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MK11_HUMAN
ID   MK11_HUMAN              Reviewed;         364 AA.
AC   Q15759; A8K730; B0LPG1; B7Z630; E7ETQ1; L7RT27; O00284; O15472; Q2XNF2;
DT   01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT   20-MAR-2007, sequence version 2.
DT   03-AUG-2022, entry version 213.
DE   RecName: Full=Mitogen-activated protein kinase 11;
DE            Short=MAP kinase 11;
DE            Short=MAPK 11;
DE            EC=2.7.11.24;
DE   AltName: Full=Mitogen-activated protein kinase p38 beta;
DE            Short=MAP kinase p38 beta;
DE            Short=p38b;
DE   AltName: Full=Stress-activated protein kinase 2b;
DE            Short=SAPK2b;
DE   AltName: Full=p38-2;
GN   Name=MAPK11; Synonyms=PRKM11, SAPK2, SAPK2B;
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).
RC   TISSUE=Placenta;
RX   PubMed=8663524; DOI=10.1074/jbc.271.30.17920;
RA   Jiang Y., Chen C., Li Z., Guo W., Gegner J.A., Lin S., Han J.;
RT   "Characterization of the structure and function of a new mitogen-activated
RT   protein kinase (p38beta).";
RL   J. Biol. Chem. 271:17920-17926(1996).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RA   Jiang Y., Han J.;
RL   Submitted (APR-1997) to the EMBL/GenBank/DDBJ databases.
RN   [3]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC   TISSUE=Brain;
RX   PubMed=9207191; DOI=10.1006/bbrc.1997.6849;
RA   Kumar S., McDonnell P.C., Gum R.J., Hand A.T., Lee J.C., Young P.R.;
RT   "Novel homologues of CSBP/p38 MAP kinase: activation, substrate specificity
RT   and sensitivity to inhibition by pyridinyl imidazoles.";
RL   Biochem. Biophys. Res. Commun. 235:533-538(1997).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION IN PHOSPHORYLATION OF
RP   ATF2; ELK1 AND MBP, AND ACTIVITY REGULATION.
RC   TISSUE=Brain;
RX   PubMed=9430721; DOI=10.1074/jbc.273.3.1741;
RA   Enslen H., Raingeaud J., Davis R.J.;
RT   "Selective activation of p38 mitogen-activated protein (MAP) kinase
RT   isoforms by the MAP kinase kinases MKK3 and MKK6.";
RL   J. Biol. Chem. 273:1741-1748(1998).
RN   [5]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND ACTIVITY REGULATION.
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   [6]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX   PubMed=9235954; DOI=10.1074/jbc.272.31.19509;
RA   Stein B., Yang M.X., Young D.B., Janknecht R., Hunter T., Murray B.W.,
RA   Barbosa M.S.;
RT   "p38-2, a novel mitogen-activated protein kinase with distinct
RT   properties.";
RL   J. Biol. Chem. 272:19509-19517(1997).
RN   [7]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RX   PubMed=15461802; DOI=10.1186/gb-2004-5-10-r84;
RA   Collins J.E., Wright C.L., Edwards C.A., Davis M.P., Grinham J.A.,
RA   Cole C.G., Goward M.E., Aguado B., Mallya M., Mokrab Y., Huckle E.J.,
RA   Beare D.M., Dunham I.;
RT   "A genome annotation-driven approach to cloning the human ORFeome.";
RL   Genome Biol. 5:R84.1-R84.11(2004).
RN   [8]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC   TISSUE=Brain;
RX   PubMed=14702039; DOI=10.1038/ng1285;
RA   Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA   Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA   Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA   Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA   Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA   Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA   Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA   Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA   Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA   Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA   Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA   Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA   Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA   Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA   Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA   Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA   Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA   Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA   Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA   Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA   Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA   Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA   Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA   Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA   Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA   Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA   Isogai T., Sugano S.;
RT   "Complete sequencing and characterization of 21,243 full-length human
RT   cDNAs.";
RL   Nat. Genet. 36:40-45(2004).
RN   [9]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT HIS-275.
RG   NIEHS SNPs program;
RL   Submitted (NOV-2005) to the EMBL/GenBank/DDBJ databases.
RN   [10]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG   NHLBI resequencing and genotyping service (RS&G);
RL   Submitted (AUG-2012) to the EMBL/GenBank/DDBJ databases.
RN   [11]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=10591208; DOI=10.1038/990031;
RA   Dunham I., Hunt A.R., Collins J.E., Bruskiewich R., Beare D.M., Clamp M.,
RA   Smink L.J., Ainscough R., Almeida J.P., Babbage A.K., Bagguley C.,
RA   Bailey J., Barlow K.F., Bates K.N., Beasley O.P., Bird C.P., Blakey S.E.,
RA   Bridgeman A.M., Buck D., Burgess J., Burrill W.D., Burton J., Carder C.,
RA   Carter N.P., Chen Y., Clark G., Clegg S.M., Cobley V.E., Cole C.G.,
RA   Collier R.E., Connor R., Conroy D., Corby N.R., Coville G.J., Cox A.V.,
RA   Davis J., Dawson E., Dhami P.D., Dockree C., Dodsworth S.J., Durbin R.M.,
RA   Ellington A.G., Evans K.L., Fey J.M., Fleming K., French L., Garner A.A.,
RA   Gilbert J.G.R., Goward M.E., Grafham D.V., Griffiths M.N.D., Hall C.,
RA   Hall R.E., Hall-Tamlyn G., Heathcott R.W., Ho S., Holmes S., Hunt S.E.,
RA   Jones M.C., Kershaw J., Kimberley A.M., King A., Laird G.K., Langford C.F.,
RA   Leversha M.A., Lloyd C., Lloyd D.M., Martyn I.D., Mashreghi-Mohammadi M.,
RA   Matthews L.H., Mccann O.T., Mcclay J., Mclaren S., McMurray A.A.,
RA   Milne S.A., Mortimore B.J., Odell C.N., Pavitt R., Pearce A.V., Pearson D.,
RA   Phillimore B.J.C.T., Phillips S.H., Plumb R.W., Ramsay H., Ramsey Y.,
RA   Rogers L., Ross M.T., Scott C.E., Sehra H.K., Skuce C.D., Smalley S.,
RA   Smith M.L., Soderlund C., Spragon L., Steward C.A., Sulston J.E.,
RA   Swann R.M., Vaudin M., Wall M., Wallis J.M., Whiteley M.N., Willey D.L.,
RA   Williams L., Williams S.A., Williamson H., Wilmer T.E., Wilming L.,
RA   Wright C.L., Hubbard T., Bentley D.R., Beck S., Rogers J., Shimizu N.,
RA   Minoshima S., Kawasaki K., Sasaki T., Asakawa S., Kudoh J., Shintani A.,
RA   Shibuya K., Yoshizaki Y., Aoki N., Mitsuyama S., Roe B.A., Chen F., Chu L.,
RA   Crabtree J., Deschamps S., Do A., Do T., Dorman A., Fang F., Fu Y., Hu P.,
RA   Hua A., Kenton S., Lai H., Lao H.I., Lewis J., Lewis S., Lin S.-P., Loh P.,
RA   Malaj E., Nguyen T., Pan H., Phan S., Qi S., Qian Y., Ray L., Ren Q.,
RA   Shaull S., Sloan D., Song L., Wang Q., Wang Y., Wang Z., White J.,
RA   Willingham D., Wu H., Yao Z., Zhan M., Zhang G., Chissoe S., Murray J.,
RA   Miller N., Minx P., Fulton R., Johnson D., Bemis G., Bentley D.,
RA   Bradshaw H., Bourne S., Cordes M., Du Z., Fulton L., Goela D., Graves T.,
RA   Hawkins J., Hinds K., Kemp K., Latreille P., Layman D., Ozersky P.,
RA   Rohlfing T., Scheet P., Walker C., Wamsley A., Wohldmann P., Pepin K.,
RA   Nelson J., Korf I., Bedell J.A., Hillier L.W., Mardis E., Waterston R.,
RA   Wilson R., Emanuel B.S., Shaikh T., Kurahashi H., Saitta S., Budarf M.L.,
RA   McDermid H.E., Johnson A., Wong A.C.C., Morrow B.E., Edelmann L., Kim U.J.,
RA   Shizuya H., Simon M.I., Dumanski J.P., Peyrard M., Kedra D., Seroussi E.,
RA   Fransson I., Tapia I., Bruder C.E., O'Brien K.P., Wilkinson P.,
RA   Bodenteich A., Hartman K., Hu X., Khan A.S., Lane L., Tilahun Y.,
RA   Wright H.;
RT   "The DNA sequence of human chromosome 22.";
RL   Nature 402:489-495(1999).
RN   [12]
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 (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN   [13]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC   TISSUE=Brain;
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   [14]
RP   FUNCTION IN ACTIVATION OF RPS6KA5/MSK1.
RX   PubMed=9687510; DOI=10.1093/emboj/17.15.4426;
RA   Deak M., Clifton A.D., Lucocq J.M., Alessi D.R.;
RT   "Mitogen- and stress-activated protein kinase-1 (MSK1) is directly
RT   activated by MAPK and SAPK2/p38, and may mediate activation of CREB.";
RL   EMBO J. 17:4426-4441(1998).
RN   [15]
RP   FUNCTION IN PHOSPHORYLATION OF MEF2A AND MEF2C.
RX   PubMed=10330143; DOI=10.1128/mcb.19.6.4028;
RA   Yang S.-H., Galanis A., Sharrocks A.D.;
RT   "Targeting of p38 mitogen-activated protein kinases to MEF2 transcription
RT   factors.";
RL   Mol. Cell. Biol. 19:4028-4038(1999).
RN   [16]
RP   INTERACTION WITH DUSP16, AND ACTIVITY REGULATION.
RX   PubMed=11359773; DOI=10.1074/jbc.m101981200;
RA   Tanoue T., Yamamoto T., Maeda R., Nishida E.;
RT   "A Novel MAPK phosphatase MKP-7 acts preferentially on JNK/SAPK and p38
RT   alpha and beta MAPKs.";
RL   J. Biol. Chem. 276:26629-26639(2001).
RN   [17]
RP   FUNCTION AS MKNK2 KINASE.
RX   PubMed=11154262; DOI=10.1128/mcb.21.3.743-754.2001;
RA   Scheper G.C., Morrice N.A., Kleijn M., Proud C.G.;
RT   "The mitogen-activated protein kinase signal-integrating kinase Mnk2 is a
RT   eukaryotic initiation factor 4E kinase with high levels of basal activity
RT   in mammalian cells.";
RL   Mol. Cell. Biol. 21:743-754(2001).
RN   [18]
RP   INTERACTION WITH HDAC3, PHOSPHORYLATION AT THR-180 AND TYR-182, ACTIVITY
RP   REGULATION, AND FUNCTION IN ATF2 ACTIVATION.
RX   PubMed=15356147; DOI=10.4049/jimmunol.173.6.3979;
RA   Mahlknecht U., Will J., Varin A., Hoelzer D., Herbein G.;
RT   "Histone deacetylase 3, a class I histone deacetylase, suppresses MAPK11-
RT   mediated activating transcription factor-2 activation and represses TNF
RT   gene expression.";
RL   J. Immunol. 173:3979-3990(2004).
RN   [19]
RP   REVIEW ON FUNCTION.
RX   PubMed=12452429; DOI=10.1515/bc.2002.173;
RA   Shi Y., Gaestel M.;
RT   "In the cellular garden of forking paths: how p38 MAPKs signal for
RT   downstream assistance.";
RL   Biol. Chem. 383:1519-1536(2002).
RN   [20]
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   [21]
RP   REVIEW ON ACTIVITY REGULATION, AND REVIEW ON FUNCTION.
RX   PubMed=20626350; DOI=10.1042/bj20100323;
RA   Cuadrado A., Nebreda A.R.;
RT   "Mechanisms and functions of p38 MAPK signalling.";
RL   Biochem. J. 429:403-417(2010).
RN   [22]
RP   X-RAY CRYSTALLOGRAPHY (2.05 ANGSTROMS) IN COMPLEX WITH INHIBITOR.
RX   PubMed=19622861; DOI=10.1107/s090744490901600x;
RA   Patel S.B., Cameron P.M., O'Keefe S.J., Frantz-Wattley B., Thompson J.,
RA   O'Neill E.A., Tennis T., Liu L., Becker J.W., Scapin G.;
RT   "The three-dimensional structure of MAP kinase p38beta: different features
RT   of the ATP-binding site in p38beta compared with p38alpha.";
RL   Acta Crystallogr. D 65:777-785(2009).
RN   [23]
RP   VARIANTS [LARGE SCALE ANALYSIS] VAL-221 AND HIS-275.
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. MAPK11 is one of the
CC       four p38 MAPKs which play an important role in the cascades of cellular
CC       responses evoked by extracellular stimuli such as pro-inflammatory
CC       cytokines or physical stress leading to direct activation of
CC       transcription factors. Accordingly, p38 MAPKs phosphorylate a broad
CC       range of proteins and it has been estimated that they may have
CC       approximately 200 to 300 substrates each. MAPK11 functions are mostly
CC       redundant with those of MAPK14. Some of the targets are downstream
CC       kinases which are activated through phosphorylation and further
CC       phosphorylate additional targets. RPS6KA5/MSK1 and RPS6KA4/MSK2 can
CC       directly phosphorylate and activate transcription factors such as
CC       CREB1, ATF1, the NF-kappa-B isoform RELA/NFKB3, STAT1 and STAT3, but
CC       can also phosphorylate histone H3 and the nucleosomal protein HMGN1.
CC       RPS6KA5/MSK1 and RPS6KA4/MSK2 play important roles in the rapid
CC       induction of immediate-early genes in response to stress or mitogenic
CC       stimuli, either by inducing chromatin remodeling or by recruiting the
CC       transcription machinery. On the other hand, two other kinase targets,
CC       MAPKAPK2/MK2 and MAPKAPK3/MK3, participate in the control of gene
CC       expression mostly at the post-transcriptional level, by phosphorylating
CC       ZFP36 (tristetraprolin) and ELAVL1, and by regulating EEF2K, which is
CC       important for the elongation of mRNA during translation. MKNK1/MNK1 and
CC       MKNK2/MNK2, two other kinases activated by p38 MAPKs, regulate protein
CC       synthesis by phosphorylating the initiation factor EIF4E2. In the
CC       cytoplasm, the p38 MAPK pathway is an important regulator of protein
CC       turnover. For example, CFLAR is an inhibitor of TNF-induced apoptosis
CC       whose proteasome-mediated degradation is regulated by p38 MAPK
CC       phosphorylation. Ectodomain shedding of transmembrane proteins is
CC       regulated by p38 MAPKs as well. In response to inflammatory stimuli,
CC       p38 MAPKs phosphorylate the membrane-associated metalloprotease ADAM17.
CC       Such phosphorylation is required for ADAM17-mediated ectodomain
CC       shedding of TGF-alpha family ligands, which results in the activation
CC       of EGFR signaling and cell proliferation. Additional examples of p38
CC       MAPK substrates are the FGFR1. FGFR1 can be translocated from the
CC       extracellular space into the cytosol and nucleus of target cells, and
CC       regulates processes such as rRNA synthesis and cell growth. FGFR1
CC       translocation requires p38 MAPK activation. In the nucleus, many
CC       transcription factors are phosphorylated and activated by p38 MAPKs in
CC       response to different stimuli. Classical examples include ATF1, ATF2,
CC       ATF6, ELK1, PTPRH, DDIT3, TP53/p53 and MEF2C and MEF2A. The p38 MAPKs
CC       are emerging as important modulators of gene expression by regulating
CC       chromatin modifiers and remodelers. The promoters of several genes
CC       involved in the inflammatory response, such as IL6, IL8 and IL12B,
CC       display a p38 MAPK-dependent enrichment of histone H3 phosphorylation
CC       on 'Ser-10' (H3S10ph) in LPS-stimulated myeloid cells. This
CC       phosphorylation enhances the accessibility of the cryptic NF-kappa-B-
CC       binding sites marking promoters for increased NF-kappa-B recruitment.
CC       {ECO:0000269|PubMed:10330143, ECO:0000269|PubMed:11154262,
CC       ECO:0000269|PubMed:15356147, ECO:0000269|PubMed:9430721,
CC       ECO:0000269|PubMed:9687510}.
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=2.7.11.24;
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=2.7.11.24;
CC   -!- COFACTOR:
CC       Name=Mg(2+); Xref=ChEBI:CHEBI:18420; Evidence={ECO:0000250};
CC   -!- ACTIVITY REGULATION: Activated by phosphorylation on threonine and
CC       tyrosine by MAP2K3/MKK3, MAP2K4/MKK4 and MAP2K6/MKK6. MAP2K3/MKK3 and
CC       MAP2K6/MKK6 are both essential for the activation of MAPK11 induced by
CC       environmental stress. HDAC3 interacts directly and selectively with
CC       MAPK11 to repress ATF2 transcriptional activity, and regulate TNF gene
CC       expression in LPS-stimulated cells. Inhibited by SB203580 and
CC       pyridinyl-imidazole related compounds. {ECO:0000269|PubMed:11359773,
CC       ECO:0000269|PubMed:15356147, ECO:0000269|PubMed:9218798,
CC       ECO:0000269|PubMed:9430721}.
CC   -!- SUBUNIT: Interacts with HDAC3 and DUSP16. {ECO:0000269|PubMed:11359773,
CC       ECO:0000269|PubMed:15356147, ECO:0000269|PubMed:19622861}.
CC   -!- INTERACTION:
CC       Q15759; Q86V38: ATN1; NbExp=3; IntAct=EBI-298304, EBI-11954292;
CC       Q15759; P02489: CRYAA; NbExp=3; IntAct=EBI-298304, EBI-6875961;
CC       Q15759; P50570-2: DNM2; NbExp=3; IntAct=EBI-298304, EBI-10968534;
CC       Q15759; Q14204: DYNC1H1; NbExp=3; IntAct=EBI-298304, EBI-356015;
CC       Q15759; P22607: FGFR3; NbExp=3; IntAct=EBI-298304, EBI-348399;
CC       Q15759; O14908-2: GIPC1; NbExp=3; IntAct=EBI-298304, EBI-25913156;
CC       Q15759; Q92993: KAT5; NbExp=3; IntAct=EBI-298304, EBI-399080;
CC       Q15759; Q92876: KLK6; NbExp=3; IntAct=EBI-298304, EBI-2432309;
CC       Q15759; Q8TAP4-4: LMO3; NbExp=3; IntAct=EBI-298304, EBI-11742507;
CC       Q15759; Q16644: MAPKAPK3; NbExp=4; IntAct=EBI-298304, EBI-1384657;
CC       Q15759; Q13153: PAK1; NbExp=3; IntAct=EBI-298304, EBI-1307;
CC       Q15759; P17252: PRKCA; NbExp=3; IntAct=EBI-298304, EBI-1383528;
CC       Q15759; Q15047-2: SETDB1; NbExp=3; IntAct=EBI-298304, EBI-9090795;
CC       Q15759; Q16637: SMN2; NbExp=3; IntAct=EBI-298304, EBI-395421;
CC       Q15759; Q13148: TARDBP; NbExp=6; IntAct=EBI-298304, EBI-372899;
CC       Q15759; P04637: TP53; NbExp=2; IntAct=EBI-298304, EBI-366083;
CC       Q15759; P61981: YWHAG; NbExp=3; IntAct=EBI-298304, EBI-359832;
CC       Q15759; O43257: ZNHIT1; NbExp=2; IntAct=EBI-298304, EBI-347522;
CC   -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}. Nucleus {ECO:0000250}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=2;
CC       Name=1;
CC         IsoId=Q15759-1; Sequence=Displayed;
CC       Name=2;
CC         IsoId=Q15759-3; Sequence=VSP_055221, VSP_055222, VSP_055223;
CC   -!- TISSUE SPECIFICITY: Highest levels in the brain and heart. Also
CC       expressed in the placenta, lung, liver, skeletal muscle, kidney and
CC       pancreas.
CC   -!- DOMAIN: The TXY motif contains the threonine and tyrosine residues
CC       whose phosphorylation activates the MAP kinases.
CC   -!- PTM: Dually phosphorylated on Thr-180 and Tyr-182 by MAP2K3/MKK3,
CC       MAP2K4/MKK4 and MAP2K6/MKK6, which activates the enzyme.
CC       {ECO:0000269|PubMed:15356147}.
CC   -!- SIMILARITY: Belongs to the protein kinase superfamily. CMGC Ser/Thr
CC       protein kinase family. MAP kinase subfamily. {ECO:0000305}.
CC   -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC       URL="http://egp.gs.washington.edu/data/mapk11/";
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DR   EMBL; U53442; AAB05036.1; -; mRNA.
DR   EMBL; AF001008; AAC51250.1; -; mRNA.
DR   EMBL; AF001174; AAC51373.1; -; mRNA.
DR   EMBL; AF031135; AAC12714.1; -; mRNA.
DR   EMBL; Y14440; CAA74792.1; -; mRNA.
DR   EMBL; U92268; AAB66313.1; -; mRNA.
DR   EMBL; CR456514; CAG30400.1; -; mRNA.
DR   EMBL; DQ279722; ABB72677.1; -; Genomic_DNA.
DR   EMBL; AK291845; BAF84534.1; -; mRNA.
DR   EMBL; AK299745; BAH13116.1; -; mRNA.
DR   EMBL; EU332851; ABY87540.1; -; Genomic_DNA.
DR   EMBL; JX512451; AGC09598.1; -; Genomic_DNA.
DR   EMBL; AL022328; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; CH471138; EAW73524.1; -; Genomic_DNA.
DR   EMBL; CH471138; EAW73525.1; -; Genomic_DNA.
DR   EMBL; CH471138; EAW73526.1; -; Genomic_DNA.
DR   EMBL; BC027933; AAH27933.1; -; mRNA.
DR   CCDS; CCDS14090.1; -. [Q15759-1]
DR   PIR; G02524; G02524.
DR   PIR; JC5529; JC5529.
DR   RefSeq; NP_002742.3; NM_002751.6. [Q15759-1]
DR   PDB; 3GC8; X-ray; 2.40 A; A/B=1-364.
DR   PDB; 3GC9; X-ray; 2.05 A; A/B=1-364.
DR   PDB; 3GP0; X-ray; 1.90 A; A=5-350.
DR   PDBsum; 3GC8; -.
DR   PDBsum; 3GC9; -.
DR   PDBsum; 3GP0; -.
DR   AlphaFoldDB; Q15759; -.
DR   SMR; Q15759; -.
DR   BioGRID; 111586; 40.
DR   IntAct; Q15759; 37.
DR   MINT; Q15759; -.
DR   STRING; 9606.ENSP00000333685; -.
DR   BindingDB; Q15759; -.
DR   ChEMBL; CHEMBL3961; -.
DR   DrugBank; DB05157; KC706.
DR   DrugBank; DB01017; Minocycline.
DR   DrugBank; DB08896; Regorafenib.
DR   DrugCentral; Q15759; -.
DR   GuidetoPHARMACOLOGY; 1500; -.
DR   iPTMnet; Q15759; -.
DR   PhosphoSitePlus; Q15759; -.
DR   BioMuta; MAPK11; -.
DR   DMDM; 134047835; -.
DR   CPTAC; CPTAC-872; -.
DR   CPTAC; CPTAC-873; -.
DR   EPD; Q15759; -.
DR   jPOST; Q15759; -.
DR   MassIVE; Q15759; -.
DR   MaxQB; Q15759; -.
DR   PaxDb; Q15759; -.
DR   PeptideAtlas; Q15759; -.
DR   PRIDE; Q15759; -.
DR   ProteomicsDB; 60745; -. [Q15759-1]
DR   ProteomicsDB; 6736; -.
DR   Antibodypedia; 28468; 514 antibodies from 38 providers.
DR   DNASU; 5600; -.
DR   Ensembl; ENST00000330651.11; ENSP00000333685.6; ENSG00000185386.15. [Q15759-1]
DR   Ensembl; ENST00000395764.5; ENSP00000379113.1; ENSG00000185386.15. [Q15759-1]
DR   GeneID; 5600; -.
DR   KEGG; hsa:5600; -.
DR   MANE-Select; ENST00000330651.11; ENSP00000333685.6; NM_002751.7; NP_002742.3.
DR   UCSC; uc003bkr.4; human. [Q15759-1]
DR   CTD; 5600; -.
DR   DisGeNET; 5600; -.
DR   GeneCards; MAPK11; -.
DR   HGNC; HGNC:6873; MAPK11.
DR   HPA; ENSG00000185386; Tissue enhanced (brain).
DR   MIM; 602898; gene.
DR   neXtProt; NX_Q15759; -.
DR   OpenTargets; ENSG00000185386; -.
DR   PharmGKB; PA30618; -.
DR   VEuPathDB; HostDB:ENSG00000185386; -.
DR   eggNOG; KOG0660; Eukaryota.
DR   GeneTree; ENSGT00940000160790; -.
DR   HOGENOM; CLU_000288_181_1_1; -.
DR   InParanoid; Q15759; -.
DR   OMA; MDIPRPE; -.
DR   OrthoDB; 683132at2759; -.
DR   PhylomeDB; Q15759; -.
DR   TreeFam; TF105100; -.
DR   BRENDA; 2.7.11.24; 2681.
DR   PathwayCommons; Q15759; -.
DR   Reactome; R-HSA-168638; NOD1/2 Signaling Pathway.
DR   Reactome; R-HSA-171007; p38MAPK events.
DR   Reactome; R-HSA-198753; ERK/MAPK targets.
DR   Reactome; R-HSA-2151209; Activation of PPARGC1A (PGC-1alpha) by phosphorylation.
DR   Reactome; R-HSA-2559580; Oxidative Stress Induced Senescence.
DR   Reactome; R-HSA-376172; DSCAM interactions.
DR   Reactome; R-HSA-4420097; VEGFA-VEGFR2 Pathway.
DR   Reactome; R-HSA-450302; activated TAK1 mediates p38 MAPK activation.
DR   Reactome; R-HSA-450341; Activation of the AP-1 family of transcription factors.
DR   Reactome; R-HSA-450604; KSRP (KHSRP) binds and destabilizes mRNA.
DR   Reactome; R-HSA-525793; Myogenesis.
DR   Reactome; R-HSA-5668599; RHO GTPases Activate NADPH Oxidases.
DR   Reactome; R-HSA-6804756; Regulation of TP53 Activity through Phosphorylation.
DR   SignaLink; Q15759; -.
DR   SIGNOR; Q15759; -.
DR   BioGRID-ORCS; 5600; 13 hits in 1114 CRISPR screens.
DR   EvolutionaryTrace; Q15759; -.
DR   GeneWiki; MAPK11; -.
DR   GenomeRNAi; 5600; -.
DR   Pharos; Q15759; Tchem.
DR   PRO; PR:Q15759; -.
DR   Proteomes; UP000005640; Chromosome 22.
DR   RNAct; Q15759; protein.
DR   Bgee; ENSG00000185386; Expressed in right frontal lobe and 115 other tissues.
DR   ExpressionAtlas; Q15759; baseline and differential.
DR   Genevisible; Q15759; HS.
DR   GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR   GO; GO:0005829; C:cytosol; TAS:Reactome.
DR   GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR   GO; GO:0005634; C:nucleus; IBA:GO_Central.
DR   GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR   GO; GO:0004707; F:MAP kinase activity; IDA:UniProtKB.
DR   GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR   GO; GO:0004674; F:protein serine/threonine kinase activity; IBA:GO_Central.
DR   GO; GO:0060348; P:bone development; IEA:Ensembl.
DR   GO; GO:0060038; P:cardiac muscle cell proliferation; IEA:Ensembl.
DR   GO; GO:0071347; P:cellular response to interleukin-1; IDA:UniProtKB.
DR   GO; GO:0098586; P:cellular response to virus; IMP:UniProtKB.
DR   GO; GO:0090398; P:cellular senescence; TAS:Reactome.
DR   GO; GO:0035556; P:intracellular signal transduction; IBA:GO_Central.
DR   GO; GO:0060044; P:negative regulation of cardiac muscle cell proliferation; IEA:Ensembl.
DR   GO; GO:0001649; P:osteoblast differentiation; IEA:Ensembl.
DR   GO; GO:0038066; P:p38MAPK cascade; TAS:Reactome.
DR   GO; GO:0010628; P:positive regulation of gene expression; IMP:UniProtKB.
DR   GO; GO:0032735; P:positive regulation of interleukin-12 production; IMP:UniProtKB.
DR   GO; GO:0051149; P:positive regulation of muscle cell differentiation; TAS:Reactome.
DR   GO; GO:0006468; P:protein phosphorylation; IEA:Ensembl.
DR   GO; GO:0051403; P:stress-activated MAPK cascade; IDA:UniProtKB.
DR   InterPro; IPR011009; Kinase-like_dom_sf.
DR   InterPro; IPR003527; MAP_kinase_CS.
DR   InterPro; IPR008352; MAPK_p38-like.
DR   InterPro; IPR000719; Prot_kinase_dom.
DR   InterPro; IPR017441; Protein_kinase_ATP_BS.
DR   Pfam; PF00069; Pkinase; 1.
DR   PRINTS; PR01773; P38MAPKINASE.
DR   SMART; SM00220; S_TKc; 1.
DR   SUPFAM; SSF56112; SSF56112; 1.
DR   PROSITE; PS01351; MAPK; 1.
DR   PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR   PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Alternative splicing; ATP-binding; Cytoplasm; Kinase;
KW   Nucleotide-binding; Nucleus; Phosphoprotein; Reference proteome;
KW   Serine/threonine-protein kinase; Stress response; Transcription;
KW   Transcription regulation; Transferase.
FT   CHAIN           1..364
FT                   /note="Mitogen-activated protein kinase 11"
FT                   /id="PRO_0000186280"
FT   DOMAIN          24..308
FT                   /note="Protein kinase"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   REGION          311..331
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          343..364
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   MOTIF           180..182
FT                   /note="TXY"
FT   ACT_SITE        150
FT                   /note="Proton acceptor"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   BINDING         30..38
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   BINDING         53
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   BINDING         71
FT                   /ligand="nilotinib"
FT                   /ligand_id="ChEBI:CHEBI:52172"
FT   MOD_RES         180
FT                   /note="Phosphothreonine; by MAP2K3, MAP2K4 and MAP2K6"
FT                   /evidence="ECO:0000305|PubMed:15356147"
FT   MOD_RES         182
FT                   /note="Phosphotyrosine; by MAP2K3, MAP2K4 and MAP2K6"
FT                   /evidence="ECO:0000305|PubMed:15356147"
FT   MOD_RES         323
FT                   /note="Phosphotyrosine; by ZAP70"
FT                   /evidence="ECO:0000250"
FT   VAR_SEQ         1..108
FT                   /note="Missing (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:14702039"
FT                   /id="VSP_055221"
FT   VAR_SEQ         204..321
FT                   /note="VDIWSVGCIMAELLQGKALFPGSDYIDQLKRIMEVVGTPSPEVLAKISSEHA
FT                   RTYIQSLPPMPQKDLSSIFRGANPLAIDLLGRMLVLDSDQRVSAAEALAHAYFSQYHDP
FT                   EDEPEAE -> GAGGRPWGDEGQGPRLALDWLCMPGLRGQARSPRMWDPHSKVALQRPL
FT                   EHDGCWPPLAVQLWTSPCLGGLGMAEEGVCPSWGLDVTVGLLEEGRGVGTLMEVPSPSH
FT                   SGYLVRGLHHG (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:14702039"
FT                   /id="VSP_055222"
FT   VAR_SEQ         322..364
FT                   /note="Missing (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:14702039"
FT                   /id="VSP_055223"
FT   VARIANT         221
FT                   /note="A -> V (in a lung neuroendocrine carcinoma sample;
FT                   somatic mutation)"
FT                   /evidence="ECO:0000269|PubMed:17344846"
FT                   /id="VAR_042264"
FT   VARIANT         275
FT                   /note="R -> H (in dbSNP:rs33932986)"
FT                   /evidence="ECO:0000269|PubMed:17344846, ECO:0000269|Ref.9"
FT                   /id="VAR_025176"
FT   MUTAGEN         180
FT                   /note="T->A: Inactivation."
FT   MUTAGEN         182
FT                   /note="Y->F: Inactivation."
FT   CONFLICT        98
FT                   /note="D -> V (in Ref. 8; BAF84534)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        122..123
FT                   /note="LS -> GAHQGARLAL (in Ref. 1; AAB05036)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        326
FT                   /note="S -> G (in Ref. 6; AAB66313)"
FT                   /evidence="ECO:0000305"
FT   STRAND          8..15
FT                   /evidence="ECO:0007829|PDB:3GP0"
FT   STRAND          17..21
FT                   /evidence="ECO:0007829|PDB:3GP0"
FT   STRAND          24..29
FT                   /evidence="ECO:0007829|PDB:3GP0"
FT   STRAND          31..33
FT                   /evidence="ECO:0007829|PDB:3GC8"
FT   TURN            34..37
FT                   /evidence="ECO:0007829|PDB:3GC9"
FT   STRAND          38..43
FT                   /evidence="ECO:0007829|PDB:3GP0"
FT   TURN            44..47
FT                   /evidence="ECO:0007829|PDB:3GP0"
FT   STRAND          48..54
FT                   /evidence="ECO:0007829|PDB:3GP0"
FT   HELIX           62..77
FT                   /evidence="ECO:0007829|PDB:3GP0"
FT   STRAND          86..90
FT                   /evidence="ECO:0007829|PDB:3GP0"
FT   HELIX           96..98
FT                   /evidence="ECO:0007829|PDB:3GP0"
FT   STRAND          103..107
FT                   /evidence="ECO:0007829|PDB:3GP0"
FT   STRAND          110..112
FT                   /evidence="ECO:0007829|PDB:3GP0"
FT   HELIX           113..119
FT                   /evidence="ECO:0007829|PDB:3GP0"
FT   HELIX           124..143
FT                   /evidence="ECO:0007829|PDB:3GP0"
FT   HELIX           153..155
FT                   /evidence="ECO:0007829|PDB:3GP0"
FT   STRAND          156..158
FT                   /evidence="ECO:0007829|PDB:3GP0"
FT   STRAND          164..166
FT                   /evidence="ECO:0007829|PDB:3GP0"
FT   HELIX           179..182
FT                   /evidence="ECO:0007829|PDB:3GC8"
FT   HELIX           185..188
FT                   /evidence="ECO:0007829|PDB:3GP0"
FT   HELIX           191..194
FT                   /evidence="ECO:0007829|PDB:3GP0"
FT   HELIX           203..218
FT                   /evidence="ECO:0007829|PDB:3GP0"
FT   HELIX           228..239
FT                   /evidence="ECO:0007829|PDB:3GP0"
FT   HELIX           244..249
FT                   /evidence="ECO:0007829|PDB:3GP0"
FT   TURN            253..255
FT                   /evidence="ECO:0007829|PDB:3GP0"
FT   HELIX           256..260
FT                   /evidence="ECO:0007829|PDB:3GP0"
FT   HELIX           270..273
FT                   /evidence="ECO:0007829|PDB:3GP0"
FT   TURN            274..276
FT                   /evidence="ECO:0007829|PDB:3GC8"
FT   HELIX           279..285
FT                   /evidence="ECO:0007829|PDB:3GP0"
FT   TURN            286..288
FT                   /evidence="ECO:0007829|PDB:3GP0"
FT   HELIX           293..295
FT                   /evidence="ECO:0007829|PDB:3GP0"
FT   HELIX           299..302
FT                   /evidence="ECO:0007829|PDB:3GP0"
FT   HELIX           306..308
FT                   /evidence="ECO:0007829|PDB:3GP0"
FT   TURN            309..311
FT                   /evidence="ECO:0007829|PDB:3GP0"
FT   HELIX           314..316
FT                   /evidence="ECO:0007829|PDB:3GP0"
FT   HELIX           326..329
FT                   /evidence="ECO:0007829|PDB:3GP0"
FT   HELIX           334..347
FT                   /evidence="ECO:0007829|PDB:3GP0"
SQ   SEQUENCE   364 AA;  41357 MW;  68DA4C7B7C721475 CRC64;
     MSGPRAGFYR QELNKTVWEV PQRLQGLRPV GSGAYGSVCS AYDARLRQKV AVKKLSRPFQ
     SLIHARRTYR ELRLLKHLKH ENVIGLLDVF TPATSIEDFS EVYLVTTLMG ADLNNIVKCQ
     ALSDEHVQFL VYQLLRGLKY IHSAGIIHRD LKPSNVAVNE DCELRILDFG LARQADEEMT
     GYVATRWYRA PEIMLNWMHY NQTVDIWSVG CIMAELLQGK ALFPGSDYID QLKRIMEVVG
     TPSPEVLAKI SSEHARTYIQ SLPPMPQKDL SSIFRGANPL AIDLLGRMLV LDSDQRVSAA
     EALAHAYFSQ YHDPEDEPEA EPYDESVEAK ERTLEEWKEL TYQEVLSFKP PEPPKPPGSL
     EIEQ
 
 
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