumar Reddy E.;
RT   "Signaling by dual specificity kinases.";
RL   Oncogene 17:1447-1455(1998).
RN   [28]
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   [29]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma;
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   [30]
RP   X-RAY CRYSTALLOGRAPHY (2.35 ANGSTROMS) OF 45-332 OF MUTANT ASP-207 AND
RP   ASP-211, AND SUBUNIT.
RX   PubMed=19141286; DOI=10.1016/j.str.2008.11.007;
RA   Min X., Akella R., He H., Humphreys J.M., Tsutakawa S.E., Lee S.J.,
RA   Tainer J.A., Cobb M.H., Goldsmith E.J.;
RT   "The structure of the MAP2K MEK6 reveals an autoinhibitory dimer.";
RL   Structure 17:96-104(2009).
RN   [31]
RP   X-RAY CRYSTALLOGRAPHY (2.26 ANGSTROMS) OF 47-334.
RG   Structural genomics consortium (SGC);
RT   "Crystal structure of human mitogen-activated protein kinase kinase 6
RT   (mek6) activated mutant (s207d, t211d).";
RL   Submitted (JUL-2011) to the PDB data bank.
CC   -!- FUNCTION: Dual specificity protein kinase which acts as an essential
CC       component of the MAP kinase signal transduction pathway. With
CC       MAP3K3/MKK3, catalyzes the concomitant phosphorylation of a threonine
CC       and a tyrosine residue in the MAP kinases p38 MAPK11, MAPK12, MAPK13
CC       and MAPK14 and plays an important role in the regulation of cellular
CC       responses to cytokines and all kinds of stresses. Especially,
CC       MAP2K3/MKK3 and MAP2K6/MKK6 are both essential for the activation of
CC       MAPK11 and MAPK13 induced by environmental stress, whereas MAP2K6/MKK6
CC       is the major MAPK11 activator in response to TNF. MAP2K6/MKK6 also
CC       phosphorylates and activates PAK6. The p38 MAP kinase signal
CC       transduction pathway leads to direct activation of transcription
CC       factors. Nuclear targets of p38 MAP kinase include the transcription
CC       factors ATF2 and ELK1. Within the p38 MAPK signal transduction pathway,
CC       MAP3K6/MKK6 mediates phosphorylation of STAT4 through MAPK14
CC       activation, and is therefore required for STAT4 activation and STAT4-
CC       regulated gene expression in response to IL-12 stimulation. The pathway
CC       is also crucial for IL-6-induced SOCS3 expression and down-regulation
CC       of IL-6-mediated gene induction; and for IFNG-dependent gene
CC       transcription. Has a role in osteoclast differentiation through NF-
CC       kappa-B transactivation by TNFSF11, and in endochondral ossification
CC       and since SOX9 is another likely downstream target of the p38 MAPK
CC       pathway. MAP2K6/MKK6 mediates apoptotic cell death in thymocytes. Acts
CC       also as a regulator for melanocytes dendricity, through the modulation
CC       of Rho family GTPases. {ECO:0000269|PubMed:10961885,
CC       ECO:0000269|PubMed:11727828, ECO:0000269|PubMed:15550393,
CC       ECO:0000269|PubMed:20869211, ECO:0000269|PubMed:8622669,
CC       ECO:0000269|PubMed:8626699, ECO:0000269|PubMed:8663074,
CC       ECO:0000269|PubMed:9218798}.
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=2.7.12.2;
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=2.7.12.2;
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl-
CC         [protein]; Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA-
CC         COMP:10137, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858,
CC         ChEBI:CHEBI:82620, ChEBI:CHEBI:456216; EC=2.7.12.2;
CC   -!- ACTIVITY REGULATION: Activated by dual phosphorylation on Ser-207 and
CC       Thr-211 in response to a variety of cellular stresses, including UV
CC       radiation, osmotic shock, hypoxia, inflammatory cytokines, interferon
CC       gamma (IFNG), and less often by growth factors. MAP2K6/MKK6 is
CC       activated by the majority of M3Ks, such as MAP3K5/ASK1, MAP3K1/MEKK1,
CC       MAP3K2/MEKK2, MAP3K3/MEKK3, MAP3K4/MEKK4, MAP3K7/TAK1, MAP3K11/MLK3 and
CC       MAP3K17/TAOK2. {ECO:0000269|PubMed:20364819,
CC       ECO:0000269|PubMed:8626699, ECO:0000269|PubMed:8663074}.
CC   -!- SUBUNIT: Dimer. Interacts with Yersinia yopJ. Interacts (via its D
CC       domain) with its substrates MAPK11, MAPK12, MAPK13 and MAPK14 (By
CC       similarity). Interacts (via its DVD domain) with MAP3Ks activators like
CC       MAP3K5/ASK1, MAP3K1/MEKK1, MAP3K2/MEKK2, MAP3K3/MEKK3, MAP3K4/MEKK4,
CC       MAP3K7/TAK1, MAP3K11/MLK3 and MAP3K17/TAOK2 (By similarity). Interacts
CC       with DCTN1. Interacts with EIF2AK2/PKR. {ECO:0000250,
CC       ECO:0000269|PubMed:10497253, ECO:0000269|PubMed:15229216,
CC       ECO:0000269|PubMed:15375157, ECO:0000269|PubMed:19141286}.
CC   -!- INTERACTION:
CC       P24522:GADD45A; NbExp=2; IntAct=EBI-448135, EBI-448167;
CC       Q5S007:LRRK2; NbExp=4; IntAct=EBI-448135, EBI-5323863;
CC       Q9Y6R4:MAP3K4; NbExp=2; IntAct=EBI-448135, EBI-448104;
CC   -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:9768359}. Cytoplasm
CC       {ECO:0000269|PubMed:9768359}. Cytoplasm, cytoskeleton
CC       {ECO:0000269|PubMed:9768359}. Note=Binds to microtubules.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=2;
CC       Name=1; Synonyms=MKK6b;
CC         IsoId=P52564-1; Sequence=Displayed;
CC       Name=2; Synonyms=MKK6;
CC         IsoId=P52564-2; Sequence=VSP_004882;
CC   -!- TISSUE SPECIFICITY: Isoform 2 is only expressed in skeletal muscle.
CC       Isoform 1 is expressed in skeletal muscle, heart, and in lesser extent
CC       in liver or pancreas. {ECO:0000269|PubMed:8621675}.
CC   -!- INDUCTION: Strongly activated by UV, anisomycin, and osmotic shock but
CC       not by phorbol esters, NGF or EGF.
CC   -!- DOMAIN: The DVD domain (residues 311-334) contains a conserved docking
CC       site and is found in the mammalian MAP kinase kinases (MAP2Ks). The DVD
CC       sites bind to their specific upstream MAP kinase kinase kinases
CC       (MAP3Ks) and are essential for activation.
CC       {ECO:0000269|PubMed:15866172}.
CC   -!- DOMAIN: The D domain (residues 4-19) contains a conserved docking site
CC       and is required for the binding to MAPK substrates. {ECO:0000250}.
CC   -!- PTM: Weakly autophosphorylated. Phosphorylated at Ser-207 and Thr-211
CC       by the majority of M3Ks, such as MAP3K5/ASK1, MAP3K1/MEKK1,
CC       MAP3K2/MEKK2, MAP3K3/MEKK3, MAP3K4/MEKK4, MAP3K7/TAK1, MAP3K11/MLK3 and
CC       MAP3K17/TAOK2. {ECO:0000269|PubMed:16728640}.
CC   -!- PTM: Acetylation of Ser-207 and Thr-211 by Yersinia yopJ prevents
CC       phosphorylation and activation, thus blocking the MAPK signaling
CC       pathway. {ECO:0000269|PubMed:16728640}.
CC   -!- SIMILARITY: Belongs to the protein kinase superfamily. STE Ser/Thr
CC       protein kinase family. MAP kinase kinase subfamily. {ECO:0000305}.
DR   EMBL; U39657; AAC50389.1; -; mRNA.
DR   EMBL; U39656; AAC50388.1; -; mRNA.
DR   EMBL; U49732; AAB05035.1; -; mRNA.
DR   EMBL; U39065; AAB03705.1; -; mRNA.
DR   EMBL; U39064; AAB03708.1; -; mRNA.
DR   EMBL; D87905; BAA13496.1; -; mRNA.
DR   EMBL; X96757; CAA65532.1; -; mRNA.
DR   EMBL; BC012009; AAH12009.1; -; mRNA.
DR   CCDS; CCDS11686.1; -. [P52564-1]
DR   CCDS; CCDS82194.1; -. [P52564-2]
DR   PIR; S71631; S71631.
DR   RefSeq; NP_002749.2; NM_002758.3. [P52564-1]
DR   PDB; 2Y8O; X-ray; 1.95 A; B=4-17.
DR   PDB; 3ENM; X-ray; 2.35 A; A/B/C/D=45-332.
DR   PDB; 3FME; X-ray; 2.26 A; A=47-334.
DR   PDB; 3VN9; X-ray; 2.60 A; A=1-334.
DR   PDB; 5ETF; X-ray; 2.40 A; B=4-17.
DR   PDBsum; 2Y8O; -.
DR   PDBsum; 3ENM; -.
DR   PDBsum; 3FME; -.
DR   PDBsum; 3VN9; -.
DR   PDBsum; 5ETF; -.
DR   SMR; P52564; -.
DR   BioGrid; 111594; 43.
DR   DIP; DIP-31346N; -.
DR   ELM; P52564; -.
DR   IntAct; P52564; 13.
DR   MINT; P52564; -.
DR   STRING; 9606.ENSP00000468348; -.
DR   BindingDB; P52564; -.
DR   ChEMBL; CHEMBL2171; -.
DR   DrugBank; DB12010; Fostamatinib.
DR   DrugCentral; P52564; -.
DR   GuidetoPHARMACOLOGY; 2067; -.
DR   iPTMnet; P52564; -.
DR   PhosphoSitePlus; P52564; -.
DR   BioMuta; MAP2K6; -.
DR   DMDM; 1709088; -.
DR   CPTAC; CPTAC-820; -.
DR   CPTAC; CPTAC-821; -.
DR   EPD; P52564; -.
DR   jPOST; P52564; -.
DR   MassIVE; P52564; -.
DR   MaxQB; P52564; -.
DR   PaxDb; P52564; -.
DR   PeptideAtlas; P52564; -.
DR   PRIDE; P52564; -.
DR   ProteomicsDB; 56487; -. [P52564-1]
DR   ProteomicsDB; 56488; -. [P52564-2]
DR   DNASU; 5608; -.
DR   Ensembl; ENST00000589647; ENSP00000467213; ENSG00000108984. [P52564-2]
DR   Ensembl; ENST00000590474; ENSP00000468348; ENSG00000108984. [P52564-1]
DR   Ensembl; ENST00000613873; ENSP00000477701; ENSG00000108984. [P52564-2]
DR   GeneID; 5608; -.
DR   KEGG; hsa:5608; -.
DR   UCSC; uc002jij.4; human. [P52564-1]
DR   CTD; 5608; -.
DR   DisGeNET; 5608; -.
DR   EuPathDB; HostDB:ENSG00000108984.13; -.
DR   GeneCards; MAP2K6; -.
DR   HGNC; HGNC:6846; MAP2K6.
DR   HPA; CAB007744; -.
DR   HPA; HPA031134; -.
DR   MIM; 601254; gene.
DR   neXtProt; NX_P52564; -.
DR   OpenTargets; ENSG00000108984; -.
DR   PharmGKB; PA30591; -.
DR   eggNOG; KOG0984; Eukaryota.
DR   eggNOG; ENOG410XT3F; LUCA.
DR   GeneTree; ENSGT00940000157836; -.
DR   HOGENOM; HOG000234206; -.
DR   InParanoid; P52564; -.
DR   KO; K04433; -.
DR   OMA; WGTPFEQ; -.
DR   OrthoDB; 688282at2759; -.
DR   PhylomeDB; P52564; -.
DR   BRENDA; 2.7.12.2; 2681.
DR   Reactome; R-HSA-168638; NOD1/2 Signaling Pathway.
DR   Reactome; R-HSA-2559580; Oxidative Stress Induced Senescence.
DR   Reactome; R-HSA-450302; activated TAK1 mediates p38 MAPK activation.
DR   Reactome; R-HSA-5210891; Uptake and function of anthrax toxins. [P52564-1]
DR   Reactome; R-HSA-525793; Myogenesis.
DR   Reactome; R-HSA-6811555; PI5P Regulates TP53 Acetylation.
DR   Reactome; R-HSA-9020702; Interleukin-1 signaling.
DR   SignaLink; P52564; -.
DR   SIGNOR; P52564; -.
DR   ChiTaRS; MAP2K6; human.
DR   EvolutionaryTrace; P52564; -.
DR   GeneWiki; MAP2K6; -.
DR   GenomeRNAi; 5608; -.
DR   Pharos; P52564; Tchem.
DR   PRO; PR:P52564; -.
DR   Proteomes; UP000005640; Chromosome 17.
DR   RNAct; P52564; protein.
DR   Bgee; ENSG00000108984; Expressed in 203 organ(s), highest expression level in quadriceps femoris.
DR   ExpressionAtlas; P52564; baseline and differential.
DR   Genevisible; P52564; HS.
DR   GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR   GO; GO:0005856; C:cytoskeleton; IEA:UniProtKB-SubCell.
DR   GO; GO:0005829; C:cytosol; IDA:HPA.
DR   GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR   GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR   GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR   GO; GO:0004708; F:MAP kinase kinase activity; IDA:UniProtKB.
DR   GO; GO:0019901; F:protein kinase binding; IPI:UniProtKB.
DR   GO; GO:0004674; F:protein serine/threonine kinase activity; IBA:GO_Central.
DR   GO; GO:0004713; F:protein tyrosine kinase activity; IEA:UniProtKB-KW.
DR   GO; GO:0000187; P:activation of MAPK activity; IDA:UniProtKB.
DR   GO; GO:0032147; P:activation of protein kinase activity; IBA:GO_Central.
DR   GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
DR   GO; GO:0060048; P:cardiac muscle contraction; IEA:Ensembl.
DR   GO; GO:0007050; P:cell cycle arrest; TAS:ProtInc.
DR   GO; GO:0072709; P:cellular response to sorbitol; IEA:Ensembl.
DR   GO; GO:0006975; P:DNA damage induced protein phosphorylation; TAS:ProtInc.
DR   GO; GO:0120163; P:negative regulation of cold-induced thermogenesis; ISS:YuBioLab.
DR   GO; GO:0070423; P:nucleotide-binding oligomerization domain containing signaling pathway; TAS:Reactome.
DR   GO; GO:0022602; P:ovulation cycle process; IEA:Ensembl.
DR   GO; GO:0043065; P:positive regulation of apoptotic process; IEA:Ensembl.
DR   GO; GO:0051770; P:positive regulation of nitric-oxide synthase biosynthetic process; IEA:Ensembl.
DR   GO; GO:0032308; P:positive regulation of prostaglandin secretion; IEA:Ensembl.
DR   GO; GO:0042493; P:response to drug; IEA:Ensembl.
DR   GO; GO:0002931; P:response to ischemia; IEA:Ensembl.
DR   GO; GO:0007165; P:signal transduction; TAS:ProtInc.
DR   GO; GO:0023014; P:signal transduction by protein phosphorylation; IBA:GO_Central.
DR   DisProt; DP01342; -.
DR   InterPro; IPR011009; Kinase-like_dom_sf.
DR   InterPro; IPR000719; Prot_kinase_dom.
DR   InterPro; IPR017441; Protein_kinase_ATP_BS.
DR   InterPro; IPR008271; Ser/Thr_kinase_AS.
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;
DR   PRODOM; P52564.
DR   SWISS-2DPAGE; P52564.
KW   3D-structure; Acetylation; Alternative splicing; Apoptosis; ATP-binding;
KW   Cytoplasm; Cytoskeleton; Kinase; Nucleotide-binding; Nucleus;
KW   Phosphoprotein; Reference proteome; Serine/threonine-protein kinase;
KW   Stress response; Transcription; Transcription regulation; Transferase;
KW   Tyrosine-protein kinase.
FT   CHAIN           1..334
FT                   /note="Dual specificity mitogen-activated protein kinase
FT                   kinase 6"
FT                   /id="PRO_0000086386"
FT   DOMAIN          53..314
FT                   /note="Protein kinase"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   NP_BIND         59..67
FT                   /note="ATP"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   REGION          4..19
FT                   /note="D domain"
FT                   /evidence="ECO:0000250"
FT   REGION          311..334
FT                   /note="DVD domain"
FT   ACT_SITE        179
FT                   /note="Proton acceptor"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT                   ECO:0000255|PROSITE-ProRule:PRU10027"
FT   BINDING         82
FT                   /note="ATP"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   SITE            14..15
FT                   /note="Cleavage; by anthrax lethal factor"
FT   MOD_RES         207
FT                   /note="O-acetylserine; by Yersinia yopJ; alternate"
FT                   /evidence="ECO:0000269|PubMed:16728640"
FT   MOD_RES         207
FT                   /note="Phosphoserine; by MAP3K; alternate"
FT                   /evidence="ECO:0000269|PubMed:16728640"
FT   MOD_RES         211
FT                   /note="O-acetylthreonine; by Yersinia yopJ; alternate"
FT                   /evidence="ECO:0000269|PubMed:16728640"
FT   MOD_RES         211
FT                   /note="Phosphothreonine; by MAP3K; alternate"
FT                   /evidence="ECO:0000269|PubMed:16728640"
FT   VAR_SEQ         1..56
FT                   /note="Missing (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:8621675"
FT                   /id="VSP_004882"
FT   MUTAGEN         207
FT                   /note="S->A: Inactivation."
FT   MUTAGEN         207
FT                   /note="S->E: Constitutive activation according to
FT                   PubMed:8622669, but not to PubMed:8621675."
FT   MUTAGEN         211
FT                   /note="T->A: Inactivation."
FT   MUTAGEN         211
FT                   /note="T->E: Constitutive activation according to
FT                   PubMed:8622669, but not to PubMed:8621675."
FT   CONFLICT        125
FT                   /note="V -> M (in Ref. 3; AAB03705/AAB03708)"
FT                   /evidence="ECO:0000305"
FT   HELIX           50..52
FT                   /evidence="ECO:0000244|PDB:3FME"
FT   STRAND          53..61
FT                   /evidence="ECO:0000244|PDB:3FME"
FT   STRAND          63..72
FT                   /evidence="ECO:0000244|PDB:3FME"
FT   TURN            73..76
FT                   /evidence="ECO:0000244|PDB:3FME"
FT   STRAND          77..84
FT                   /evidence="ECO:0000244|PDB:3FME"
FT   HELIX           90..104
FT                   /evidence="ECO:0000244|PDB:3FME"
FT   TURN            110..112
FT                   /evidence="ECO:0000244|PDB:3VN9"
FT   STRAND          115..120
FT                   /evidence="ECO:0000244|PDB:3FME"
FT   STRAND          122..130
FT                   /evidence="ECO:0000244|PDB:3FME"
FT   STRAND          133..135
FT                   /evidence="ECO:0000244|PDB:3FME"
FT   HELIX           136..145
FT                   /evidence="ECO:0000244|PDB:3FME"
FT   HELIX           152..172
FT                   /evidence="ECO:0000244|PDB:3FME"
FT   HELIX           182..184
FT                   /evidence="ECO:0000244|PDB:3FME"
FT   STRAND          185..187
FT                   /evidence="ECO:0000244|PDB:3ENM"
FT   STRAND          193..195
FT                   /evidence="ECO:0000244|PDB:3FME"
FT   HELIX           201..203
FT                   /evidence="ECO:0000244|PDB:3ENM"
FT   HELIX           207..212
FT                   /evidence="ECO:0000244|PDB:3VN9"
FT   HELIX           222..225
FT                   /evidence="ECO:0000244|PDB:3FME"
FT   HELIX           236..252
FT                   /evidence="ECO:0000244|PDB:3FME"
FT   HELIX           263..272
FT                   /evidence="ECO:0000244|PDB:3FME"
FT   TURN            280..282
FT                   /evidence="ECO:0000244|PDB:3FME"
FT   HELIX           285..294
FT                   /evidence="ECO:0000244|PDB:3FME"
FT   HELIX           299..301
FT                   /evidence="ECO:0000244|PDB:3FME"
FT   HELIX           305..308
FT                   /evidence="ECO:0000244|PDB:3FME"
FT   HELIX           312..319
FT                   /evidence="ECO:0000244|PDB:3FME"
FT   HELIX           324..332
FT                   /evidence="ECO:0000244|PDB:3FME"
SQ   SEQUENCE   334 AA;  37492 MW;  4ECA8014522216AF CRC64;
     MSQSKGKKRN PGLKIPKEAF EQPQTSSTPP RDLDSKACIS IGNQNFEVKA DDLEPIMELG
     RGAYGVVEKM RHVPSGQIMA VKRIRATVNS QEQKRLLMDL DISMRTVDCP FTVTFYGALF
     REGDVWICME LMDTSLDKFY KQVIDKGQTI PEDILGKIAV SIVKALEHLH SKLSVIHRDV
     KPSNVLINAL GQVKMCDFGI SGYLVDSVAK TIDAGCKPYM APERINPELN QKGYSVKSDI
     WSLGITMIEL AILRFPYDSW GTPFQQLKQV VEEPSPQLPA DKFSAEFVDF TSQCLKKNSK
     ERPTYPELMQ HPFFTLHESK GTDVASFVKL ILGD
//

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