MK12_MOUSE
ID MK12_MOUSE Reviewed; 367 AA.
AC O08911; Q9D0M4;
DT 15-JUL-1998, integrated into UniProtKB/Swiss-Prot.
DT 01-JUL-1997, sequence version 1.
DT 03-AUG-2022, entry version 188.
DE RecName: Full=Mitogen-activated protein kinase 12;
DE Short=MAP kinase 12;
DE Short=MAPK 12;
DE EC=2.7.11.24;
DE AltName: Full=Extracellular signal-regulated kinase 6;
DE Short=ERK-6;
DE AltName: Full=Mitogen-activated protein kinase p38 gamma;
DE Short=MAP kinase p38 gamma;
DE AltName: Full=Stress-activated protein kinase 3;
GN Name=Mapk12; Synonyms=Sapk3;
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].
RC TISSUE=Skeletal muscle;
RA Goedert M., Craxton M.;
RL Submitted (JUN-1997) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Embryo;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=FVB/N;
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 TISSUE SPECIFICITY.
RX PubMed=11991731; DOI=10.1006/jmcc.2001.1523;
RA Court N.W., dos Remedios C.G., Cordell J., Bogoyevitch M.A.;
RT "Cardiac expression and subcellular localization of the p38 mitogen-
RT activated protein kinase member, stress-activated protein kinase-3
RT (SAPK3).";
RL J. Mol. Cell. Cardiol. 34:413-426(2002).
RN [5]
RP FUNCTION.
RX PubMed=20026657; DOI=10.1083/jcb.200907037;
RA Gillespie M.A., Le Grand F., Scime A., Kuang S., von Maltzahn J., Seale V.,
RA Cuenda A., Ranish J.A., Rudnicki M.A.;
RT "p38-{gamma}-dependent gene silencing restricts entry into the myogenic
RT differentiation program.";
RL J. Cell Biol. 187:991-1005(2009).
RN [6]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-183 AND TYR-185, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Heart, and Lung;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [7]
RP PHOSPHORYLATION, 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 [8]
RP FUNCTION.
RX PubMed=21170151; DOI=10.1007/s13238-010-0075-1;
RA Wu C.C., Wu X., Han J., Sun P.;
RT "p38gamma regulates UV-induced checkpoint signaling and repair of UV-
RT induced DNA damage.";
RL Protein Cell 1:573-583(2010).
RN [9]
RP FUNCTION.
RX PubMed=21558321; DOI=10.1093/carcin/bgr079;
RA Cerezo-Guisado M.I., del Reino P., Remy G., Kuma Y., Arthur J.S.,
RA Gallego-Ortega D., Cuenda A.;
RT "Evidence of p38gamma and p38delta involvement in cell transformation
RT processes.";
RL Carcinogenesis 32:1093-1099(2011).
RN [10]
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. MAPK12 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 such as ELK1 and ATF2. Accordingly, p38 MAPKs
CC phosphorylate a broad range of proteins and it has been estimated that
CC they may have approximately 200 to 300 substrates each. Some of the
CC targets are downstream kinases such as MAPKAPK2, which are activated
CC through phosphorylation and further phosphorylate additional targets.
CC Plays a role in myoblast differentiation and also in the down-
CC regulation of cyclin D1 in response to hypoxia in adrenal cells
CC suggesting MAPK12 may inhibit cell proliferation while promoting
CC differentiation. Phosphorylates DLG1. Following osmotic shock, MAPK12
CC in the cell nucleus increases its association with nuclear DLG1,
CC thereby causing dissociation of DLG1-SFPQ complexes. This function is
CC independent of its catalytic activity and could affect mRNA processing
CC and/or gene transcription to aid cell adaptation to osmolarity changes
CC in the environment. Regulates UV-induced checkpoint signaling and
CC repair of UV-induced DNA damage and G2 arrest after gamma-radiation
CC exposure. MAPK12 is involved in the regulation of SLC2A1 expression and
CC basal glucose uptake in L6 myotubes; and negatively regulates SLC2A4
CC expression and contraction-mediated glucose uptake in adult skeletal
CC muscle. C-Jun (JUN) phosphorylation is stimulated by MAPK14 and
CC inhibited by MAPK12, leading to a distinct AP-1 regulation. MAPK12 is
CC required for the normal kinetochore localization of PLK1, prevents
CC chromosomal instability and supports mitotic cell viability. MAPK12-
CC signaling is also positively regulating the expansion of transient
CC amplifying myogenic precursor cells during muscle growth and
CC regeneration. {ECO:0000269|PubMed:20026657,
CC ECO:0000269|PubMed:21170151, ECO:0000269|PubMed:21558321}.
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;
CC Note=Binds 2 magnesium ions.;
CC -!- ACTIVITY REGULATION: Activated by phosphorylation on threonine and
CC tyrosine. MAP2K3/MKK3 and MAP2K6/MKK6 are both essential for the
CC activation of MAPK12 induced by environmental stress, whereas
CC MAP2K6/MKK6 is the major MAPK12 activator in response to TNF-alpha.
CC {ECO:0000269|PubMed:20004242}.
CC -!- SUBUNIT: Monomer. Interacts with the PDZ domain of the syntrophin SNTA1
CC (By similarity). Interacts with SH3BP5, LIN7C, SCRIB and SYNJ2BP (By
CC similarity). Interacts with PTPN4; this interaction induces the
CC activation of PTPN4 phosphatase activity.
CC {ECO:0000250|UniProtKB:P53778, ECO:0000250|UniProtKB:Q63538}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}. Nucleus {ECO:0000250}.
CC Mitochondrion {ECO:0000250}. Note=Mitochondrial when associated with
CC SH3BP5. In skeletal muscle colocalizes with SNTA1 at the neuromuscular
CC junction and throughout the sarcolemma. {ECO:0000250}.
CC -!- TISSUE SPECIFICITY: Highly expressed in skeletal muscle. Also expressed
CC in the heart, particularly in cardiac myocytes, lung, thymus and
CC testes. {ECO:0000269|PubMed:11991731}.
CC -!- DOMAIN: The TXY motif contains the threonine and tyrosine residues
CC whose phosphorylation activates the MAP kinases.
CC -!- PTM: Dually phosphorylated on Thr-183 and Tyr-185 by MAP2K3/MKK3 and
CC MAP2K6/MKK6, which activates the enzyme. {ECO:0000269|PubMed:20004242}.
CC -!- PTM: Ubiquitinated. Ubiquitination leads to degradation by the
CC proteasome pathway (By similarity). {ECO:0000250}.
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; Y13439; CAA73850.1; -; mRNA.
DR EMBL; AK011286; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; BC021640; AAH21640.1; -; mRNA.
DR CCDS; CCDS27740.1; -.
DR RefSeq; NP_038899.1; NM_013871.3.
DR AlphaFoldDB; O08911; -.
DR SMR; O08911; -.
DR BioGRID; 205924; 5.
DR DIP; DIP-49622N; -.
DR IntAct; O08911; 2.
DR STRING; 10090.ENSMUSP00000086207; -.
DR BindingDB; O08911; -.
DR ChEMBL; CHEMBL2111473; -.
DR iPTMnet; O08911; -.
DR PhosphoSitePlus; O08911; -.
DR MaxQB; O08911; -.
DR PaxDb; O08911; -.
DR PeptideAtlas; O08911; -.
DR PRIDE; O08911; -.
DR ProteomicsDB; 290254; -.
DR Antibodypedia; 14291; 548 antibodies from 38 providers.
DR DNASU; 29857; -.
DR Ensembl; ENSMUST00000088827; ENSMUSP00000086207; ENSMUSG00000022610.
DR GeneID; 29857; -.
DR KEGG; mmu:29857; -.
DR UCSC; uc007xfl.2; mouse.
DR CTD; 6300; -.
DR MGI; MGI:1353438; Mapk12.
DR VEuPathDB; HostDB:ENSMUSG00000022610; -.
DR eggNOG; KOG0660; Eukaryota.
DR GeneTree; ENSGT00940000156189; -.
DR HOGENOM; CLU_000288_181_1_1; -.
DR InParanoid; O08911; -.
DR OMA; PYVAAYH; -.
DR OrthoDB; 683132at2759; -.
DR PhylomeDB; O08911; -.
DR TreeFam; TF105100; -.
DR Reactome; R-MMU-168638; NOD1/2 Signaling Pathway.
DR Reactome; R-MMU-376172; DSCAM interactions.
DR Reactome; R-MMU-4420097; VEGFA-VEGFR2 Pathway.
DR Reactome; R-MMU-525793; Myogenesis.
DR Reactome; R-MMU-5675221; Negative regulation of MAPK pathway.
DR BioGRID-ORCS; 29857; 0 hits in 77 CRISPR screens.
DR PRO; PR:O08911; -.
DR Proteomes; UP000000589; Chromosome 15.
DR RNAct; O08911; protein.
DR Bgee; ENSMUSG00000022610; Expressed in hindlimb stylopod muscle and 207 other tissues.
DR Genevisible; O08911; MM.
DR GO; GO:0005737; C:cytoplasm; ISO:MGI.
DR GO; GO:0005739; C:mitochondrion; IEA:UniProtKB-SubCell.
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:0000287; F:magnesium ion binding; ISO:MGI.
DR GO; GO:0004707; F:MAP kinase activity; ISO:MGI.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; ISO:MGI.
DR GO; GO:0007049; P:cell cycle; IEA:UniProtKB-KW.
DR GO; GO:0035556; P:intracellular signal transduction; IBA:GO_Central.
DR GO; GO:0045445; P:myoblast differentiation; ISO:MGI.
DR GO; GO:0045786; P:negative regulation of cell cycle; ISO:MGI.
DR GO; GO:0018105; P:peptidyl-serine phosphorylation; ISO:MGI.
DR GO; GO:0006468; P:protein phosphorylation; ISO:MGI.
DR CDD; cd07880; STKc_p38gamma; 1.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR003527; MAP_kinase_CS.
DR InterPro; IPR008352; MAPK_p38-like.
DR InterPro; IPR038786; p38gamma.
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; Cell cycle; Cytoplasm; Kinase; Magnesium; Metal-binding;
KW Mitochondrion; Nucleotide-binding; Nucleus; Phosphoprotein;
KW Reference proteome; Serine/threonine-protein kinase; Stress response;
KW Transcription; Transcription regulation; Transferase; Ubl conjugation.
FT CHAIN 1..367
FT /note="Mitogen-activated protein kinase 12"
FT /id="PRO_0000186283"
FT DOMAIN 27..311
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOTIF 183..185
FT /note="TXY"
FT ACT_SITE 153
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 33..41
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 56
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOD_RES 183
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 185
FT /note="Phosphotyrosine"
FT /evidence="ECO:0007744|PubMed:21183079"
SQ SEQUENCE 367 AA; 42043 MW; AB36A40EF3C59981 CRC64;
MSSPPPARKG FYRQEVTKTA WEVRAVYQDL QPVGSGAYGA VCSAVDSRTG NKVAIKKLYR
PFQSELFAKR AYRELRLLKH MRHENVIGLL DVFTPDESLD DFTDFYLVMP FMGTDLGKLM
KHETLSEDRI QFLVYQMLKG LKYIHAAGVI HRDLKPGNLA VNEDCELKIL DFGLARQADS
EMTGYVVTRW YRAPEVILNW MRYTQTVDIW SVGCIMAEMI TGKILFKGND HLDQLKEIMK
ITGTPPPEFV QKLQSAEAKN YMEGLPELEK KDFASVLTNA SPQAVNLLER MLVLDAEQRV
TAAEALTHPY FESLRDTEDE PKAQKYDDSF DDVDRTLEEW KRVTYKEVLS FKPPRQLGAR
VPKETAL
