MK11_MOUSE
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 03-AUG-2022, entry version 179.
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}.
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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; Q9WUI1; -.
DR PRIDE; Q9WUI1; -.
DR ProteomicsDB; 291465; -.
DR Antibodypedia; 28468; 514 antibodies from 38 providers.
DR DNASU; 19094; -.
DR Ensembl; ENSMUST00000088823; ENSMUSP00000086204; ENSMUSG00000053137.
DR GeneID; 19094; -.
DR KEGG; mmu:19094; -.
DR UCSC; uc007xfp.2; mouse.
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; 683132at2759; -.
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 75 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 165 other tissues.
DR Genevisible; Q9WUI1; MM.
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: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: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:0006468; P:protein phosphorylation; 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 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 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
