ID MK12_HUMAN Reviewed; 367 AA. AC P53778; Q14260; Q6IC53; Q99588; Q99672; DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot. DT 15-JUL-1998, sequence version 3. DT 27-MAR-2024, entry version 228. DE RecName: Full=Mitogen-activated protein kinase 12; DE Short=MAP kinase 12; DE Short=MAPK 12; DE EC=2.7.11.24 {ECO:0000269|PubMed:10212242}; 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=ERK6, SAPK3; 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), FUNCTION, TISSUE SPECIFICITY, AND RP MUTAGENESIS OF TYR-185. RC TISSUE=Skeletal muscle; RX PubMed=8633070; DOI=10.1073/pnas.93.9.4355; RA Lechner C., Zahalka M.A., Giot J.-F., Moeller N.P.H., Ullrich A.; RT "ERK6, a mitogen-activated protein kinase involved in C2C12 myoblast RT differentiation."; RL Proc. Natl. Acad. Sci. U.S.A. 93:4355-4359(1996). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RC TISSUE=Skeletal muscle; RX PubMed=9169156; DOI=10.1006/geno.1997.4633; RA Goedert M., Hasegawa J., Craxton M., Leversha M.A., Clegg S.; RT "Assignment of the human stress-activated protein kinase-3 gene (SAPK3) to RT chromosome 22q13.3 by fluorescence in situ hybridization."; RL Genomics 41:501-502(1997). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RX PubMed=8920915; DOI=10.1006/bbrc.1996.1662; RA Li Z., Jiang Y., Ulevitch R.J., Han J.; RT "The primary structure of p38 gamma: a new member of p38 group of MAP RT kinases."; RL Biochem. Biophys. Res. Commun. 228:334-340(1996). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2), AND VARIANT MET-103. 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 [5] 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 [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Pancreas; 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 [7] RP FUNCTION IN PHOSPHORYLATION OF ATF2; ELK1 AND MBP, AND ACTIVITY REGULATION. 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 [8] RP INTERACTION WITH SNTA1, ACTIVITY REGULATION, BIOPHYSICOCHEMICAL PROPERTIES, RP AND CATALYTIC ACTIVITY. RX PubMed=10212242; DOI=10.1074/jbc.274.18.12626; RA Hasegawa M., Cuenda A., Spillantini M.G., Thomas G.M., Buee-Scherrer V., RA Cohen P., Goedert M.; RT "Stress-activated protein kinase-3 interacts with the PDZ domain of alpha1- RT syntrophin. A mechanism for specific substrate recognition."; RL J. Biol. Chem. 274:12626-12631(1999). RN [9] RP PHOSPHORYLATION BY MAP2K6/MKK6. RX PubMed=11010976; DOI=10.1074/jbc.m007835200; RA Alonso G., Ambrosino C., Jones M., Nebreda A.R.; RT "Differential activation of p38 mitogen-activated protein kinase isoforms RT depending on signal strength."; RL J. Biol. Chem. 275:40641-40648(2000). RN [10] RP FUNCTION IN REGULATION OF THE G2 CHECKPOINT. RX PubMed=10848581; DOI=10.1128/mcb.20.13.4543-4552.2000; RA Wang X., McGowan C.H., Zhao M., He L., Downey J.S., Fearns C., Wang Y., RA Huang S., Han J.; RT "Involvement of the MKK6-p38gamma cascade in gamma-radiation-induced cell RT cycle arrest."; RL Mol. Cell. Biol. 20:4543-4552(2000). RN [11] RP SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY. RC TISSUE=Heart; 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 [12] RP MUTAGENESIS, SUBCELLULAR LOCATION, AND INTERACTION WITH SH3BP5. RX PubMed=12167088; DOI=10.1042/bj20020553; RA Wiltshire C., Matsushita M., Tsukada S., Gillespie D.A., May G.H.; RT "A new c-Jun N-terminal kinase (JNK)-interacting protein, Sab (SH3BP5), RT associates with mitochondria."; RL Biochem. J. 367:577-585(2002). RN [13] RP FUNCTION. RX PubMed=14592936; DOI=10.1152/ajpregu.00563.2003; RA Ho R.C., Alcazar O., Fujii N., Hirshman M.F., Goodyear L.J.; RT "p38gamma MAPK regulation of glucose transporter expression and glucose RT uptake in L6 myotubes and mouse skeletal muscle."; RL Am. J. Physiol. 286:R342-R349(2004). RN [14] RP MUTAGENESIS OF ASP-179 AND PHE-330. RX PubMed=15284239; DOI=10.1074/jbc.m404595200; RA Diskin R., Askari N., Capone R., Engelberg D., Livnah O.; RT "Active mutants of the human p38alpha mitogen-activated protein kinase."; RL J. Biol. Chem. 279:47040-47049(2004). RN [15] RP FUNCTION, INDUCTION, PHOSPHORYLATION, SUBCELLULAR LOCATION, AND RP UBIQUITINATION. RX PubMed=17724032; DOI=10.1074/jbc.m703857200; RA Qi X., Pohl N.M., Loesch M., Hou S., Li R., Qin J.Z., Cuenda A., Chen G.; RT "p38alpha antagonizes p38gamma activity through c-Jun-dependent ubiquitin- RT proteasome pathways in regulating Ras transformation and stress response."; RL J. Biol. Chem. 282:31398-31408(2007). RN [16] RP FUNCTION IN PHOSPHORYLATION OF DLG1. RX PubMed=20605917; DOI=10.1242/jcs.066514; RA Sabio G., Cerezo-Guisado M.I., Del Reino P., Inesta-Vaquera F.A., RA Rousseau S., Arthur J.S., Campbell D.G., Centeno F., Cuenda A.; RT "p38gamma regulates interaction of nuclear PSF and RNA with the tumour- RT suppressor hDlg in response to osmotic shock."; RL J. Cell Sci. 123:2596-2604(2010). RN [17] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [18] RP FUNCTION. RX PubMed=21172807; DOI=10.1242/jcs.068254; RA Kukkonen-Macchi A., Sicora O., Kaczynska K., Oetken-Lindholm C., RA Pouwels J., Laine L., Kallio M.J.; RT "Loss of p38gamma MAPK induces pleiotropic mitotic defects and massive cell RT death."; RL J. Cell Sci. 124:216-227(2011). RN [19] RP INVOLVEMENT IN CANCER. RX PubMed=21532888; DOI=10.1593/neo.101748; RA Meng F., Zhang H., Liu G., Kreike B., Chen W., Sethi S., Miller F.R., RA Wu G.; RT "p38gamma mitogen-activated protein kinase contributes to oncogenic RT properties maintenance and resistance to poly (ADP-ribose)-polymerase-1 RT inhibition in breast cancer."; RL Neoplasia 13:472-482(2011). RN [20] 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 [21] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-185, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [22] RP INTERACTION WITH PTPN4. RX PubMed=27246854; DOI=10.1074/jbc.m115.707208; RA Maisonneuve P., Caillet-Saguy C., Vaney M.C., Bibi-Zainab E., Sawyer K., RA Raynal B., Haouz A., Delepierre M., Lafon M., Cordier F., Wolff N.; RT "Molecular Basis of the Interaction of the Human Protein Tyrosine RT Phosphatase Non-receptor Type 4 (PTPN4) with the Mitogen-activated Protein RT Kinase p38gamma."; RL J. Biol. Chem. 291:16699-16708(2016). RN [23] RP X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS), COFACTOR, AND SUBUNIT. RX PubMed=10508788; DOI=10.1016/s0969-2126(99)80173-7; RA Bellon S., Fitzgibbon M.J., Fox T., Hsiao H.M., Wilson K.P.; RT "The structure of phosphorylated p38gamma is monomeric and reveals a RT conserved activation-loop conformation."; RL Structure 7:1057-1065(1999). RN [24] RP VARIANTS [LARGE SCALE ANALYSIS] MET-103 AND ASN-230. 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. 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:10848581, CC ECO:0000269|PubMed:14592936, ECO:0000269|PubMed:17724032, CC ECO:0000269|PubMed:20605917, ECO:0000269|PubMed:21172807, CC ECO:0000269|PubMed:8633070, ECO:0000269|PubMed:9430721}. 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:10212242}; 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:10212242}; CC -!- COFACTOR: CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420; CC Evidence={ECO:0000269|PubMed:10508788}; CC Note=Binds 2 magnesium ions. {ECO:0000269|PubMed:10508788}; 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:10212242, ECO:0000269|PubMed:9430721}. CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=37 uM for ATP {ECO:0000269|PubMed:10212242}; CC KM=313 uM for EGFR substrate peptide {ECO:0000269|PubMed:10212242}; CC KM=254 uM for GST-ATF2 {ECO:0000269|PubMed:10212242}; CC -!- SUBUNIT: Monomer. Interacts with the PDZ domain of the syntrophin CC SNTA1. Interacts with SH3BP5. Interacts with LIN7C, SCRIB and SYNJ2BP CC (By similarity). Interacts with PTPN4; this interaction induces the CC activation of PTPN4 phosphatase activity. {ECO:0000250, CC ECO:0000269|PubMed:27246854}. CC -!- INTERACTION: CC P53778; P05067: APP; NbExp=3; IntAct=EBI-602406, EBI-77613; CC P53778; Q12959: DLG1; NbExp=2; IntAct=EBI-602406, EBI-357481; CC P53778; Q16512: PKN1; NbExp=2; IntAct=EBI-602406, EBI-602382; CC P53778; P29074: PTPN4; NbExp=2; IntAct=EBI-602406, EBI-710431; CC P53778; Q14160: SCRIB; NbExp=6; IntAct=EBI-602406, EBI-357345; CC P53778; Q8IUQ4: SIAH1; NbExp=3; IntAct=EBI-602406, EBI-747107; CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Mitochondrion. CC Note=Mitochondrial when associated with SH3BP5. In skeletal muscle CC colocalizes with SNTA1 at the neuromuscular junction and throughout the CC sarcolemma (By similarity). {ECO:0000250}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=P53778-1; Sequence=Displayed; CC Name=2; CC IsoId=P53778-2; Sequence=VSP_055224; CC -!- TISSUE SPECIFICITY: Highly expressed in skeletal muscle and heart. CC {ECO:0000269|PubMed:11991731, ECO:0000269|PubMed:8633070}. CC -!- INDUCTION: Expression of MAPK12 is down-regulation by MAPK14 CC activation. {ECO:0000269|PubMed:17724032}. 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:11010976, CC ECO:0000269|PubMed:17724032}. CC -!- PTM: Ubiquitinated. Ubiquitination leads to degradation by the CC proteasome pathway. {ECO:0000269|PubMed:17724032}. CC -!- DISEASE: Note=MAPK is overexpressed in highly metastatic breast cancer CC cell lines and its expression is preferentially associated with basal- CC like and metastatic phenotypes of breast tumor samples. CC -!- SIMILARITY: Belongs to the protein kinase superfamily. CMGC Ser/Thr CC protein kinase family. MAP kinase subfamily. {ECO:0000305}. CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and CC Haematology; CC URL="https://atlasgeneticsoncology.org/gene/41290/MAPK12"; 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; X79483; CAA55984.1; -; mRNA. DR EMBL; Y10487; CAA71511.1; -; mRNA. DR EMBL; U66243; AAB40118.1; -; mRNA. DR EMBL; CR456515; CAG30401.1; -; mRNA. DR EMBL; AL022328; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC015741; AAH15741.1; -; mRNA. DR CCDS; CCDS14089.1; -. [P53778-1] DR CCDS; CCDS77688.1; -. [P53778-2] DR PIR; JC5252; JC5252. DR PIR; JC6138; JC6138. DR RefSeq; NP_001290181.1; NM_001303252.2. [P53778-2] DR RefSeq; NP_002960.2; NM_002969.5. [P53778-1] DR PDB; 1CM8; X-ray; 2.40 A; A/B=1-367. DR PDB; 4QUM; X-ray; 2.52 A; B=182-190. DR PDB; 6UNA; X-ray; 2.55 A; A/B=7-367. DR PDB; 7CGA; X-ray; 3.15 A; A/B/C/D=9-353. DR PDBsum; 1CM8; -. DR PDBsum; 4QUM; -. DR PDBsum; 6UNA; -. DR PDBsum; 7CGA; -. DR AlphaFoldDB; P53778; -. DR SMR; P53778; -. DR BioGRID; 112207; 71. DR CORUM; P53778; -. DR DIP; DIP-34241N; -. DR IntAct; P53778; 31. DR MINT; P53778; -. DR STRING; 9606.ENSP00000215659; -. DR BindingDB; P53778; -. DR ChEMBL; CHEMBL4674; -. DR DrugBank; DB05403; CEP-1347. DR DrugBank; DB05157; KC706. DR DrugBank; DB01017; Minocycline. DR DrugBank; DB04395; Phosphoaminophosphonic Acid-Adenylate Ester. DR DrugBank; DB02482; Phosphonothreonine. DR DrugCentral; P53778; -. DR GuidetoPHARMACOLOGY; 1501; -. DR iPTMnet; P53778; -. DR PhosphoSitePlus; P53778; -. DR BioMuta; MAPK12; -. DR DMDM; 2851522; -. DR CPTAC; CPTAC-2913; -. DR CPTAC; CPTAC-2914; -. DR CPTAC; CPTAC-874; -. DR CPTAC; CPTAC-875; -. DR EPD; P53778; -. DR jPOST; P53778; -. DR MassIVE; P53778; -. DR MaxQB; P53778; -. DR PaxDb; 9606-ENSP00000215659; -. DR PeptideAtlas; P53778; -. DR ProteomicsDB; 56615; -. [P53778-1] DR Pumba; P53778; -. DR Antibodypedia; 14291; 601 antibodies from 38 providers. DR DNASU; 6300; -. DR Ensembl; ENST00000215659.13; ENSP00000215659.8; ENSG00000188130.14. [P53778-1] DR Ensembl; ENST00000622558.4; ENSP00000479972.1; ENSG00000188130.14. [P53778-2] DR GeneID; 6300; -. DR KEGG; hsa:6300; -. DR MANE-Select; ENST00000215659.13; ENSP00000215659.8; NM_002969.6; NP_002960.2. DR UCSC; uc003bkl.2; human. [P53778-1] DR AGR; HGNC:6874; -. DR CTD; 6300; -. DR DisGeNET; 6300; -. DR GeneCards; MAPK12; -. DR HGNC; HGNC:6874; MAPK12. DR HPA; ENSG00000188130; Group enriched (skeletal muscle, tongue). DR MIM; 602399; gene. DR neXtProt; NX_P53778; -. DR OpenTargets; ENSG00000188130; -. DR PharmGKB; PA30619; -. DR VEuPathDB; HostDB:ENSG00000188130; -. DR eggNOG; KOG0660; Eukaryota. DR GeneTree; ENSGT00940000156189; -. DR InParanoid; P53778; -. DR OMA; PYVAAYH; -. DR OrthoDB; 158564at2759; -. DR PhylomeDB; P53778; -. DR TreeFam; TF105100; -. DR BRENDA; 2.7.11.24; 2681. DR PathwayCommons; P53778; -. DR Reactome; R-HSA-168638; NOD1/2 Signaling Pathway. DR Reactome; R-HSA-171007; p38MAPK events. DR Reactome; R-HSA-2151209; Activation of PPARGC1A (PGC-1alpha) by phosphorylation. DR Reactome; R-HSA-376172; DSCAM interactions. DR Reactome; R-HSA-4420097; VEGFA-VEGFR2 Pathway. DR Reactome; R-HSA-525793; Myogenesis. DR Reactome; R-HSA-5675221; Negative regulation of MAPK pathway. DR SignaLink; P53778; -. DR SIGNOR; P53778; -. DR BioGRID-ORCS; 6300; 6 hits in 1188 CRISPR screens. DR ChiTaRS; MAPK12; human. DR EvolutionaryTrace; P53778; -. DR GeneWiki; MAPK12; -. DR GenomeRNAi; 6300; -. DR Pharos; P53778; Tchem. DR PRO; PR:P53778; -. DR Proteomes; UP000005640; Chromosome 22. DR RNAct; P53778; Protein. DR Bgee; ENSG00000188130; Expressed in gastrocnemius and 163 other cell types or tissues. DR ExpressionAtlas; P53778; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central. DR GO; GO:0005829; C:cytosol; TAS:Reactome. 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; IEA:UniProtKB-KW. DR GO; GO:0000287; F:magnesium ion binding; IDA:UniProtKB. DR GO; GO:0004707; F:MAP kinase activity; TAS:ProtInc. 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:0000165; P:MAPK cascade; TAS:Reactome. DR GO; GO:0007517; P:muscle organ development; TAS:ProtInc. DR GO; GO:0045445; P:myoblast differentiation; IDA:UniProtKB. DR GO; GO:0045786; P:negative regulation of cell cycle; IEA:Ensembl. DR GO; GO:0018105; P:peptidyl-serine phosphorylation; IDA:BHF-UCL. DR GO; GO:0051149; P:positive regulation of muscle cell differentiation; TAS:Reactome. DR GO; GO:0010952; P:positive regulation of peptidase activity; NAS:ParkinsonsUK-UCL. DR GO; GO:0051726; P:regulation of cell cycle; TAS:ProtInc. DR GO; GO:0007165; P:signal transduction; TAS:ProtInc. DR GO; GO:0042770; P:signal transduction in response to DNA damage; TAS:ProtInc. DR CDD; cd07880; STKc_p38gamma; 1. 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; IPR038786; MAPK12. 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:SF146; MITOGEN-ACTIVATED PROTEIN KINASE 12; 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; P53778; HS. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; ATP-binding; Cell cycle; Cytoplasm; KW Kinase; Magnesium; Metal-binding; Mitochondrion; Nucleotide-binding; KW Nucleus; Phosphoprotein; Reference proteome; KW Serine/threonine-protein kinase; Stress response; Transcription; KW Transcription regulation; Transferase; Ubl conjugation. FT CHAIN 1..367 FT /note="Mitogen-activated protein kinase 12" FT /id="PRO_0000186282" 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:0000250|UniProtKB:Q63538" FT MOD_RES 185 FT /note="Phosphotyrosine" FT /evidence="ECO:0007744|PubMed:23186163" FT VAR_SEQ 142..151 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:15461802" FT /id="VSP_055224" FT VARIANT 103 FT /note="T -> M (in dbSNP:rs34422484)" FT /evidence="ECO:0000269|PubMed:15461802, FT ECO:0000269|PubMed:17344846" FT /id="VAR_042265" FT VARIANT 230 FT /note="D -> N (in dbSNP:rs35396905)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_042266" FT VARIANT 244 FT /note="T -> M (in dbSNP:rs2066776)" FT /id="VAR_012002" FT MUTAGEN 179 FT /note="D->A: Emulation of the active state." FT /evidence="ECO:0000269|PubMed:15284239" FT MUTAGEN 185 FT /note="Y->F: Loss of activity." FT /evidence="ECO:0000269|PubMed:8633070" FT MUTAGEN 330 FT /note="F->S: No effect." FT /evidence="ECO:0000269|PubMed:15284239" FT CONFLICT 7 FT /note="A -> T (in Ref. 1; CAA55984)" FT /evidence="ECO:0000305" FT CONFLICT 70 FT /note="R -> L (in Ref. 1; CAA55984)" FT /evidence="ECO:0000305" FT CONFLICT 138 FT /note="L -> M (in Ref. 1; CAA55984)" FT /evidence="ECO:0000305" FT CONFLICT 201..202 FT /note="MR -> IA (in Ref. 1; CAA55984)" FT /evidence="ECO:0000305" FT CONFLICT 261 FT /note="Y -> N (in Ref. 3; AAB40118)" FT /evidence="ECO:0000305" FT CONFLICT 297..298 FT /note="EQ -> DI (in Ref. 1; CAA55984)" FT /evidence="ECO:0000305" FT CONFLICT 300 FT /note="V -> L (in Ref. 1; CAA55984)" FT /evidence="ECO:0000305" FT CONFLICT 305 FT /note="A -> F (in Ref. 1; CAA55984)" FT /evidence="ECO:0000305" FT CONFLICT 307 FT /note="A -> S (in Ref. 1; CAA55984)" FT /evidence="ECO:0000305" FT CONFLICT 332..333 FT /note="DV -> YF (in Ref. 1; CAA55984)" FT /evidence="ECO:0000305" FT STRAND 11..15 FT /evidence="ECO:0007829|PDB:6UNA" FT STRAND 17..21 FT /evidence="ECO:0007829|PDB:1CM8" FT STRAND 24..32 FT /evidence="ECO:0007829|PDB:1CM8" FT STRAND 41..46 FT /evidence="ECO:0007829|PDB:1CM8" FT TURN 47..49 FT /evidence="ECO:0007829|PDB:1CM8" FT STRAND 52..57 FT /evidence="ECO:0007829|PDB:1CM8" FT HELIX 65..80 FT /evidence="ECO:0007829|PDB:1CM8" FT STRAND 90..93 FT /evidence="ECO:0007829|PDB:1CM8" FT TURN 99..101 FT /evidence="ECO:0007829|PDB:1CM8" FT STRAND 106..110 FT /evidence="ECO:0007829|PDB:1CM8" FT STRAND 113..115 FT /evidence="ECO:0007829|PDB:1CM8" FT HELIX 116..122 FT /evidence="ECO:0007829|PDB:1CM8" FT HELIX 127..146 FT /evidence="ECO:0007829|PDB:1CM8" FT HELIX 156..158 FT /evidence="ECO:0007829|PDB:1CM8" FT STRAND 159..161 FT /evidence="ECO:0007829|PDB:1CM8" FT STRAND 167..169 FT /evidence="ECO:0007829|PDB:1CM8" FT HELIX 189..191 FT /evidence="ECO:0007829|PDB:1CM8" FT HELIX 195..198 FT /evidence="ECO:0007829|PDB:1CM8" FT TURN 199..201 FT /evidence="ECO:0007829|PDB:1CM8" FT HELIX 207..221 FT /evidence="ECO:0007829|PDB:1CM8" FT HELIX 231..242 FT /evidence="ECO:0007829|PDB:1CM8" FT HELIX 247..251 FT /evidence="ECO:0007829|PDB:1CM8" FT HELIX 256..264 FT /evidence="ECO:0007829|PDB:1CM8" FT HELIX 273..275 FT /evidence="ECO:0007829|PDB:1CM8" FT HELIX 282..291 FT /evidence="ECO:0007829|PDB:1CM8" FT TURN 296..298 FT /evidence="ECO:0007829|PDB:1CM8" FT HELIX 302..307 FT /evidence="ECO:0007829|PDB:1CM8" FT HELIX 309..311 FT /evidence="ECO:0007829|PDB:1CM8" FT TURN 312..314 FT /evidence="ECO:0007829|PDB:1CM8" FT HELIX 329..332 FT /evidence="ECO:0007829|PDB:6UNA" FT HELIX 337..349 FT /evidence="ECO:0007829|PDB:1CM8" SQ SEQUENCE 367 AA; 41940 MW; EF680401D8E40610 CRC64; MSSPPPARSG FYRQEVTKTA WEVRAVYRDL QPVGSGAYGA VCSAVDGRTG AKVAIKKLYR PFQSELFAKR AYRELRLLKH MRHENVIGLL DVFTPDETLD DFTDFYLVMP FMGTDLGKLM KHEKLGEDRI QFLVYQMLKG LRYIHAAGII HRDLKPGNLA VNEDCELKIL DFGLARQADS EMTGYVVTRW YRAPEVILNW MRYTQTVDIW SVGCIMAEMI TGKTLFKGSD HLDQLKEIMK VTGTPPAEFV QRLQSDEAKN YMKGLPELEK KDFASILTNA SPLAVNLLEK MLVLDAEQRV TAGEALAHPY FESLHDTEDE PQVQKYDDSF DDVDRTLDEW KRVTYKEVLS FKPPRQLGAR VSKETPL //