MP2K3_MOUSE
ID MP2K3_MOUSE Reviewed; 347 AA.
AC O09110; P97293; Q91VX1;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-2002, sequence version 2.
DT 03-AUG-2022, entry version 189.
DE RecName: Full=Dual specificity mitogen-activated protein kinase kinase 3;
DE Short=MAP kinase kinase 3;
DE Short=MAPKK 3;
DE EC=2.7.12.2 {ECO:0000250|UniProtKB:P46734};
DE AltName: Full=MAPK/ERK kinase 3;
DE Short=MEK 3;
GN Name=Map2k3; Synonyms=Mkk3, Prkmk3;
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] (ISOFORM 1).
RA Neininger A., Gaestel M.;
RL Submitted (JAN-1997) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RX PubMed=8900184; DOI=10.1074/jbc.271.43.26981;
RA Moriguchi T., Toyoshima F., Gotoh Y., Iwamatsu A., Irie K., Mori E.,
RA Kuroyanagi N., Hagiwara M., Matsumoto K., Nishida E.;
RT "Purification and identification of a major activator for p38 from
RT osmotically shocked cells: activation of mitogen-activated protein kinase
RT kinase 6 by osmotic shock, tumor necrosis factor-alpha, and H2O2.";
RL J. Biol. Chem. 271:26981-26988(1996).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC STRAIN=C57BL/6J; TISSUE=Embryonic liver, and Small intestine;
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 [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Mammary gland;
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 [5]
RP INTERACTION WITH MAP3K3; RAC1 AND CCM2.
RX PubMed=14634666; DOI=10.1038/ncb1071;
RA Uhlik M.T., Abell A.N., Johnson N.L., Sun W., Cuevas B.D., Lobel-Rice K.E.,
RA Horne E.A., Dell'Acqua M.L., Johnson G.L.;
RT "Rac-MEKK3-MKK3 scaffolding for p38 MAPK activation during hyperosmotic
RT shock.";
RL Nat. Cell Biol. 5:1104-1110(2003).
RN [6]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brown adipose tissue, Heart, Kidney, Liver, Lung, Pancreas, Spleen,
RC and Testis;
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).
CC -!- FUNCTION: Dual specificity kinase. Is activated by cytokines and
CC environmental stress in vivo. Catalyzes the concomitant phosphorylation
CC of a threonine and a tyrosine residue in the MAP kinase p38. Part of a
CC signaling cascade that begins with the activation of the adrenergic
CC receptor ADRA1B and leads to the activation of MAPK14.
CC {ECO:0000250|UniProtKB:P46734}.
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=2.7.12.2;
CC Evidence={ECO:0000250|UniProtKB:P46734};
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=2.7.12.2; Evidence={ECO:0000250|UniProtKB:P46734};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl-
CC [protein]; Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA-
CC COMP:10137, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858,
CC ChEBI:CHEBI:82620, ChEBI:CHEBI:456216; EC=2.7.12.2;
CC Evidence={ECO:0000250|UniProtKB:P46734};
CC -!- ACTIVITY REGULATION: Activated by dual phosphorylation on Ser-218 and
CC Thr-222. {ECO:0000250|UniProtKB:P46734}.
CC -!- SUBUNIT: Component of a signaling complex containing at least AKAP13,
CC PKN1, MAPK14, ZAK and MAP2K3. Within this complex, AKAP13 interacts
CC directly with PKN1, which in turn recruits MAPK14, MAP2K3 and ZAK.
CC Binds to DYRK1B/MIRK and increases its kinase activity (By similarity).
CC Part of a complex with MAP3K3, RAC1 and CCM2 (PubMed:14634666).
CC Interacts with ARRB1 (By similarity). {ECO:0000250|UniProtKB:P46734,
CC ECO:0000269|PubMed:14634666}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=2; Synonyms=3b;
CC IsoId=O09110-1; Sequence=Displayed;
CC Name=1;
CC IsoId=O09110-2; Sequence=VSP_004879;
CC -!- PTM: Autophosphorylated. Phosphorylation on Ser-218 and Thr-222 by MAP
CC kinase kinase kinases regulates positively the kinase activity.
CC Phosphorylated by TAOK2. {ECO:0000250|UniProtKB:P46734}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. STE Ser/Thr
CC protein kinase family. MAP kinase kinase subfamily. {ECO:0000305}.
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DR EMBL; X93150; CAA63649.1; -; mRNA.
DR EMBL; D87115; BAA13247.1; -; mRNA.
DR EMBL; AK011002; BAB27321.1; -; mRNA.
DR EMBL; AK008141; BAB25489.1; -; mRNA.
DR EMBL; BC007467; AAH07467.1; -; mRNA.
DR CCDS; CCDS24804.1; -. [O09110-1]
DR RefSeq; NP_032954.1; NM_008928.4. [O09110-1]
DR PDB; 1LEZ; X-ray; 2.30 A; B=16-32.
DR PDBsum; 1LEZ; -.
DR AlphaFoldDB; O09110; -.
DR SMR; O09110; -.
DR BioGRID; 204951; 9.
DR IntAct; O09110; 1.
DR STRING; 10090.ENSMUSP00000019076; -.
DR ChEMBL; CHEMBL3721303; -.
DR iPTMnet; O09110; -.
DR PhosphoSitePlus; O09110; -.
DR EPD; O09110; -.
DR MaxQB; O09110; -.
DR PaxDb; O09110; -.
DR PeptideAtlas; O09110; -.
DR PRIDE; O09110; -.
DR ProteomicsDB; 252600; -. [O09110-1]
DR ProteomicsDB; 252601; -. [O09110-2]
DR Antibodypedia; 4342; 1466 antibodies from 43 providers.
DR DNASU; 26397; -.
DR Ensembl; ENSMUST00000019076; ENSMUSP00000019076; ENSMUSG00000018932. [O09110-1]
DR GeneID; 26397; -.
DR KEGG; mmu:26397; -.
DR UCSC; uc007jgw.1; mouse. [O09110-1]
DR CTD; 5606; -.
DR MGI; MGI:1346868; Map2k3.
DR VEuPathDB; HostDB:ENSMUSG00000018932; -.
DR eggNOG; KOG0984; Eukaryota.
DR GeneTree; ENSGT00940000160875; -.
DR HOGENOM; CLU_000288_63_23_1; -.
DR InParanoid; O09110; -.
DR OMA; RITCVSK; -.
DR PhylomeDB; O09110; -.
DR TreeFam; TF350701; -.
DR BRENDA; 2.7.12.2; 3474.
DR Reactome; R-MMU-2559580; Oxidative Stress Induced Senescence.
DR Reactome; R-MMU-450302; activated TAK1 mediates p38 MAPK activation.
DR BioGRID-ORCS; 26397; 8 hits in 74 CRISPR screens.
DR PRO; PR:O09110; -.
DR Proteomes; UP000000589; Chromosome 11.
DR RNAct; O09110; protein.
DR Bgee; ENSMUSG00000018932; Expressed in temporalis muscle and 243 other tissues.
DR ExpressionAtlas; O09110; baseline and differential.
DR Genevisible; O09110; MM.
DR GO; GO:0005829; C:cytosol; ISO:MGI.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0004708; F:MAP kinase kinase activity; IDA:MGI.
DR GO; GO:0019901; F:protein kinase binding; IPI:UniProtKB.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; IEA:UniProtKB-KW.
DR GO; GO:0004713; F:protein tyrosine kinase activity; IEA:UniProtKB-KW.
DR GO; GO:0060048; P:cardiac muscle contraction; IMP:MGI.
DR GO; GO:0071222; P:cellular response to lipopolysaccharide; ISO:MGI.
DR GO; GO:0072709; P:cellular response to sorbitol; IEA:Ensembl.
DR GO; GO:0035924; P:cellular response to vascular endothelial growth factor stimulus; ISO:MGI.
DR GO; GO:0007507; P:heart development; IEA:Ensembl.
DR GO; GO:0006954; P:inflammatory response; IMP:MGI.
DR GO; GO:0000165; P:MAPK cascade; IDA:MGI.
DR GO; GO:0035331; P:negative regulation of hippo signaling; ISO:MGI.
DR GO; GO:0038066; P:p38MAPK cascade; ISO:MGI.
DR GO; GO:0043536; P:positive regulation of blood vessel endothelial cell migration; ISO:MGI.
DR GO; GO:0043410; P:positive regulation of MAPK cascade; IDA:MGI.
DR GO; GO:0051770; P:positive regulation of nitric-oxide synthase biosynthetic process; ISO:MGI.
DR GO; GO:0045860; P:positive regulation of protein kinase activity; ISO:MGI.
DR GO; GO:0001934; P:positive regulation of protein phosphorylation; ISO:MGI.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; ISO:MGI.
DR GO; GO:0001817; P:regulation of cytokine production; IMP:MGI.
DR GO; GO:0002931; P:response to ischemia; IEA:Ensembl.
DR IDEAL; IID50191; -.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR Pfam; PF00069; Pkinase; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; ATP-binding; Kinase;
KW Nucleotide-binding; Phosphoprotein; Reference proteome;
KW Serine/threonine-protein kinase; Transferase; Tyrosine-protein kinase.
FT CHAIN 1..347
FT /note="Dual specificity mitogen-activated protein kinase
FT kinase 3"
FT /id="PRO_0000086379"
FT DOMAIN 64..325
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 1..45
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 190
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10027"
FT BINDING 70..78
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 93
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOD_RES 1
FT /note="N-acetylmethionine"
FT /evidence="ECO:0000250|UniProtKB:P46734"
FT MOD_RES 3
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P46734"
FT MOD_RES 218
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P46734"
FT MOD_RES 222
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:P46734"
FT VAR_SEQ 1..37
FT /note="MESPAASPPASLPQTKGKSKRKKDLRISCVSKPPVSN -> MSKP (in
FT isoform 1)"
FT /evidence="ECO:0000303|PubMed:15489334, ECO:0000303|Ref.1"
FT /id="VSP_004879"
FT CONFLICT 39
FT /note="T -> A (in Ref. 1)"
FT /evidence="ECO:0000305"
FT CONFLICT 60
FT /note="E -> K (in Ref. 1; CAA63649)"
FT /evidence="ECO:0000305"
FT CONFLICT 173..347
FT /note="IVRALEHLHSKLSVIHRDVKPSNVLINKEGHVKMCDFGISGYLVDSVAKTMD
FT AGCKPYMAPERINPELNQKGYNVKSDVWSLGITMIEMAILRFPYESWGTPFQQLKQVVE
FT EPSPQLPADQFSPEFVDFTSQCLRKNPAERMSYLELMEHPFFTLHKTKKTDIAAFVKEI
FT LGEDS -> M (in Ref. 4)"
FT /evidence="ECO:0000305"
FT CONFLICT 216
FT /note="V -> E (in Ref. 1; CAA63649)"
FT /evidence="ECO:0000305"
FT CONFLICT 292
FT /note="D -> Y (in Ref. 1; CAA63649)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 347 AA; 39296 MW; 4A2A420EDCA8A2BC CRC64;
MESPAASPPA SLPQTKGKSK RKKDLRISCV SKPPVSNPTP PRNLDSRTFI TIGDRNFEVE
ADDLVTISEL GRGAYGVVEK VRHAQSGTIM AVKRIRATVN TQEQKRLLMD LDINMRTVDC
FYTVTFYGAL FREGDVWICM ELMDTSLDKF YRKVLEKNMK IPEDILGEIA VSIVRALEHL
HSKLSVIHRD VKPSNVLINK EGHVKMCDFG ISGYLVDSVA KTMDAGCKPY MAPERINPEL
NQKGYNVKSD VWSLGITMIE MAILRFPYES WGTPFQQLKQ VVEEPSPQLP ADQFSPEFVD
FTSQCLRKNP AERMSYLELM EHPFFTLHKT KKTDIAAFVK EILGEDS
