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 03-AUG-2022, entry version 209.
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 (MICROBIAL INFECTION), AND IDENTIFICATION BY
RP 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 ACETYLATION AT SER-207 AND THR-211 (MICROBIAL INFECTION).
RX PubMed=22802624; DOI=10.1073/pnas.1008203109;
RA Paquette N., Conlon J., Sweet C., Rus F., Wilson L., Pereira A.,
RA Rosadini C.V., Goutagny N., Weber A.N., Lane W.S., Shaffer S.A.,
RA Maniatis S., Fitzgerald K.A., Stuart L., Silverman N.;
RT "Serine/threonine acetylation of TGFbeta-activated kinase (TAK1) by
RT Yersinia pestis YopJ inhibits innate immune signaling.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12710-12715(2012).
RN [30]
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 [31]
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 [32]
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 (via its D domain) with its substrates
CC MAPK11, MAPK12, MAPK13 and MAPK14 (By similarity). Interacts (via its
CC DVD domain) with MAP3Ks activators like MAP3K5/ASK1, MAP3K1/MEKK1,
CC MAP3K2/MEKK2, MAP3K3/MEKK3, MAP3K4/MEKK4, MAP3K7/TAK1, MAP3K11/MLK3 and
CC MAP3K17/TAOK2 (By similarity). Interacts with DCTN1. Interacts with
CC EIF2AK2/PKR. {ECO:0000250, ECO:0000269|PubMed:10497253,
CC ECO:0000269|PubMed:15229216, ECO:0000269|PubMed:15375157,
CC ECO:0000269|PubMed:19141286}.
CC -!- SUBUNIT: (Microbial infection) Interacts with Yersinia YopJ.
CC {ECO:0000269|PubMed:16728640}.
CC -!- INTERACTION:
CC P52564; Q5S007: LRRK2; NbExp=4; IntAct=EBI-448135, EBI-5323863;
CC P52564; Q16539: MAPK14; NbExp=3; IntAct=EBI-448135, EBI-73946;
CC P52564; Q16236: NFE2L2; NbExp=5; IntAct=EBI-448135, EBI-2007911;
CC P52564; Q9NRD5: PICK1; NbExp=3; IntAct=EBI-448135, EBI-79165;
CC P52564; O76024: WFS1; NbExp=3; IntAct=EBI-448135, EBI-720609;
CC P52564-1; P52564-1: MAP2K6; NbExp=3; IntAct=EBI-15750978, EBI-15750978;
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: (Microbial infection) Acetylation of Ser-207 and Thr-211 by
CC Yersinia YopJ prevents phosphorylation and activation, thus blocking
CC the MAPK signaling pathway. {ECO:0000269|PubMed:16728640,
CC ECO:0000269|PubMed:22802624}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. STE Ser/Thr
CC protein kinase family. MAP kinase kinase subfamily. {ECO:0000305}.
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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 AlphaFoldDB; P52564; -.
DR SMR; P52564; -.
DR BioGRID; 111594; 63.
DR DIP; DIP-31346N; -.
DR ELM; P52564; -.
DR IntAct; P52564; 19.
DR MINT; P52564; -.
DR STRING; 9606.ENSP00000468348; -.
DR BindingDB; P52564; -.
DR ChEMBL; CHEMBL2171; -.
DR DrugBank; DB12010; Fostamatinib.
DR DrugCentral; P52564; -.
DR GuidetoPHARMACOLOGY; 2067; -.
DR GlyGen; P52564; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; P52564; -.
DR MetOSite; 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 Antibodypedia; 3570; 891 antibodies from 41 providers.
DR DNASU; 5608; -.
DR Ensembl; ENST00000589647.5; ENSP00000467213.1; ENSG00000108984.15. [P52564-2]
DR Ensembl; ENST00000590474.7; ENSP00000468348.1; ENSG00000108984.15. [P52564-1]
DR Ensembl; ENST00000613873.4; ENSP00000477701.1; ENSG00000108984.15. [P52564-2]
DR GeneID; 5608; -.
DR KEGG; hsa:5608; -.
DR MANE-Select; ENST00000590474.7; ENSP00000468348.1; NM_002758.4; NP_002749.2.
DR UCSC; uc002jij.4; human. [P52564-1]
DR CTD; 5608; -.
DR DisGeNET; 5608; -.
DR GeneCards; MAP2K6; -.
DR HGNC; HGNC:6846; MAP2K6.
DR HPA; ENSG00000108984; Tissue enhanced (skeletal).
DR MIM; 601254; gene.
DR neXtProt; NX_P52564; -.
DR OpenTargets; ENSG00000108984; -.
DR PharmGKB; PA30591; -.
DR VEuPathDB; HostDB:ENSG00000108984; -.
DR eggNOG; KOG0984; Eukaryota.
DR GeneTree; ENSGT00940000157836; -.
DR HOGENOM; CLU_000288_63_23_1; -.
DR InParanoid; P52564; -.
DR OMA; YTVQFYG; -.
DR PhylomeDB; P52564; -.
DR BRENDA; 2.7.12.2; 2681.
DR PathwayCommons; P52564; -.
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 BioGRID-ORCS; 5608; 13 hits in 1109 CRISPR screens.
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 rectum and 175 other tissues.
DR ExpressionAtlas; P52564; baseline and differential.
DR Genevisible; P52564; HS.
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:0019211; F:phosphatase activator activity; IEA:Ensembl.
DR GO; GO:0019901; F:protein kinase binding; IPI:UniProtKB.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0043539; F:protein serine/threonine kinase activator activity; IEA:Ensembl.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; TAS:Reactome.
DR GO; GO:0004713; F:protein tyrosine kinase activity; IEA:UniProtKB-KW.
DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
DR GO; GO:0060348; P:bone development; IEA:Ensembl.
DR GO; GO:0060048; P:cardiac muscle contraction; IEA:Ensembl.
DR GO; GO:0072709; P:cellular response to sorbitol; IEA:Ensembl.
DR GO; GO:0090398; P:cellular senescence; TAS:Reactome.
DR GO; GO:0006975; P:DNA damage induced protein phosphorylation; TAS:ProtInc.
DR GO; GO:0000165; P:MAPK cascade; IDA:GO_Central.
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:0001649; P:osteoblast differentiation; IEA:Ensembl.
DR GO; GO:0022602; P:ovulation cycle process; IEA:Ensembl.
DR GO; GO:0038066; P:p38MAPK cascade; TAS:Reactome.
DR GO; GO:0043065; P:positive regulation of apoptotic process; IEA:Ensembl.
DR GO; GO:0043406; P:positive regulation of MAP kinase activity; 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:0051726; P:regulation of cell cycle; TAS:ProtInc.
DR GO; GO:1901796; P:regulation of signal transduction by p53 class mediator; TAS:Reactome.
DR GO; GO:0002931; P:response to ischemia; IEA:Ensembl.
DR GO; GO:0009410; P:response to xenobiotic stimulus; IEA:Ensembl.
DR GO; GO:0007165; P:signal transduction; TAS:ProtInc.
DR GO; GO:0051403; P:stress-activated MAPK cascade; IDA:UniProtKB.
DR DisProt; DP01342; -.
DR IDEAL; IID00455; -.
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;
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 REGION 1..34
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 4..19
FT /note="D domain"
FT /evidence="ECO:0000250"
FT REGION 311..334
FT /note="DVD domain"
FT COMPBIAS 20..34
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 179
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10027"
FT BINDING 59..67
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 82
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT SITE 14..15
FT /note="Cleavage; by anthrax lethal factor"
FT MOD_RES 207
FT /note="(Microbial infection) O-acetylserine; by Yersinia
FT YopJ; alternate"
FT /evidence="ECO:0000269|PubMed:16728640,
FT ECO:0000269|PubMed:22802624"
FT MOD_RES 207
FT /note="Phosphoserine; by MAP3K; alternate"
FT /evidence="ECO:0000269|PubMed:16728640"
FT MOD_RES 211
FT /note="(Microbial infection) O-acetylthreonine; by Yersinia
FT YopJ; alternate"
FT /evidence="ECO:0000269|PubMed:16728640,
FT ECO:0000269|PubMed:22802624"
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:0007829|PDB:3FME"
FT STRAND 53..61
FT /evidence="ECO:0007829|PDB:3FME"
FT STRAND 63..72
FT /evidence="ECO:0007829|PDB:3FME"
FT TURN 73..76
FT /evidence="ECO:0007829|PDB:3FME"
FT STRAND 77..84
FT /evidence="ECO:0007829|PDB:3FME"
FT HELIX 90..104
FT /evidence="ECO:0007829|PDB:3FME"
FT TURN 110..112
FT /evidence="ECO:0007829|PDB:3VN9"
FT STRAND 115..120
FT /evidence="ECO:0007829|PDB:3FME"
FT STRAND 122..130
FT /evidence="ECO:0007829|PDB:3FME"
FT STRAND 133..135
FT /evidence="ECO:0007829|PDB:3FME"
FT HELIX 136..145
FT /evidence="ECO:0007829|PDB:3FME"
FT HELIX 152..172
FT /evidence="ECO:0007829|PDB:3FME"
FT HELIX 182..184
FT /evidence="ECO:0007829|PDB:3FME"
FT STRAND 185..187
FT /evidence="ECO:0007829|PDB:3ENM"
FT STRAND 193..195
FT /evidence="ECO:0007829|PDB:3FME"
FT HELIX 201..203
FT /evidence="ECO:0007829|PDB:3ENM"
FT HELIX 207..212
FT /evidence="ECO:0007829|PDB:3VN9"
FT HELIX 222..225
FT /evidence="ECO:0007829|PDB:3FME"
FT HELIX 236..252
FT /evidence="ECO:0007829|PDB:3FME"
FT HELIX 263..272
FT /evidence="ECO:0007829|PDB:3FME"
FT TURN 280..282
FT /evidence="ECO:0007829|PDB:3FME"
FT HELIX 285..294
FT /evidence="ECO:0007829|PDB:3FME"
FT HELIX 299..301
FT /evidence="ECO:0007829|PDB:3FME"
FT HELIX 305..308
FT /evidence="ECO:0007829|PDB:3FME"
FT HELIX 312..319
FT /evidence="ECO:0007829|PDB:3FME"
FT HELIX 324..332
FT /evidence="ECO:0007829|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
