Full text data of MAP2K3
MAP2K3
(MEK3, MKK3, PRKMK3, SKK2)
[Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Dual specificity mitogen-activated protein kinase kinase 3; MAP kinase kinase 3; MAPKK 3; 2.7.12.2 (MAPK/ERK kinase 3; MEK 3; Stress-activated protein kinase kinase 2; SAPK kinase 2; SAPKK-2; SAPKK2)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Dual specificity mitogen-activated protein kinase kinase 3; MAP kinase kinase 3; MAPKK 3; 2.7.12.2 (MAPK/ERK kinase 3; MEK 3; Stress-activated protein kinase kinase 2; SAPK kinase 2; SAPKK-2; SAPKK2)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
P46734
ID MP2K3_HUMAN Reviewed; 347 AA.
AC P46734; B3KSK7; Q99441; Q9UE71; Q9UE72;
DT 01-NOV-1995, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-NOV-2002, sequence version 2.
DT 22-JAN-2014, entry version 146.
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;
DE AltName: Full=MAPK/ERK kinase 3;
DE Short=MEK 3;
DE AltName: Full=Stress-activated protein kinase kinase 2;
DE Short=SAPK kinase 2;
DE Short=SAPKK-2;
DE Short=SAPKK2;
GN Name=MAP2K3; Synonyms=MEK3, MKK3, PRKMK3, SKK2;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Brain;
RX PubMed=7839144; DOI=10.1126/science.7839144;
RA Derijard B., Raingeaud J., Barrett T., Wu I.-H., Han J.,
RA Ulevitch R.J., Davis R.J.;
RT "Independent human MAP-kinase signal transduction pathways defined by
RT MEK and MKK isoforms.";
RL Science 267:682-685(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3).
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
RT kinase kinase 6 by osmotic shock, tumor necrosis factor-alpha, and
RT H2O2.";
RL J. Biol. Chem. 271:26981-26988(1996).
RN [3]
RP NUCLEOTIDE SEQUENCE (ISOFORMS 2 AND 3).
RA Han J.;
RL Submitted (AUG-1996) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Trachea;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
RC TISSUE=Leukocyte;
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
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP PHOSPHORYLATION AT SER-218 AND THR-222, AND MUTAGENESIS OF SER-218 AND
RP THR-222.
RX PubMed=8622669;
RA Raingeaud J., Whitmarsh A.J., Barrett T., Derijard B., Davis R.J.;
RT "MKK3- and MKK6-regulated gene expression is mediated by the p38
RT mitogen-activated protein kinase signal transduction pathway.";
RL Mol. Cell. Biol. 16:1247-1255(1996).
RN [7]
RP PHOSPHORYLATION BY TAOK2.
RX PubMed=11279118; DOI=10.1074/jbc.M100681200;
RA Chen Z., Cobb M.H.;
RT "Regulation of stress-responsive mitogen-activated protein (MAP)
RT kinase pathways by TAO2.";
RL J. Biol. Chem. 276:16070-16075(2001).
RN [8]
RP INTERACTION WITH DYRK1B.
RC TISSUE=Muscle;
RX PubMed=11980910; DOI=10.1074/jbc.M203257200;
RA Lim S., Jin K., Friedman E.;
RT "Mirk protein kinase is activated by MKK3 and functions as a
RT transcriptional activator of HNF1alpha.";
RL J. Biol. Chem. 277:25040-25046(2002).
RN [9]
RP INTERACTION WITH ARRB1.
RX PubMed=16709866;
RA McLaughlin N.J., Banerjee A., Kelher M.R., Gamboni-Robertson F.,
RA Hamiel C., Sheppard F.R., Moore E.E., Silliman C.C.;
RT "Platelet-activating factor-induced clathrin-mediated endocytosis
RT requires beta-arrestin-1 recruitment and activation of the p38 MAPK
RT signalosome at the plasma membrane for actin bundle formation.";
RL J. Immunol. 176:7039-7050(2006).
RN [10]
RP INTERACTION WITH YOPJ, AND ACETYLATION.
RX PubMed=16728640; DOI=10.1126/science.1126867;
RA Mukherjee S., Keitany G., Li Y., Wang Y., Ball H.L., Goldsmith E.J.,
RA Orth K.;
RT "Yersinia YopJ acetylates and inhibits kinase activation by blocking
RT phosphorylation.";
RL Science 312:1211-1214(2006).
RN [11]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND MASS SPECTROMETRY.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [12]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, PHOSPHORYLATION [LARGE
RP SCALE ANALYSIS] AT SER-3 AND SER-15, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [13]
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.,
RA Buerckstuemmer T., 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 [14]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND MASS SPECTROMETRY.
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [15]
RP VARIANTS COLON CANCER TRP-175 AND VAL-215.
RX PubMed=11414763; DOI=10.1006/geno.2001.6551;
RA Teng D.-H., Chen Y., Lian L., Ha P.C., Tavtigian S.V., Wong A.K.C.;
RT "Mutation analyses of 268 candidate genes in human tumor cell lines.";
RL Genomics 74:352-364(2001).
RN [16]
RP VARIANTS [LARGE SCALE ANALYSIS] THR-26; PRO-68; THR-84; ILE-90;
RP LEU-94; TRP-96; HIS-293 AND MET-339.
RX PubMed=17344846; DOI=10.1038/nature05610;
RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C.,
RA Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S.,
RA O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S.,
RA Bhamra G., Buck G., Choudhury B., Clements J., Cole J., Dicks E.,
RA Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J.,
RA Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K.,
RA Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T.,
RA West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P.,
RA Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E.,
RA DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E.,
RA Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T.,
RA Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.;
RT "Patterns of somatic mutation in human cancer genomes.";
RL Nature 446:153-158(2007).
CC -!- FUNCTION: Dual specificity kinase. Is activated by cytokines and
CC environmental stress in vivo. Catalyzes the concomitant
CC phosphorylation of a threonine and a tyrosine residue in the MAP
CC kinase p38.
CC -!- CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein.
CC -!- ENZYME REGULATION: Activated by dual phosphorylation on Ser-218
CC and Thr-222.
CC -!- SUBUNIT: Binds to DYRK1B/MIRK and increases its kinase activity.
CC Part of a complex with MAP3K3, RAC1 and CCM2. Interacts with
CC ARRB1. Interacts with Yersinia yopJ.
CC -!- INTERACTION:
CC Q9Y463:DYRK1B; NbExp=2; IntAct=EBI-602462, EBI-634187;
CC Q5S007:LRRK2; NbExp=5; IntAct=EBI-602462, EBI-5323863;
CC Q99683:MAP3K5; NbExp=2; IntAct=EBI-602462, EBI-476263;
CC Q16539:MAPK14; NbExp=2; IntAct=EBI-602462, EBI-73946;
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=3; Synonyms=3b;
CC IsoId=P46734-1; Sequence=Displayed;
CC Name=1;
CC IsoId=P46734-2; Sequence=VSP_004878;
CC Name=2; Synonyms=3c;
CC IsoId=P46734-3; Sequence=VSP_004877;
CC -!- TISSUE SPECIFICITY: Abundant expression is seen in the skeletal
CC muscle. It is also widely expressed in other tissues.
CC -!- PTM: Autophosphorylated. Phosphorylation on Ser-218 and Thr-222 by
CC MAP kinase kinase kinases regulates positively the kinase
CC activity. Phosphorylated by TAOK2.
CC -!- PTM: Yersinia yopJ may acetylate Ser/Thr residues, preventing
CC phosphorylation and activation, thus blocking the MAPK signaling
CC pathway.
CC -!- DISEASE: Note=Defects in MAP2K3 may be involved in colon cancer.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. STE Ser/Thr
CC protein kinase family. MAP kinase kinase subfamily.
CC -!- SIMILARITY: Contains 1 protein kinase domain.
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; L36719; AAC41718.1; -; mRNA.
DR EMBL; D87116; BAA13248.1; -; mRNA.
DR EMBL; U66839; AAB40652.1; -; mRNA.
DR EMBL; U66840; AAB40653.1; -; Genomic_DNA.
DR EMBL; AK093838; BAG52769.1; -; mRNA.
DR EMBL; BC032478; AAH32478.1; -; mRNA.
DR RefSeq; NP_002747.2; NM_002756.4.
DR RefSeq; NP_659731.1; NM_145109.2.
DR RefSeq; XP_005256779.1; XM_005256722.1.
DR RefSeq; XP_005256780.1; XM_005256723.1.
DR UniGene; Hs.514012; -.
DR ProteinModelPortal; P46734; -.
DR SMR; P46734; 16-345.
DR DIP; DIP-34242N; -.
DR IntAct; P46734; 8.
DR MINT; MINT-4300215; -.
DR STRING; 9606.ENSP00000345083; -.
DR BindingDB; P46734; -.
DR ChEMBL; CHEMBL2109; -.
DR GuidetoPHARMACOLOGY; 2064; -.
DR PhosphoSite; P46734; -.
DR DMDM; 24638466; -.
DR PaxDb; P46734; -.
DR PRIDE; P46734; -.
DR DNASU; 5606; -.
DR Ensembl; ENST00000316920; ENSP00000319139; ENSG00000034152.
DR Ensembl; ENST00000342679; ENSP00000345083; ENSG00000034152.
DR Ensembl; ENST00000361818; ENSP00000355081; ENSG00000034152.
DR GeneID; 5606; -.
DR KEGG; hsa:5606; -.
DR UCSC; uc002gys.3; human.
DR CTD; 5606; -.
DR GeneCards; GC17P021187; -.
DR HGNC; HGNC:6843; MAP2K3.
DR HPA; CAB018548; -.
DR HPA; HPA044497; -.
DR MIM; 602315; gene.
DR neXtProt; NX_P46734; -.
DR PharmGKB; PA30588; -.
DR eggNOG; COG0515; -.
DR HOGENOM; HOG000234206; -.
DR HOVERGEN; HBG108518; -.
DR KO; K04432; -.
DR OMA; NYLELME; -.
DR BRENDA; 2.7.12.2; 2681.
DR Reactome; REACT_120956; Cellular responses to stress.
DR Reactome; REACT_6782; TRAF6 Mediated Induction of proinflammatory cytokines.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; P46734; -.
DR ChiTaRS; MAP2K3; human.
DR GeneWiki; MAP2K3; -.
DR GenomeRNAi; 5606; -.
DR NextBio; 21784; -.
DR PMAP-CutDB; P46734; -.
DR PRO; PR:P46734; -.
DR ArrayExpress; P46734; -.
DR Bgee; P46734; -.
DR CleanEx; HS_MAP2K3; -.
DR Genevestigator; P46734; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0004708; F:MAP kinase kinase activity; TAS:ProtInc.
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; IEA:Ensembl.
DR GO; GO:0006954; P:inflammatory response; IEA:Ensembl.
DR GO; GO:0045087; P:innate immune response; TAS:Reactome.
DR GO; GO:0002755; P:MyD88-dependent toll-like receptor signaling pathway; TAS:Reactome.
DR GO; GO:0018108; P:peptidyl-tyrosine phosphorylation; IEA:GOC.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-dependent; IDA:UniProtKB.
DR GO; GO:0042035; P:regulation of cytokine biosynthetic process; IEA:Ensembl.
DR GO; GO:0051403; P:stress-activated MAPK cascade; TAS:Reactome.
DR GO; GO:0034166; P:toll-like receptor 10 signaling pathway; TAS:Reactome.
DR GO; GO:0034134; P:toll-like receptor 2 signaling pathway; TAS:Reactome.
DR GO; GO:0034138; P:toll-like receptor 3 signaling pathway; TAS:Reactome.
DR GO; GO:0034142; P:toll-like receptor 4 signaling pathway; TAS:Reactome.
DR GO; GO:0034146; P:toll-like receptor 5 signaling pathway; TAS:Reactome.
DR GO; GO:0034162; P:toll-like receptor 9 signaling pathway; TAS:Reactome.
DR GO; GO:0038123; P:toll-like receptor TLR1:TLR2 signaling pathway; TAS:Reactome.
DR GO; GO:0038124; P:toll-like receptor TLR6:TLR2 signaling pathway; TAS:Reactome.
DR GO; GO:0035666; P:TRIF-dependent toll-like receptor signaling pathway; TAS:Reactome.
DR InterPro; IPR011009; Kinase-like_dom.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR002290; Ser/Thr_dual-sp_kinase_dom.
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 Acetylation; Alternative splicing; ATP-binding; Complete proteome;
KW Disease mutation; Kinase; Nucleotide-binding; Phosphoprotein;
KW Polymorphism; Reference proteome; Serine/threonine-protein kinase;
KW Transferase; Tyrosine-protein kinase.
FT CHAIN 1 347 Dual specificity mitogen-activated
FT protein kinase kinase 3.
FT /FTId=PRO_0000086378.
FT DOMAIN 64 325 Protein kinase.
FT NP_BIND 70 78 ATP (By similarity).
FT ACT_SITE 190 190 Proton acceptor (By similarity).
FT BINDING 93 93 ATP (By similarity).
FT MOD_RES 1 1 N-acetylmethionine.
FT MOD_RES 3 3 Phosphoserine.
FT MOD_RES 15 15 Phosphoserine.
FT MOD_RES 218 218 Phosphoserine.
FT MOD_RES 222 222 Phosphothreonine.
FT VAR_SEQ 1 29 Missing (in isoform 1).
FT /FTId=VSP_004878.
FT VAR_SEQ 1 16 MESPASSQPASMPQSK -> MGVQGTLMSRDSQTPHLLSIL
FT (in isoform 2).
FT /FTId=VSP_004877.
FT VARIANT 26 26 R -> T.
FT /FTId=VAR_040817.
FT VARIANT 40 40 P -> T (in dbSNP:rs33911218).
FT /FTId=VAR_046062.
FT VARIANT 55 55 R -> T (in dbSNP:rs36047035).
FT /FTId=VAR_061742.
FT VARIANT 68 68 S -> P (in dbSNP:rs34105301).
FT /FTId=VAR_046063.
FT VARIANT 84 84 A -> T (in dbSNP:rs2305873).
FT /FTId=VAR_046064.
FT VARIANT 90 90 M -> I (in dbSNP:rs36076766).
FT /FTId=VAR_046065.
FT VARIANT 94 94 R -> L (in dbSNP:rs56067280).
FT /FTId=VAR_046066.
FT VARIANT 96 96 R -> W (in dbSNP:rs56216806).
FT /FTId=VAR_046067.
FT VARIANT 175 175 R -> W (in colon cancer).
FT /FTId=VAR_014208.
FT VARIANT 215 215 L -> V (in colon cancer).
FT /FTId=VAR_014209.
FT VARIANT 293 293 R -> H (in dbSNP:rs35206134).
FT /FTId=VAR_046068.
FT VARIANT 339 339 V -> M (in dbSNP:rs2363198).
FT /FTId=VAR_046069.
FT MUTAGEN 218 218 S->A: Inactivation.
FT MUTAGEN 218 218 S->E: Constitutive activation.
FT MUTAGEN 222 222 T->A: Inactivation.
FT MUTAGEN 222 222 T->E: Constitutive activation.
FT CONFLICT 341 341 E -> K (in Ref. 1 and 3).
SQ SEQUENCE 347 AA; 39318 MW; A80BA4FDFF8F75A2 CRC64;
MESPASSQPA SMPQSKGKSK RKKDLRISCM SKPPAPNPTP PRNLDSRTFI TIGDRNFEVE
ADDLVTISEL GRGAYGVVEK VRHAQSGTIM AVKRIRATVN SQEQKRLLMD LDINMRTVDC
FYTVTFYGAL FREGDVWICM ELMDTSLDKF YRKVLDKNMT IPEDILGEIA VSIVRALEHL
HSKLSVIHRD VKPSNVLINK EGHVKMCDFG ISGYLVDSVA KTMDAGCKPY MAPERINPEL
NQKGYNVKSD VWSLGITMIE MAILRFPYES WGTPFQQLKQ VVEEPSPQLP ADRFSPEFVD
FTAQCLRKNP AERMSYLELM EHPFFTLHKT KKTDIAAFVK EILGEDS
//
ID MP2K3_HUMAN Reviewed; 347 AA.
AC P46734; B3KSK7; Q99441; Q9UE71; Q9UE72;
DT 01-NOV-1995, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-NOV-2002, sequence version 2.
DT 22-JAN-2014, entry version 146.
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;
DE AltName: Full=MAPK/ERK kinase 3;
DE Short=MEK 3;
DE AltName: Full=Stress-activated protein kinase kinase 2;
DE Short=SAPK kinase 2;
DE Short=SAPKK-2;
DE Short=SAPKK2;
GN Name=MAP2K3; Synonyms=MEK3, MKK3, PRKMK3, SKK2;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Brain;
RX PubMed=7839144; DOI=10.1126/science.7839144;
RA Derijard B., Raingeaud J., Barrett T., Wu I.-H., Han J.,
RA Ulevitch R.J., Davis R.J.;
RT "Independent human MAP-kinase signal transduction pathways defined by
RT MEK and MKK isoforms.";
RL Science 267:682-685(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3).
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
RT kinase kinase 6 by osmotic shock, tumor necrosis factor-alpha, and
RT H2O2.";
RL J. Biol. Chem. 271:26981-26988(1996).
RN [3]
RP NUCLEOTIDE SEQUENCE (ISOFORMS 2 AND 3).
RA Han J.;
RL Submitted (AUG-1996) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Trachea;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
RC TISSUE=Leukocyte;
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
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP PHOSPHORYLATION AT SER-218 AND THR-222, AND MUTAGENESIS OF SER-218 AND
RP THR-222.
RX PubMed=8622669;
RA Raingeaud J., Whitmarsh A.J., Barrett T., Derijard B., Davis R.J.;
RT "MKK3- and MKK6-regulated gene expression is mediated by the p38
RT mitogen-activated protein kinase signal transduction pathway.";
RL Mol. Cell. Biol. 16:1247-1255(1996).
RN [7]
RP PHOSPHORYLATION BY TAOK2.
RX PubMed=11279118; DOI=10.1074/jbc.M100681200;
RA Chen Z., Cobb M.H.;
RT "Regulation of stress-responsive mitogen-activated protein (MAP)
RT kinase pathways by TAO2.";
RL J. Biol. Chem. 276:16070-16075(2001).
RN [8]
RP INTERACTION WITH DYRK1B.
RC TISSUE=Muscle;
RX PubMed=11980910; DOI=10.1074/jbc.M203257200;
RA Lim S., Jin K., Friedman E.;
RT "Mirk protein kinase is activated by MKK3 and functions as a
RT transcriptional activator of HNF1alpha.";
RL J. Biol. Chem. 277:25040-25046(2002).
RN [9]
RP INTERACTION WITH ARRB1.
RX PubMed=16709866;
RA McLaughlin N.J., Banerjee A., Kelher M.R., Gamboni-Robertson F.,
RA Hamiel C., Sheppard F.R., Moore E.E., Silliman C.C.;
RT "Platelet-activating factor-induced clathrin-mediated endocytosis
RT requires beta-arrestin-1 recruitment and activation of the p38 MAPK
RT signalosome at the plasma membrane for actin bundle formation.";
RL J. Immunol. 176:7039-7050(2006).
RN [10]
RP INTERACTION WITH YOPJ, AND ACETYLATION.
RX PubMed=16728640; DOI=10.1126/science.1126867;
RA Mukherjee S., Keitany G., Li Y., Wang Y., Ball H.L., Goldsmith E.J.,
RA Orth K.;
RT "Yersinia YopJ acetylates and inhibits kinase activation by blocking
RT phosphorylation.";
RL Science 312:1211-1214(2006).
RN [11]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND MASS SPECTROMETRY.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [12]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, PHOSPHORYLATION [LARGE
RP SCALE ANALYSIS] AT SER-3 AND SER-15, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [13]
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.,
RA Buerckstuemmer T., 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 [14]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND MASS SPECTROMETRY.
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [15]
RP VARIANTS COLON CANCER TRP-175 AND VAL-215.
RX PubMed=11414763; DOI=10.1006/geno.2001.6551;
RA Teng D.-H., Chen Y., Lian L., Ha P.C., Tavtigian S.V., Wong A.K.C.;
RT "Mutation analyses of 268 candidate genes in human tumor cell lines.";
RL Genomics 74:352-364(2001).
RN [16]
RP VARIANTS [LARGE SCALE ANALYSIS] THR-26; PRO-68; THR-84; ILE-90;
RP LEU-94; TRP-96; HIS-293 AND MET-339.
RX PubMed=17344846; DOI=10.1038/nature05610;
RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C.,
RA Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S.,
RA O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S.,
RA Bhamra G., Buck G., Choudhury B., Clements J., Cole J., Dicks E.,
RA Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J.,
RA Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K.,
RA Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T.,
RA West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P.,
RA Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E.,
RA DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E.,
RA Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T.,
RA Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.;
RT "Patterns of somatic mutation in human cancer genomes.";
RL Nature 446:153-158(2007).
CC -!- FUNCTION: Dual specificity kinase. Is activated by cytokines and
CC environmental stress in vivo. Catalyzes the concomitant
CC phosphorylation of a threonine and a tyrosine residue in the MAP
CC kinase p38.
CC -!- CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein.
CC -!- ENZYME REGULATION: Activated by dual phosphorylation on Ser-218
CC and Thr-222.
CC -!- SUBUNIT: Binds to DYRK1B/MIRK and increases its kinase activity.
CC Part of a complex with MAP3K3, RAC1 and CCM2. Interacts with
CC ARRB1. Interacts with Yersinia yopJ.
CC -!- INTERACTION:
CC Q9Y463:DYRK1B; NbExp=2; IntAct=EBI-602462, EBI-634187;
CC Q5S007:LRRK2; NbExp=5; IntAct=EBI-602462, EBI-5323863;
CC Q99683:MAP3K5; NbExp=2; IntAct=EBI-602462, EBI-476263;
CC Q16539:MAPK14; NbExp=2; IntAct=EBI-602462, EBI-73946;
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=3; Synonyms=3b;
CC IsoId=P46734-1; Sequence=Displayed;
CC Name=1;
CC IsoId=P46734-2; Sequence=VSP_004878;
CC Name=2; Synonyms=3c;
CC IsoId=P46734-3; Sequence=VSP_004877;
CC -!- TISSUE SPECIFICITY: Abundant expression is seen in the skeletal
CC muscle. It is also widely expressed in other tissues.
CC -!- PTM: Autophosphorylated. Phosphorylation on Ser-218 and Thr-222 by
CC MAP kinase kinase kinases regulates positively the kinase
CC activity. Phosphorylated by TAOK2.
CC -!- PTM: Yersinia yopJ may acetylate Ser/Thr residues, preventing
CC phosphorylation and activation, thus blocking the MAPK signaling
CC pathway.
CC -!- DISEASE: Note=Defects in MAP2K3 may be involved in colon cancer.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. STE Ser/Thr
CC protein kinase family. MAP kinase kinase subfamily.
CC -!- SIMILARITY: Contains 1 protein kinase domain.
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; L36719; AAC41718.1; -; mRNA.
DR EMBL; D87116; BAA13248.1; -; mRNA.
DR EMBL; U66839; AAB40652.1; -; mRNA.
DR EMBL; U66840; AAB40653.1; -; Genomic_DNA.
DR EMBL; AK093838; BAG52769.1; -; mRNA.
DR EMBL; BC032478; AAH32478.1; -; mRNA.
DR RefSeq; NP_002747.2; NM_002756.4.
DR RefSeq; NP_659731.1; NM_145109.2.
DR RefSeq; XP_005256779.1; XM_005256722.1.
DR RefSeq; XP_005256780.1; XM_005256723.1.
DR UniGene; Hs.514012; -.
DR ProteinModelPortal; P46734; -.
DR SMR; P46734; 16-345.
DR DIP; DIP-34242N; -.
DR IntAct; P46734; 8.
DR MINT; MINT-4300215; -.
DR STRING; 9606.ENSP00000345083; -.
DR BindingDB; P46734; -.
DR ChEMBL; CHEMBL2109; -.
DR GuidetoPHARMACOLOGY; 2064; -.
DR PhosphoSite; P46734; -.
DR DMDM; 24638466; -.
DR PaxDb; P46734; -.
DR PRIDE; P46734; -.
DR DNASU; 5606; -.
DR Ensembl; ENST00000316920; ENSP00000319139; ENSG00000034152.
DR Ensembl; ENST00000342679; ENSP00000345083; ENSG00000034152.
DR Ensembl; ENST00000361818; ENSP00000355081; ENSG00000034152.
DR GeneID; 5606; -.
DR KEGG; hsa:5606; -.
DR UCSC; uc002gys.3; human.
DR CTD; 5606; -.
DR GeneCards; GC17P021187; -.
DR HGNC; HGNC:6843; MAP2K3.
DR HPA; CAB018548; -.
DR HPA; HPA044497; -.
DR MIM; 602315; gene.
DR neXtProt; NX_P46734; -.
DR PharmGKB; PA30588; -.
DR eggNOG; COG0515; -.
DR HOGENOM; HOG000234206; -.
DR HOVERGEN; HBG108518; -.
DR KO; K04432; -.
DR OMA; NYLELME; -.
DR BRENDA; 2.7.12.2; 2681.
DR Reactome; REACT_120956; Cellular responses to stress.
DR Reactome; REACT_6782; TRAF6 Mediated Induction of proinflammatory cytokines.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; P46734; -.
DR ChiTaRS; MAP2K3; human.
DR GeneWiki; MAP2K3; -.
DR GenomeRNAi; 5606; -.
DR NextBio; 21784; -.
DR PMAP-CutDB; P46734; -.
DR PRO; PR:P46734; -.
DR ArrayExpress; P46734; -.
DR Bgee; P46734; -.
DR CleanEx; HS_MAP2K3; -.
DR Genevestigator; P46734; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0004708; F:MAP kinase kinase activity; TAS:ProtInc.
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; IEA:Ensembl.
DR GO; GO:0006954; P:inflammatory response; IEA:Ensembl.
DR GO; GO:0045087; P:innate immune response; TAS:Reactome.
DR GO; GO:0002755; P:MyD88-dependent toll-like receptor signaling pathway; TAS:Reactome.
DR GO; GO:0018108; P:peptidyl-tyrosine phosphorylation; IEA:GOC.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-dependent; IDA:UniProtKB.
DR GO; GO:0042035; P:regulation of cytokine biosynthetic process; IEA:Ensembl.
DR GO; GO:0051403; P:stress-activated MAPK cascade; TAS:Reactome.
DR GO; GO:0034166; P:toll-like receptor 10 signaling pathway; TAS:Reactome.
DR GO; GO:0034134; P:toll-like receptor 2 signaling pathway; TAS:Reactome.
DR GO; GO:0034138; P:toll-like receptor 3 signaling pathway; TAS:Reactome.
DR GO; GO:0034142; P:toll-like receptor 4 signaling pathway; TAS:Reactome.
DR GO; GO:0034146; P:toll-like receptor 5 signaling pathway; TAS:Reactome.
DR GO; GO:0034162; P:toll-like receptor 9 signaling pathway; TAS:Reactome.
DR GO; GO:0038123; P:toll-like receptor TLR1:TLR2 signaling pathway; TAS:Reactome.
DR GO; GO:0038124; P:toll-like receptor TLR6:TLR2 signaling pathway; TAS:Reactome.
DR GO; GO:0035666; P:TRIF-dependent toll-like receptor signaling pathway; TAS:Reactome.
DR InterPro; IPR011009; Kinase-like_dom.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR002290; Ser/Thr_dual-sp_kinase_dom.
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 Acetylation; Alternative splicing; ATP-binding; Complete proteome;
KW Disease mutation; Kinase; Nucleotide-binding; Phosphoprotein;
KW Polymorphism; Reference proteome; Serine/threonine-protein kinase;
KW Transferase; Tyrosine-protein kinase.
FT CHAIN 1 347 Dual specificity mitogen-activated
FT protein kinase kinase 3.
FT /FTId=PRO_0000086378.
FT DOMAIN 64 325 Protein kinase.
FT NP_BIND 70 78 ATP (By similarity).
FT ACT_SITE 190 190 Proton acceptor (By similarity).
FT BINDING 93 93 ATP (By similarity).
FT MOD_RES 1 1 N-acetylmethionine.
FT MOD_RES 3 3 Phosphoserine.
FT MOD_RES 15 15 Phosphoserine.
FT MOD_RES 218 218 Phosphoserine.
FT MOD_RES 222 222 Phosphothreonine.
FT VAR_SEQ 1 29 Missing (in isoform 1).
FT /FTId=VSP_004878.
FT VAR_SEQ 1 16 MESPASSQPASMPQSK -> MGVQGTLMSRDSQTPHLLSIL
FT (in isoform 2).
FT /FTId=VSP_004877.
FT VARIANT 26 26 R -> T.
FT /FTId=VAR_040817.
FT VARIANT 40 40 P -> T (in dbSNP:rs33911218).
FT /FTId=VAR_046062.
FT VARIANT 55 55 R -> T (in dbSNP:rs36047035).
FT /FTId=VAR_061742.
FT VARIANT 68 68 S -> P (in dbSNP:rs34105301).
FT /FTId=VAR_046063.
FT VARIANT 84 84 A -> T (in dbSNP:rs2305873).
FT /FTId=VAR_046064.
FT VARIANT 90 90 M -> I (in dbSNP:rs36076766).
FT /FTId=VAR_046065.
FT VARIANT 94 94 R -> L (in dbSNP:rs56067280).
FT /FTId=VAR_046066.
FT VARIANT 96 96 R -> W (in dbSNP:rs56216806).
FT /FTId=VAR_046067.
FT VARIANT 175 175 R -> W (in colon cancer).
FT /FTId=VAR_014208.
FT VARIANT 215 215 L -> V (in colon cancer).
FT /FTId=VAR_014209.
FT VARIANT 293 293 R -> H (in dbSNP:rs35206134).
FT /FTId=VAR_046068.
FT VARIANT 339 339 V -> M (in dbSNP:rs2363198).
FT /FTId=VAR_046069.
FT MUTAGEN 218 218 S->A: Inactivation.
FT MUTAGEN 218 218 S->E: Constitutive activation.
FT MUTAGEN 222 222 T->A: Inactivation.
FT MUTAGEN 222 222 T->E: Constitutive activation.
FT CONFLICT 341 341 E -> K (in Ref. 1 and 3).
SQ SEQUENCE 347 AA; 39318 MW; A80BA4FDFF8F75A2 CRC64;
MESPASSQPA SMPQSKGKSK RKKDLRISCM SKPPAPNPTP PRNLDSRTFI TIGDRNFEVE
ADDLVTISEL GRGAYGVVEK VRHAQSGTIM AVKRIRATVN SQEQKRLLMD LDINMRTVDC
FYTVTFYGAL FREGDVWICM ELMDTSLDKF YRKVLDKNMT IPEDILGEIA VSIVRALEHL
HSKLSVIHRD VKPSNVLINK EGHVKMCDFG ISGYLVDSVA KTMDAGCKPY MAPERINPEL
NQKGYNVKSD VWSLGITMIE MAILRFPYES WGTPFQQLKQ VVEEPSPQLP ADRFSPEFVD
FTAQCLRKNP AERMSYLELM EHPFFTLHKT KKTDIAAFVK EILGEDS
//
MIM
602315
*RECORD*
*FIELD* NO
602315
*FIELD* TI
*602315 MITOGEN-ACTIVATED PROTEIN KINASE KINASE 3; MAP2K3
;;PROTEIN KINASE, MITOGEN-ACTIVATED, KINASE 3; PRKMK3;;
read moreMKK3; MAPKK3;;
MAPK/ERK KINASE 3; MEK3
*FIELD* TX
DESCRIPTION
Mitogen-activated protein kinases (MAPKs) act in cellular signal
transduction pathways in response to many extracellular signals.
Activation of specific classes of MAPKs requires phosphorylation by
specific MAPK kinases (MAP2Ks), also called MKKs or MEKs (see 601254),
such as MAP2K3.
CLONING
PBS2, a yeast MKK, activates stress-activated protein kinases (SAPKs).
Derijard et al. (1995) cloned 2 human homologs of PBS2 (MKK3 and MKK4),
using primers based on distinct regions of the yeast gene to amplify
cDNA clones from brain by PCR. The predicted 322-amino acid MKK3 protein
is 40 to 42% identical to PBS2 and human MEK1 (176872) and MEK2
(601263), and 52% identical to MKK4 within the conserved region.
Northern blot analysis showed that MKK3 is widely expressed, with
highest expression in skeletal muscle.
Han et al. (1997) cloned another form of MKK3, termed MKK3b, which has
an additional 29 N-terminal amino acids. Northern blot analysis showed
that MKK3b mRNA is much more abundant than MKK3, but has a similar
expression pattern.
GENE FUNCTION
In vitro kinase assays and in vivo overexpression studies by Derijard et
al. (1995) suggested that the SAPK p38 (MAPK14; 600289) is the substrate
for MKK3.
A virulence factor from Yersinia pseudotuberculosis, YopJ, is a 33-kD
protein that perturbs a multiplicity of signaling pathways. These
include inhibition of the extracellular signal-regulated kinase ERK,
c-jun NH2-terminal kinase (JNK), and p38 mitogen-activated protein
kinase pathways and inhibition of the nuclear factor kappa B
(NF-kappa-B) pathway. The expression of YopJ has been correlated with
the induction of apoptosis by Yersinia. Using a yeast 2-hybrid screen
based on a LexA-YopJ fusion protein and a HeLa cDNA library, Orth et al.
(1999) identified mammalian binding partners of YopJ. These included the
fusion proteins of the GAL4 activation domain with MAPK kinases MKK1
(176872), MKK2 (601263), and MKK4/SEK1 (601335). YopJ was found to bind
directly to MKKs in vitro, including MKK1, MKK3, MKK4, and MKK5
(602448). Binding of YopJ to the MKK blocked both phosphorylation and
subsequent activation of the MKKs. These results explain the diverse
activities of YopJ in inhibiting the ERK, JNK, p38, and NF-kappa-B
signaling pathways, preventing cytokine synthesis and promoting
apoptosis. YopJ-related proteins that are found in a number of bacterial
pathogens of animals and plants may function to block MKKs so that host
signaling responses can be modulated upon infection.
By yeast 2-hybrid analysis of a mouse T-cell cDNA library, Uhlik et al.
(2003) showed that a C-terminal fragment of mouse Osm (CCM2; 607929)
interacted with Mekk3 (MAP3K3; 602539), a p38 activator that responds to
sorbitol-induced hyperosmotic conditions. Mekk3 and Osm colocalized in
the cytoplasmic compartment of cotransfected cells, and the Mekk3-Osm
complex was recruited to Rac1 (602048)- and cytoskeletal actin (see
102560)-containing membrane ruffles in response to sorbitol treatment.
Protein interaction assays showed that Osm interacted directly with the
Mekk3 substrate Mkk3, with actin, and with both GDP- and GTP-loaded
Rac1. Uhlik et al. (2003) concluded that the RAC1-OSM-MEKK3-MKK3 complex
is required for regulation of p38 activity in response to osmotic shock.
MAPPING
Using radiation hybrid mapping, Rampoldi et al. (1997) localized the
MAP2K3 gene to 17q11.2.
ANIMAL MODEL
Lu et al. (1999) used homologous recombination in mice to inactivate the
Mkk3 gene, 1 of 2 specific MAPK kinases that activate p38 MAPK.
Mkk3-null mice were viable and fertile, but their macrophages and
dendritic cells were defective in IL12 (see 161560) production.
Interferon-gamma (147570) production following immunization with protein
antigens and in vitro differentiation of naive T cells were also greatly
reduced, suggesting an impaired type I cytokine immune response. Lu et
al. (1999) concluded that p38 MAP kinase, activated through MKK3, was
required to produce inflammatory cytokines by both antigen presenting
cells and CD4 (186940)-positive T cells.
*FIELD* RF
1. Derijard, B.; Raingeaud, J.; Barrett, T.; Wu, I.-H.; Han, J.; Ulevitch,
R. J.; Davis, R. J.: Independent human MAP kinase signal transduction
pathways defined by MEK AND MKK isoforms. Science 267: 682-685,
1995. Note: Erratum: Science 269: 17 only, 1995.
2. Han, J.; Wang, X.; Jiang, Y.; Ulevitch, R. J.; Lin, S.: Identification
and characterization of a predominant isoform of human MKK3. FEBS
Lett. 403: 19-22, 1997.
3. Lu, H.-T.; Yang, D. D.; Wysk, M.; Gatti, E.; Mellman, I.; Davis,
R. J.; Flavell, R. A.: Defective IL-12 production in mitogen-activated
protein (MAP) kinase kinase 3 (Mkk3)-deficient mice. EMBO J. 18:
1845-1857, 1999.
4. Orth, K.; Palmer, L. E.; Bao, Z. Q.; Stewart, S.; Rudolph, A. E.;
Bliska, J. B.; Dixon, J. E.: Inhibition of the mitogen-activated
protein kinase kinase superfamily by a Yersinia effector. Science 285:
1920-1923, 1999.
5. Rampoldi, L.; Zimbello, R.; Bortoluzzi, S.; Tiso, N.; Valle, G.;
Lanfranchi, G.; Danieli, G. A.: Chromosomal localization of four
MAPK signaling cascade genes: MEK1, MEK3, MEK4 and MEKK5. Cytogenet.
Cell Genet. 78: 301-303, 1997.
6. Uhlik, M. T.; Abell, A. N.; Johnson, N. L.; Sun, W.; Cuevas, B.
D.; Lobel-Rice, K. E.; Horne, E. A.; Dell'Acqua, M. L.; Johnson, G.
L.: Rac-MEKK3-MKK3 scaffolding for p38 MAPK activation during hyperosmotic
shock. Nature Cell Biol. 5: 1104-1110, 2003.
*FIELD* CN
Patricia A. Hartz - updated: 2/24/2009
Patricia A. Hartz - updated: 3/25/2003
Ada Hamosh - updated: 9/15/1999
Victor A. McKusick - updated: 3/16/1998
*FIELD* CD
Rebekah S. Rasooly: 2/3/1998
*FIELD* ED
terry: 09/14/2012
mgross: 2/24/2009
terry: 4/5/2005
mgross: 3/25/2003
alopez: 2/28/2000
carol: 9/17/1999
terry: 9/15/1999
mgross: 9/14/1999
psherman: 3/17/1998
psherman: 3/16/1998
terry: 3/4/1998
mark: 2/12/1998
carol: 2/10/1998
*RECORD*
*FIELD* NO
602315
*FIELD* TI
*602315 MITOGEN-ACTIVATED PROTEIN KINASE KINASE 3; MAP2K3
;;PROTEIN KINASE, MITOGEN-ACTIVATED, KINASE 3; PRKMK3;;
read moreMKK3; MAPKK3;;
MAPK/ERK KINASE 3; MEK3
*FIELD* TX
DESCRIPTION
Mitogen-activated protein kinases (MAPKs) act in cellular signal
transduction pathways in response to many extracellular signals.
Activation of specific classes of MAPKs requires phosphorylation by
specific MAPK kinases (MAP2Ks), also called MKKs or MEKs (see 601254),
such as MAP2K3.
CLONING
PBS2, a yeast MKK, activates stress-activated protein kinases (SAPKs).
Derijard et al. (1995) cloned 2 human homologs of PBS2 (MKK3 and MKK4),
using primers based on distinct regions of the yeast gene to amplify
cDNA clones from brain by PCR. The predicted 322-amino acid MKK3 protein
is 40 to 42% identical to PBS2 and human MEK1 (176872) and MEK2
(601263), and 52% identical to MKK4 within the conserved region.
Northern blot analysis showed that MKK3 is widely expressed, with
highest expression in skeletal muscle.
Han et al. (1997) cloned another form of MKK3, termed MKK3b, which has
an additional 29 N-terminal amino acids. Northern blot analysis showed
that MKK3b mRNA is much more abundant than MKK3, but has a similar
expression pattern.
GENE FUNCTION
In vitro kinase assays and in vivo overexpression studies by Derijard et
al. (1995) suggested that the SAPK p38 (MAPK14; 600289) is the substrate
for MKK3.
A virulence factor from Yersinia pseudotuberculosis, YopJ, is a 33-kD
protein that perturbs a multiplicity of signaling pathways. These
include inhibition of the extracellular signal-regulated kinase ERK,
c-jun NH2-terminal kinase (JNK), and p38 mitogen-activated protein
kinase pathways and inhibition of the nuclear factor kappa B
(NF-kappa-B) pathway. The expression of YopJ has been correlated with
the induction of apoptosis by Yersinia. Using a yeast 2-hybrid screen
based on a LexA-YopJ fusion protein and a HeLa cDNA library, Orth et al.
(1999) identified mammalian binding partners of YopJ. These included the
fusion proteins of the GAL4 activation domain with MAPK kinases MKK1
(176872), MKK2 (601263), and MKK4/SEK1 (601335). YopJ was found to bind
directly to MKKs in vitro, including MKK1, MKK3, MKK4, and MKK5
(602448). Binding of YopJ to the MKK blocked both phosphorylation and
subsequent activation of the MKKs. These results explain the diverse
activities of YopJ in inhibiting the ERK, JNK, p38, and NF-kappa-B
signaling pathways, preventing cytokine synthesis and promoting
apoptosis. YopJ-related proteins that are found in a number of bacterial
pathogens of animals and plants may function to block MKKs so that host
signaling responses can be modulated upon infection.
By yeast 2-hybrid analysis of a mouse T-cell cDNA library, Uhlik et al.
(2003) showed that a C-terminal fragment of mouse Osm (CCM2; 607929)
interacted with Mekk3 (MAP3K3; 602539), a p38 activator that responds to
sorbitol-induced hyperosmotic conditions. Mekk3 and Osm colocalized in
the cytoplasmic compartment of cotransfected cells, and the Mekk3-Osm
complex was recruited to Rac1 (602048)- and cytoskeletal actin (see
102560)-containing membrane ruffles in response to sorbitol treatment.
Protein interaction assays showed that Osm interacted directly with the
Mekk3 substrate Mkk3, with actin, and with both GDP- and GTP-loaded
Rac1. Uhlik et al. (2003) concluded that the RAC1-OSM-MEKK3-MKK3 complex
is required for regulation of p38 activity in response to osmotic shock.
MAPPING
Using radiation hybrid mapping, Rampoldi et al. (1997) localized the
MAP2K3 gene to 17q11.2.
ANIMAL MODEL
Lu et al. (1999) used homologous recombination in mice to inactivate the
Mkk3 gene, 1 of 2 specific MAPK kinases that activate p38 MAPK.
Mkk3-null mice were viable and fertile, but their macrophages and
dendritic cells were defective in IL12 (see 161560) production.
Interferon-gamma (147570) production following immunization with protein
antigens and in vitro differentiation of naive T cells were also greatly
reduced, suggesting an impaired type I cytokine immune response. Lu et
al. (1999) concluded that p38 MAP kinase, activated through MKK3, was
required to produce inflammatory cytokines by both antigen presenting
cells and CD4 (186940)-positive T cells.
*FIELD* RF
1. Derijard, B.; Raingeaud, J.; Barrett, T.; Wu, I.-H.; Han, J.; Ulevitch,
R. J.; Davis, R. J.: Independent human MAP kinase signal transduction
pathways defined by MEK AND MKK isoforms. Science 267: 682-685,
1995. Note: Erratum: Science 269: 17 only, 1995.
2. Han, J.; Wang, X.; Jiang, Y.; Ulevitch, R. J.; Lin, S.: Identification
and characterization of a predominant isoform of human MKK3. FEBS
Lett. 403: 19-22, 1997.
3. Lu, H.-T.; Yang, D. D.; Wysk, M.; Gatti, E.; Mellman, I.; Davis,
R. J.; Flavell, R. A.: Defective IL-12 production in mitogen-activated
protein (MAP) kinase kinase 3 (Mkk3)-deficient mice. EMBO J. 18:
1845-1857, 1999.
4. Orth, K.; Palmer, L. E.; Bao, Z. Q.; Stewart, S.; Rudolph, A. E.;
Bliska, J. B.; Dixon, J. E.: Inhibition of the mitogen-activated
protein kinase kinase superfamily by a Yersinia effector. Science 285:
1920-1923, 1999.
5. Rampoldi, L.; Zimbello, R.; Bortoluzzi, S.; Tiso, N.; Valle, G.;
Lanfranchi, G.; Danieli, G. A.: Chromosomal localization of four
MAPK signaling cascade genes: MEK1, MEK3, MEK4 and MEKK5. Cytogenet.
Cell Genet. 78: 301-303, 1997.
6. Uhlik, M. T.; Abell, A. N.; Johnson, N. L.; Sun, W.; Cuevas, B.
D.; Lobel-Rice, K. E.; Horne, E. A.; Dell'Acqua, M. L.; Johnson, G.
L.: Rac-MEKK3-MKK3 scaffolding for p38 MAPK activation during hyperosmotic
shock. Nature Cell Biol. 5: 1104-1110, 2003.
*FIELD* CN
Patricia A. Hartz - updated: 2/24/2009
Patricia A. Hartz - updated: 3/25/2003
Ada Hamosh - updated: 9/15/1999
Victor A. McKusick - updated: 3/16/1998
*FIELD* CD
Rebekah S. Rasooly: 2/3/1998
*FIELD* ED
terry: 09/14/2012
mgross: 2/24/2009
terry: 4/5/2005
mgross: 3/25/2003
alopez: 2/28/2000
carol: 9/17/1999
terry: 9/15/1999
mgross: 9/14/1999
psherman: 3/17/1998
psherman: 3/16/1998
terry: 3/4/1998
mark: 2/12/1998
carol: 2/10/1998