ID MK11_MOUSE Reviewed; 364 AA. AC Q9WUI1; Q569F1; DT 21-FEB-2001, integrated into UniProtKB/Swiss-Prot. DT 27-JUL-2011, sequence version 2. DT 27-MAR-2024, entry version 188. 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; GN Name=Mapk11; Synonyms=Prkm11; OS Mus musculus (Mouse). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; OC Murinae; Mus; Mus. OX NCBI_TaxID=10090; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA]. RA Han J.; RT "The primary structure of murine p38beta."; RL Submitted (MAR-1999) to the EMBL/GenBank/DDBJ databases. RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. 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 [4] RP FUNCTION IN ACTIVATION OF RPS6KA5/MSK1 AND RPS6KA4/MSK2. RX PubMed=11909979; DOI=10.1128/mcb.22.8.2871-2881.2002; RA Wiggin G.R., Soloaga A., Foster J.M., Murray-Tait V., Cohen P., RA Arthur J.S.; RT "MSK1 and MSK2 are required for the mitogen- and stress-induced RT phosphorylation of CREB and ATF1 in fibroblasts."; RL Mol. Cell. Biol. 22:2871-2881(2002). RN [5] RP PHOSPHORYLATION AT THR-180 AND TYR-182, AND ACTIVITY REGULATION. RX PubMed=20004242; DOI=10.1016/j.cellsig.2009.11.020; RA Remy G., Risco A.M., Inesta-Vaquera F.A., Gonzalez-Teran B., Sabio G., RA Davis R.J., Cuenda A.; RT "Differential activation of p38MAPK isoforms by MKK6 and MKK3."; RL Cell. Signal. 22:660-667(2010). RN [6] 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 [7] 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). 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:11909979}. 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:20004242}. CC -!- SUBUNIT: Interacts with HDAC3 and DUSP16. {ECO:0000250}. CC -!- INTERACTION: CC Q9WUI1; P47811: Mapk14; NbExp=10; IntAct=EBI-645081, EBI-298727; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}. Nucleus {ECO:0000250}. 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:20004242}. CC -!- SIMILARITY: Belongs to the protein kinase superfamily. CMGC Ser/Thr CC protein kinase family. MAP kinase subfamily. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AF135185; AAD30116.1; -; mRNA. DR EMBL; CH466550; EDL04368.1; -; Genomic_DNA. DR EMBL; BC092526; AAH92526.1; -; mRNA. DR CCDS; CCDS27741.1; -. DR RefSeq; NP_035291.4; NM_011161.5. DR AlphaFoldDB; Q9WUI1; -. DR SMR; Q9WUI1; -. DR BioGRID; 202374; 163. DR IntAct; Q9WUI1; 1. DR MINT; Q9WUI1; -. DR STRING; 10090.ENSMUSP00000086204; -. DR BindingDB; Q9WUI1; -. DR ChEMBL; CHEMBL4335; -. DR iPTMnet; Q9WUI1; -. DR PhosphoSitePlus; Q9WUI1; -. DR MaxQB; Q9WUI1; -. DR PaxDb; 10090-ENSMUSP00000086204; -. DR ProteomicsDB; 291465; -. DR Pumba; Q9WUI1; -. DR Antibodypedia; 28468; 582 antibodies from 38 providers. DR DNASU; 19094; -. DR Ensembl; ENSMUST00000088823.5; ENSMUSP00000086204.4; ENSMUSG00000053137.8. DR GeneID; 19094; -. DR KEGG; mmu:19094; -. DR UCSC; uc007xfp.2; mouse. DR AGR; MGI:1338024; -. DR CTD; 5600; -. DR MGI; MGI:1338024; Mapk11. DR VEuPathDB; HostDB:ENSMUSG00000053137; -. DR eggNOG; KOG0660; Eukaryota. DR GeneTree; ENSGT00940000160790; -. DR HOGENOM; CLU_000288_181_1_1; -. DR InParanoid; Q9WUI1; -. DR OMA; MDIPRPE; -. DR OrthoDB; 158564at2759; -. DR PhylomeDB; Q9WUI1; -. DR TreeFam; TF105100; -. DR Reactome; R-MMU-168638; NOD1/2 Signaling Pathway. DR Reactome; R-MMU-171007; p38MAPK events. DR Reactome; R-MMU-198753; ERK/MAPK targets. DR Reactome; R-MMU-2559580; Oxidative Stress Induced Senescence. DR Reactome; R-MMU-376172; DSCAM interactions. DR Reactome; R-MMU-4420097; VEGFA-VEGFR2 Pathway. DR Reactome; R-MMU-450302; activated TAK1 mediates p38 MAPK activation. DR Reactome; R-MMU-450341; Activation of the AP-1 family of transcription factors. DR Reactome; R-MMU-525793; Myogenesis. DR Reactome; R-MMU-5668599; RHO GTPases Activate NADPH Oxidases. DR Reactome; R-MMU-6804756; Regulation of TP53 Activity through Phosphorylation. DR BioGRID-ORCS; 19094; 1 hit in 80 CRISPR screens. DR PRO; PR:Q9WUI1; -. DR Proteomes; UP000000589; Chromosome 15. DR RNAct; Q9WUI1; Protein. DR Bgee; ENSMUSG00000053137; Expressed in lumbar dorsal root ganglion and 168 other cell types or tissues. DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central. DR GO; GO:0005829; C:cytosol; IMP:MGI. DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome. DR GO; GO:0005634; C:nucleus; IBA:GO_Central. DR GO; GO:0005524; F:ATP binding; ISO:MGI. DR GO; GO:0004707; F:MAP kinase activity; IMP:MGI. DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA. DR GO; GO:0004674; F:protein serine/threonine kinase activity; EXP:Reactome. DR GO; GO:0060348; P:bone development; IMP:MGI. DR GO; GO:0060038; P:cardiac muscle cell proliferation; IMP:MGI. DR GO; GO:0071347; P:cellular response to interleukin-1; ISO:MGI. DR GO; GO:0071493; P:cellular response to UV-B; ISO:MGI. DR GO; GO:0098586; P:cellular response to virus; ISO:MGI. DR GO; GO:0035556; P:intracellular signal transduction; IBA:GO_Central. DR GO; GO:0000165; P:MAPK cascade; IMP:MGI. DR GO; GO:0060044; P:negative regulation of cardiac muscle cell proliferation; IMP:MGI. DR GO; GO:0001649; P:osteoblast differentiation; IMP:MGI. DR GO; GO:0038066; P:p38MAPK cascade; ISO:MGI. DR GO; GO:0016310; P:phosphorylation; IEA:UniProtKB-KW. DR GO; GO:0010628; P:positive regulation of gene expression; ISO:MGI. DR GO; GO:0032735; P:positive regulation of interleukin-12 production; ISO:MGI. DR GO; GO:0060043; P:regulation of cardiac muscle cell proliferation; IGI:MGI. DR GO; GO:0051403; P:stress-activated MAPK cascade; ISS:UniProtKB. DR GO; GO:0031098; P:stress-activated protein kinase signaling cascade; ISO:MGI. 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. DR Genevisible; Q9WUI1; MM. PE 1: Evidence at protein level; KW ATP-binding; Cytoplasm; Kinase; Nucleotide-binding; Nucleus; KW Phosphoprotein; Reference proteome; Serine/threonine-protein kinase; KW Stress response; Transcription; Transcription regulation; Transferase. FT CHAIN 1..364 FT /note="Mitogen-activated protein kinase 11" FT /id="PRO_0000186281" FT DOMAIN 24..308 FT /note="Protein kinase" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT REGION 312..331 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOTIF 180..182 FT /note="TXY" FT ACT_SITE 168 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 /evidence="ECO:0000250" FT MOD_RES 180 FT /note="Phosphothreonine; by MAP2K3, MAP2K4 and MAP2K6" FT /evidence="ECO:0000305|PubMed:20004242" FT MOD_RES 182 FT /note="Phosphotyrosine; by MAP2K3, MAP2K4 and MAP2K6" FT /evidence="ECO:0000305|PubMed:20004242" FT MOD_RES 323 FT /note="Phosphotyrosine; by ZAP70" FT /evidence="ECO:0000250" FT CONFLICT 173 FT /note="R -> P (in Ref. 1; AAD30116)" FT /evidence="ECO:0000305" FT CONFLICT 312 FT /note="H -> R (in Ref. 1; AAD30116)" FT /evidence="ECO:0000305" SQ SEQUENCE 364 AA; 41397 MW; 75C16E9972508220 CRC64; MSGPRAGFYR QELNKTVWEV PQRLQGLRPV GSGAYGSVCS AYDARLRQKV AVKKLSRPFQ SLIHARRTYR ELRLLKHLKH ENVIGLLDVF TPATSIEDFS EVYLVTTLMG ADLNNIVKCQ ALSDEHVQFL VYQLLRGLKY IHSAGIIHRD LKPSNVAVNE DCELRILDFG LARQADEEMT GYVATRWYRA PEIMLNWMHY NQTVDIWSVG CIMAELLQGK ALFPGNDYID QLKRIMEVVG TPSPEVLAKI SSEHARTYIQ SLPPMPQKDL SSVFHGANPL AIDLLGRMLV LDSDQRVSAA EALAHAYFSQ YHDPDDEPEA EPYDESVEAK ERTLEEWKEL TYQEVLSFKP LEPSQLPGTH EIEQ //