MK12_RAT
ID MK12_RAT Reviewed; 367 AA.
AC Q63538;
DT 15-JUL-1998, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1996, sequence version 1.
DT 03-AUG-2022, entry version 173.
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 Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Skeletal muscle;
RX PubMed=8925912; DOI=10.1016/0014-5793(96)00255-4;
RA Mertens S., Craxton M., Goedert M.;
RT "SAP kinase-3, a new member of the family of mammalian stress-activated
RT protein kinases.";
RL FEBS Lett. 383:273-276(1996).
RN [2]
RP INTERACTION WITH SNTA1, FUNCTION IN PHOSPHORYLATION OF SNTA1, AND
RP SUBCELLULAR LOCATION.
RX PubMed=19135240; DOI=10.1016/j.cell.2008.11.018;
RA Sumara G., Formentini I., Collins S., Sumara I., Windak R., Bodenmiller B.,
RA Ramracheya R., Caille D., Jiang H., Platt K.A., Meda P., Aebersold R.,
RA Rorsman P., Ricci R.;
RT "Regulation of PKD by the MAPK p38delta in insulin secretion and glucose
RT homeostasis.";
RL Cell 136:235-248(2009).
RN [3]
RP FUNCTION, PHOSPHORYLATION AT THR-183 AND TYR-185, AND MUTAGENESIS OF
RP THR-183 AND TYR-185.
RX PubMed=10438538; DOI=10.1074/jbc.274.33.23570;
RA Conrad P.W., Rust R.T., Han J., Millhorn D.E., Beitner-Johnson D.;
RT "Selective activation of p38alpha and p38gamma by hypoxia. Role in
RT regulation of cyclin D1 by hypoxia in PC12 cells.";
RL J. Biol. Chem. 274:23570-23576(1999).
RN [4]
RP SUBCELLULAR LOCATION, AND 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 SUBCELLULAR LOCATION, AND INTERACTION WITH SH3BP5.
RX PubMed=15158451; DOI=10.1016/j.bbrc.2004.04.148;
RA Court N.W., Kuo I., Quigley O., Bogoyevitch M.A.;
RT "Phosphorylation of the mitochondrial protein Sab by stress-activated
RT protein kinase 3.";
RL Biochem. Biophys. Res. Commun. 319:130-137(2004).
RN [6]
RP INTERACTION WITH LIN7C; SCRIB AND SYNJ2BP, AND ACTIVITY REGULATION.
RX PubMed=15878399; DOI=10.1016/j.bbamcr.2004.11.008;
RA Court N.W., Ingley E., Klinken S.P., Bogoyevitch M.A.;
RT "Outer membrane protein 25-a mitochondrial anchor and inhibitor of stress-
RT activated protein kinase-3.";
RL Biochim. Biophys. Acta 1744:68-75(2005).
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).
RN [8]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22673903; DOI=10.1038/ncomms1871;
RA Lundby A., Secher A., Lage K., Nordsborg N.B., Dmytriyev A., Lundby C.,
RA Olsen J.V.;
RT "Quantitative maps of protein phosphorylation sites across 14 different rat
RT organs and tissues.";
RL Nat. Commun. 3:876-876(2012).
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:10438538,
CC ECO:0000269|PubMed:19135240}.
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:15878399}.
CC -!- SUBUNIT: Monomer. Interacts with the PDZ domain of the syntrophin
CC SNTA1. Interacts with LIN7C, SCRIB, SYNJ2BP and SH3BP5. Interacts with
CC PTPN4; this interaction induces the activation of PTPN4 phosphatase
CC activity. {ECO:0000250|UniProtKB:P53778, ECO:0000269|PubMed:15158451,
CC ECO:0000269|PubMed:15878399, ECO:0000269|PubMed:19135240}.
CC -!- INTERACTION:
CC Q63538; Q13424: SNTA1; Xeno; NbExp=5; IntAct=EBI-783937, EBI-717191;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus {ECO:0000250}. Mitochondrion.
CC Note=Mitochondrial when associated with SH3BP5. In skeletal muscle
CC colocalizes with SNTA1 at the neuromuscular junction and throughout the
CC sarcolemma.
CC -!- TISSUE SPECIFICITY: Highly expressed in skeletal muscle, lung and
CC testes and also in the heart and thymus of both adult and neonatal
CC rats. {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:10438538}.
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; X96488; CAA65342.1; -; mRNA.
DR PIR; S68680; S68680.
DR RefSeq; NP_068514.1; NM_021746.1.
DR AlphaFoldDB; Q63538; -.
DR SMR; Q63538; -.
DR BioGRID; 248795; 2.
DR DIP; DIP-37835N; -.
DR IntAct; Q63538; 3.
DR STRING; 10116.ENSRNOP00000046455; -.
DR iPTMnet; Q63538; -.
DR PhosphoSitePlus; Q63538; -.
DR jPOST; Q63538; -.
DR PaxDb; Q63538; -.
DR PRIDE; Q63538; -.
DR Ensembl; ENSRNOT00000044376; ENSRNOP00000046455; ENSRNOG00000031233.
DR GeneID; 60352; -.
DR KEGG; rno:60352; -.
DR CTD; 6300; -.
DR RGD; 70975; Mapk12.
DR eggNOG; KOG0660; Eukaryota.
DR GeneTree; ENSGT00940000156189; -.
DR HOGENOM; CLU_000288_181_1_1; -.
DR InParanoid; Q63538; -.
DR OMA; PYVAAYH; -.
DR OrthoDB; 683132at2759; -.
DR PhylomeDB; Q63538; -.
DR TreeFam; TF105100; -.
DR Reactome; R-RNO-168638; NOD1/2 Signaling Pathway.
DR Reactome; R-RNO-376172; DSCAM interactions.
DR Reactome; R-RNO-4420097; VEGFA-VEGFR2 Pathway.
DR Reactome; R-RNO-525793; Myogenesis.
DR Reactome; R-RNO-5675221; Negative regulation of MAPK pathway.
DR PRO; PR:Q63538; -.
DR Proteomes; UP000002494; Chromosome 7.
DR Bgee; ENSRNOG00000031233; Expressed in skeletal muscle tissue and 20 other tissues.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005739; C:mitochondrion; IEA:UniProtKB-SubCell.
DR GO; GO:0005634; C:nucleus; IBA:GO_Central.
DR GO; GO:0005524; F:ATP binding; IDA:RGD.
DR GO; GO:0000287; F:magnesium ion binding; ISO:RGD.
DR GO; GO:0004707; F:MAP kinase activity; IDA:RGD.
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: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:RGD.
DR GO; GO:0045786; P:negative regulation of cell cycle; IDA:UniProtKB.
DR GO; GO:0018105; P:peptidyl-serine phosphorylation; ISO:RGD.
DR GO; GO:0006468; P:protein phosphorylation; IDA:RGD.
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_0000186284"
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; by MAP2K3 and MAP2K6"
FT /evidence="ECO:0000269|PubMed:10438538"
FT MOD_RES 185
FT /note="Phosphotyrosine; by MAP2K3 and MAP2K6"
FT /evidence="ECO:0000269|PubMed:10438538"
FT MUTAGEN 183
FT /note="T->A: Loss of kinase activity."
FT /evidence="ECO:0000269|PubMed:10438538"
FT MUTAGEN 185
FT /note="Y->A: Loss of kinase activity."
FT /evidence="ECO:0000269|PubMed:10438538"
SQ SEQUENCE 367 AA; 41985 MW; B77193D9F45E1D4E CRC64;
MSSPPPARKG FYRQEVTKTA WEVRAVYQDL QPVGSGAYGA VCSAVDSRTG NKVAIKKLYR
PFQSELFAKR AYRELRLLKH MRHENVIGLL DVFTPDETLD DFTDFYLVMP FMGTDLGKLM
KHETLSEDRI QFLVYQMLKG LKYIHAAGVI HRDLKPGNLA VNEDCELKIL DFGLARQADS
EMTGYVVTRW YRAPEVILNW MRYTQTVDIW SVGCIMAEMI TGKILFKGND HLDQLKEIMK
VTGTPPPEFV QKLQSAEAKN YMEGLPELEK KDFASVLTNA SPQAVNLLEK MLVLDAEQRV
TAAEALAHPY FESLRDTEDE PKAQKYDDSF DDVDRTLEEW KRVTYKEVLS FKPPRQLGAR
VPKETAL
