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 27-MAR-2024, entry version 222.
DE RecName: Full=Mitogen-activated protein kinase 11;
DE Short=MAP kinase 11;
DE Short=MAPK 11;
DE EC=2.7.11.24 {ECO:0000269|PubMed:35857590};
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, FUNCTION IN ATF2 ACTIVATION, AND MUTAGENESIS OF THR-180 AND
RP TYR-182.
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 FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=35857590; DOI=10.1126/science.abl6324;
RA Robinson K.S., Toh G.A., Rozario P., Chua R., Bauernfried S., Sun Z.,
RA Firdaus M.J., Bayat S., Nadkarni R., Poh Z.S., Tham K.C., Harapas C.R.,
RA Lim C.K., Chu W., Tay C.W.S., Tan K.Y., Zhao T., Bonnard C., Sobota R.,
RA Connolly J.E., Common J., Masters S.L., Chen K.W., Ho L., Wu B.,
RA Hornung V., Zhong F.L.;
RT "ZAKalpha-driven ribotoxic stress response activates the human NLRP1
RT inflammasome.";
RL Science 377:328-335(2022).
RN [23]
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 [24]
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 (PubMed:12452429,
CC PubMed:20626350, PubMed:35857590). MAPK11 is one of the four p38 MAPKs
CC which play an important role in the cascades of cellular responses
CC evoked by extracellular stimuli such as pro-inflammatory cytokines or
CC physical stress leading to direct activation of transcription factors
CC (PubMed:12452429, PubMed:20626350, PubMed:35857590). Accordingly, p38
CC MAPKs phosphorylate a broad range of proteins and it has been estimated
CC that they may have approximately 200 to 300 substrates each
CC (PubMed:12452429, PubMed:20626350, PubMed:35857590). MAPK11 functions
CC are mostly redundant with those of MAPK14 (PubMed:12452429,
CC PubMed:20626350, PubMed:35857590). Some of the targets are downstream
CC kinases which are activated through phosphorylation and further
CC phosphorylate additional targets (PubMed:12452429, PubMed:20626350).
CC RPS6KA5/MSK1 and RPS6KA4/MSK2 can directly phosphorylate and activate
CC transcription factors such as CREB1, ATF1, the NF-kappa-B isoform
CC RELA/NFKB3, STAT1 and STAT3, but can also phosphorylate histone H3 and
CC the nucleosomal protein HMGN1 (PubMed:9687510). RPS6KA5/MSK1 and
CC RPS6KA4/MSK2 play important roles in the rapid induction of immediate-
CC early genes in response to stress or mitogenic stimuli, either by
CC inducing chromatin remodeling or by recruiting the transcription
CC machinery. On the other hand, two other kinase targets, MAPKAPK2/MK2
CC and MAPKAPK3/MK3, participate in the control of gene expression mostly
CC at the post-transcriptional level, by phosphorylating ZFP36
CC (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
CC (PubMed:11154262). In the cytoplasm, the p38 MAPK pathway is an
CC important regulator of protein turnover. For example, CFLAR is an
CC inhibitor of TNF-induced apoptosis whose proteasome-mediated
CC degradation is regulated by p38 MAPK phosphorylation. Ectodomain
CC shedding of transmembrane proteins is regulated by p38 MAPKs as well.
CC In response to inflammatory stimuli, p38 MAPKs phosphorylate the
CC membrane-associated metalloprotease ADAM17. Such phosphorylation is
CC required for ADAM17-mediated ectodomain shedding of TGF-alpha family
CC ligands, which results in the activation of EGFR signaling and cell
CC proliferation. Additional examples of p38 MAPK substrates are the
CC FGFR1. FGFR1 can be translocated from the extracellular space into the
CC cytosol and nucleus of target cells, and regulates processes such as
CC rRNA synthesis and cell growth. FGFR1 translocation requires p38 MAPK
CC activation. In the nucleus, many transcription factors are
CC phosphorylated and activated by p38 MAPKs in response to different
CC stimuli. Classical examples include ATF1, ATF2, ATF6, ELK1, PTPRH,
CC DDIT3, TP53/p53 and MEF2C and MEF2A (PubMed:9430721, PubMed:10330143,
CC PubMed:15356147). The p38 MAPKs are emerging as important modulators of
CC gene expression by regulating chromatin modifiers and remodelers
CC (PubMed:9430721, PubMed:10330143, PubMed:15356147). The promoters of
CC several genes involved in the inflammatory response, such as IL6, IL8
CC and IL12B, display a p38 MAPK-dependent enrichment of histone H3
CC phosphorylation on 'Ser-10' (H3S10ph) in LPS-stimulated myeloid cells.
CC This phosphorylation enhances the accessibility of the cryptic NF-
CC kappa-B-binding sites marking promoters for increased NF-kappa-B
CC recruitment. Phosphorylates NLRP1 downstream of MAP3K20/ZAK in response
CC to UV-B irradiation and ribosome collisions, promoting activation of
CC the NLRP1 inflammasome and pyroptosis (PubMed:35857590).
CC {ECO:0000269|PubMed:10330143, ECO:0000269|PubMed:11154262,
CC ECO:0000269|PubMed:15356147, ECO:0000269|PubMed:35857590,
CC ECO:0000269|PubMed:9430721, ECO:0000269|PubMed:9687510,
CC ECO:0000303|PubMed:12452429, ECO:0000303|PubMed:20626350}.
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 Evidence={ECO:0000269|PubMed:35857590};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:17990;
CC Evidence={ECO:0000269|PubMed:35857590};
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; Evidence={ECO:0000269|PubMed:35857590};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:46609;
CC Evidence={ECO:0000269|PubMed:35857590};
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; 42.
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-2998; -.
DR CPTAC; CPTAC-872; -.
DR CPTAC; CPTAC-873; -.
DR EPD; Q15759; -.
DR jPOST; Q15759; -.
DR MassIVE; Q15759; -.
DR MaxQB; Q15759; -.
DR PaxDb; 9606-ENSP00000333685; -.
DR PeptideAtlas; Q15759; -.
DR ProteomicsDB; 60745; -. [Q15759-1]
DR ProteomicsDB; 6736; -.
DR Antibodypedia; 28468; 582 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 AGR; HGNC:6873; -.
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; 158564at2759; -.
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; 14 hits in 1199 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 116 other cell types or 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; IDA:UniProtKB.
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:0071493; P:cellular response to UV-B; 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; IDA:UniProt.
DR GO; GO:0016310; P:phosphorylation; IEA:UniProtKB-KW.
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:0051403; P:stress-activated MAPK cascade; IDA:UniProtKB.
DR GO; GO:0031098; P:stress-activated protein kinase signaling cascade; IDA:UniProt.
DR Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1.
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 PANTHER; PTHR24055; MITOGEN-ACTIVATED PROTEIN KINASE; 1.
DR PANTHER; PTHR24055:SF109; MITOGEN-ACTIVATED PROTEIN KINASE 11; 1.
DR Pfam; PF00069; Pkinase; 1.
DR PRINTS; PR01773; P38MAPKINASE.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF56112; Protein kinase-like (PK-like); 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 /evidence="ECO:0000269|PubMed:15356147"
FT MUTAGEN 182
FT /note="Y->F: Inactivation."
FT /evidence="ECO:0000269|PubMed:15356147"
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
//
