Full text data of MAP3K3
MAP3K3
(MAPKKK3, MEKK3)
[Confidence: low (only semi-automatic identification from reviews)]
Mitogen-activated protein kinase kinase kinase 3; 2.7.11.25 (MAPK/ERK kinase kinase 3; MEK kinase 3; MEKK 3)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Mitogen-activated protein kinase kinase kinase 3; 2.7.11.25 (MAPK/ERK kinase kinase 3; MEK kinase 3; MEKK 3)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
Q99759
ID M3K3_HUMAN Reviewed; 626 AA.
AC Q99759; B2RCW2; D3DU15; Q5BKZ6; Q8N3I9;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
read moreDT 13-NOV-2007, sequence version 2.
DT 22-JAN-2014, entry version 148.
DE RecName: Full=Mitogen-activated protein kinase kinase kinase 3;
DE EC=2.7.11.25;
DE AltName: Full=MAPK/ERK kinase kinase 3;
DE Short=MEK kinase 3;
DE Short=MEKK 3;
GN Name=MAP3K3; Synonyms=MAPKKK3, MEKK3;
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), AND FUNCTION.
RX PubMed=9006902; DOI=10.1074/jbc.272.5.2668;
RA Ellinger-Ziegelbauer H.C., Brown K., Kelly K., Siebenlist U.;
RT "Direct activation of the stress-activated protein kinase (SAPK) and
RT extracellular signal-regulated protein kinase (ERK) pathways by an
RT inducible mitogen-activated protein kinase/ERK kinase kinase 3 (MEKK)
RT derivative.";
RL J. Biol. Chem. 272:2668-2674(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Placenta;
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 [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Melanoma;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H.,
RA Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K.,
RA Ottenwaelder B., Poustka A., Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16625196; DOI=10.1038/nature04689;
RA Zody M.C., Garber M., Adams D.J., Sharpe T., Harrow J., Lupski J.R.,
RA Nicholson C., Searle S.M., Wilming L., Young S.K., Abouelleil A.,
RA Allen N.R., Bi W., Bloom T., Borowsky M.L., Bugalter B.E., Butler J.,
RA Chang J.L., Chen C.-K., Cook A., Corum B., Cuomo C.A., de Jong P.J.,
RA DeCaprio D., Dewar K., FitzGerald M., Gilbert J., Gibson R.,
RA Gnerre S., Goldstein S., Grafham D.V., Grocock R., Hafez N.,
RA Hagopian D.S., Hart E., Norman C.H., Humphray S., Jaffe D.B.,
RA Jones M., Kamal M., Khodiyar V.K., LaButti K., Laird G., Lehoczky J.,
RA Liu X., Lokyitsang T., Loveland J., Lui A., Macdonald P., Major J.E.,
RA Matthews L., Mauceli E., McCarroll S.A., Mihalev A.H., Mudge J.,
RA Nguyen C., Nicol R., O'Leary S.B., Osoegawa K., Schwartz D.C.,
RA Shaw-Smith C., Stankiewicz P., Steward C., Swarbreck D.,
RA Venkataraman V., Whittaker C.A., Yang X., Zimmer A.R., Bradley A.,
RA Hubbard T., Birren B.W., Rogers J., Lander E.S., Nusbaum C.;
RT "DNA sequence of human chromosome 17 and analysis of rearrangement in
RT the human lineage.";
RL Nature 440:1045-1049(2006).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Brain, and PNS;
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 [7]
RP PHOSPHORYLATION AT SER-166 AND SER-337 BY SGK1.
RX PubMed=12761204; DOI=10.1093/jb/mvg010;
RA Chun J., Kwon T., Kim D.J., Park I., Chung G., Lee E.J., Hong S.K.,
RA Chang S.I., Kim H.Y., Kang S.S.;
RT "Inhibition of mitogen-activated kinase kinase kinase 3 activity
RT through phosphorylation by the serum- and glucocorticoid-induced
RT kinase 1.";
RL J. Biochem. 133:103-108(2003).
RN [8]
RP FUNCTION, AND INTERACTION WITH MAP2K5.
RX PubMed=12912994; DOI=10.1074/jbc.C300313200;
RA Nakamura K., Johnson G.L.;
RT "PB1 domains of MEKK2 and MEKK3 interact with the MEK5 PB1 domain for
RT activation of the ERK5 pathway.";
RL J. Biol. Chem. 278:36989-36992(2003).
RN [9]
RP FUNCTION, AND INTERACTION WITH TRAF6.
RX PubMed=14661019; DOI=10.1038/ni1014;
RA Huang Q., Yang J., Lin Y., Walker C., Cheng J., Liu Z.G., Su B.;
RT "Differential regulation of interleukin 1 receptor and Toll-like
RT receptor signaling by MEKK3.";
RL Nat. Immunol. 5:98-103(2004).
RN [10]
RP FUNCTION, AND INTERACTION WITH TRAF7.
RX PubMed=14743216; DOI=10.1038/ncb1086;
RA Bouwmeester T., Bauch A., Ruffner H., Angrand P.-O., Bergamini G.,
RA Croughton K., Cruciat C., Eberhard D., Gagneur J., Ghidelli S.,
RA Hopf C., Huhse B., Mangano R., Michon A.-M., Schirle M., Schlegl J.,
RA Schwab M., Stein M.A., Bauer A., Casari G., Drewes G., Gavin A.-C.,
RA Jackson D.B., Joberty G., Neubauer G., Rick J., Kuster B.,
RA Superti-Furga G.;
RT "A physical and functional map of the human TNF-alpha/NF-kappa B
RT signal transduction pathway.";
RL Nat. Cell Biol. 6:97-105(2004).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-250; SER-337 AND
RP SER-340, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of
RT the kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-250; SER-337 AND
RP SER-340, AND MASS SPECTROMETRY.
RX PubMed=19369195; DOI=10.1074/mcp.M800588-MCP200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [13]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-337 AND SER-340, AND
RP MASS SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [14]
RP VARIANT [LARGE SCALE ANALYSIS] MET-281.
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: Component of a protein kinase signal transduction
CC cascade. Mediates activation of the NF-kappa-B, AP1 and DDIT3
CC transcriptional regulators.
CC -!- CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein.
CC -!- COFACTOR: Magnesium.
CC -!- ENZYME REGULATION: Activated by phosphorylation on Thr-530 (By
CC similarity).
CC -!- SUBUNIT: Binds both upstream activators and downstream substrates
CC in multimolecular complexes. Part of a complex with MAP2K3, RAC1
CC and CCM2. Interacts with MAP2K5 and SPAG9.
CC -!- INTERACTION:
CC Q6Q0C0:TRAF7; NbExp=3; IntAct=EBI-307281, EBI-307556;
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q99759-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q99759-2; Sequence=VSP_035967;
CC -!- PTM: Phosphorylation at Ser-166 and Ser-337 by SGK1 inhibits its
CC activity.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. STE Ser/Thr
CC protein kinase family. MAP kinase kinase kinase subfamily.
CC -!- SIMILARITY: Contains 1 OPR domain.
CC -!- SIMILARITY: Contains 1 protein kinase domain.
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DR EMBL; U78876; AAB41729.1; -; mRNA.
DR EMBL; AK315305; BAG37709.1; -; mRNA.
DR EMBL; AL834303; CAD38973.1; -; mRNA.
DR EMBL; AC046185; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471109; EAW94297.1; -; Genomic_DNA.
DR EMBL; CH471109; EAW94298.1; -; Genomic_DNA.
DR EMBL; CH471109; EAW94299.1; -; Genomic_DNA.
DR EMBL; BC090859; AAH90859.1; -; mRNA.
DR EMBL; BC093672; AAH93672.1; -; mRNA.
DR EMBL; BC093674; AAH93674.1; -; mRNA.
DR RefSeq; NP_002392.2; NM_002401.3.
DR RefSeq; NP_976226.1; NM_203351.1.
DR UniGene; Hs.29282; -.
DR PDB; 2C60; X-ray; 1.25 A; A=37-124.
DR PDB; 2JRH; NMR; -; A=42-126.
DR PDB; 2O2V; X-ray; 1.83 A; B=37-124.
DR PDB; 2PPH; NMR; -; A=42-126.
DR PDBsum; 2C60; -.
DR PDBsum; 2JRH; -.
DR PDBsum; 2O2V; -.
DR PDBsum; 2PPH; -.
DR ProteinModelPortal; Q99759; -.
DR SMR; Q99759; 43-122, 336-624.
DR DIP; DIP-27521N; -.
DR IntAct; Q99759; 13.
DR MINT; MINT-272157; -.
DR STRING; 9606.ENSP00000354927; -.
DR BindingDB; Q99759; -.
DR ChEMBL; CHEMBL5970; -.
DR GuidetoPHARMACOLOGY; 2078; -.
DR PhosphoSite; Q99759; -.
DR DMDM; 160332306; -.
DR PaxDb; Q99759; -.
DR PRIDE; Q99759; -.
DR DNASU; 4215; -.
DR Ensembl; ENST00000361357; ENSP00000354927; ENSG00000198909.
DR Ensembl; ENST00000361733; ENSP00000354485; ENSG00000198909.
DR Ensembl; ENST00000579585; ENSP00000461988; ENSG00000198909.
DR GeneID; 4215; -.
DR KEGG; hsa:4215; -.
DR UCSC; uc002jbg.3; human.
DR CTD; 4215; -.
DR GeneCards; GC17P061699; -.
DR HGNC; HGNC:6855; MAP3K3.
DR HPA; CAB007764; -.
DR MIM; 602539; gene.
DR neXtProt; NX_Q99759; -.
DR PharmGKB; PA30599; -.
DR eggNOG; COG0515; -.
DR HOGENOM; HOG000049130; -.
DR HOVERGEN; HBG006303; -.
DR KO; K04421; -.
DR OMA; QALHSIM; -.
DR OrthoDB; EOG747PHJ; -.
DR BRENDA; 2.7.12.2; 2681.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; Q99759; -.
DR ChiTaRS; MAP3K3; human.
DR EvolutionaryTrace; Q99759; -.
DR GeneWiki; MAP3K3; -.
DR GenomeRNAi; 4215; -.
DR NextBio; 16621; -.
DR PRO; PR:Q99759; -.
DR ArrayExpress; Q99759; -.
DR Bgee; Q99759; -.
DR CleanEx; HS_MAP3K3; -.
DR Genevestigator; Q99759; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0004709; F:MAP kinase kinase kinase activity; TAS:ProtInc.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0043123; P:positive regulation of I-kappaB kinase/NF-kappaB cascade; IEP:UniProtKB.
DR GO; GO:0046777; P:protein autophosphorylation; IDA:MGI.
DR InterPro; IPR011009; Kinase-like_dom.
DR InterPro; IPR000270; OPR_PB1.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR002290; Ser/Thr_dual-sp_kinase_dom.
DR Pfam; PF00564; PB1; 1.
DR Pfam; PF00069; Pkinase; 1.
DR SMART; SM00666; PB1; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; FALSE_NEG.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; FALSE_NEG.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; ATP-binding; Complete proteome;
KW Kinase; Magnesium; Metal-binding; Nucleotide-binding; Phosphoprotein;
KW Polymorphism; Reference proteome; Serine/threonine-protein kinase;
KW Transferase.
FT CHAIN 1 626 Mitogen-activated protein kinase kinase
FT kinase 3.
FT /FTId=PRO_0000086245.
FT DOMAIN 44 123 OPR.
FT DOMAIN 362 622 Protein kinase.
FT NP_BIND 368 376 ATP (By similarity).
FT ACT_SITE 489 489 Proton acceptor (By similarity).
FT BINDING 391 391 ATP (By similarity).
FT MOD_RES 166 166 Phosphoserine; by SGK1.
FT MOD_RES 250 250 Phosphoserine.
FT MOD_RES 337 337 Phosphoserine; by SGK1.
FT MOD_RES 340 340 Phosphoserine.
FT VAR_SEQ 42 42 Q -> QKKHNSSSSALLNSPTVTTSSCAGASEKKKFL (in
FT isoform 2).
FT /FTId=VSP_035967.
FT VARIANT 281 281 V -> M (in dbSNP:rs36109904).
FT /FTId=VAR_040685.
FT VARIANT 325 325 A -> G (in dbSNP:rs34042309).
FT /FTId=VAR_037275.
FT VARIANT 435 435 A -> G (in dbSNP:rs9910858).
FT /FTId=VAR_037276.
FT CONFLICT 135 135 G -> E (in Ref. 1; AAB41729).
FT STRAND 45 51
FT STRAND 54 60
FT HELIX 66 77
FT STRAND 82 86
FT STRAND 91 93
FT HELIX 97 109
FT TURN 111 114
FT STRAND 115 121
SQ SEQUENCE 626 AA; 70898 MW; 28129168A57571DD CRC64;
MDEQEALNSI MNDLVALQMN RRHRMPGYET MKNKDTGHSN RQSDVRIKFE HNGERRIIAF
SRPVKYEDVE HKVTTVFGQP LDLHYMNNEL SILLKNQDDL DKAIDILDRS SSMKSLRILL
LSQDRNHNSS SPHSGVSRQV RIKASQSAGD INTIYQPPEP RSRHLSVSSQ NPGRSSPPPG
YVPERQQHIA RQGSYTSINS EGEFIPETSE QCMLDPLSSA ENSLSGSCQS LDRSADSPSF
RKSRMSRAQS FPDNRQEYSD RETQLYDKGV KGGTYPRRYH VSVHHKDYSD GRRTFPRIRR
HQGNLFTLVP SSRSLSTNGE NMGLAVQYLD PRGRLRSADS ENALSVQERN VPTKSPSAPI
NWRRGKLLGQ GAFGRVYLCY DVDTGRELAS KQVQFDPDSP ETSKEVSALE CEIQLLKNLQ
HERIVQYYGC LRDRAEKTLT IFMEYMPGGS VKDQLKAYGA LTESVTRKYT RQILEGMSYL
HSNMIVHRDI KGANILRDSA GNVKLGDFGA SKRLQTICMS GTGMRSVTGT PYWMSPEVIS
GEGYGRKADV WSLGCTVVEM LTEKPPWAEY EAMAAIFKIA TQPTNPQLPS HISEHGRDFL
RRIFVEARQR PSAEELLTHH FAQLMY
//
ID M3K3_HUMAN Reviewed; 626 AA.
AC Q99759; B2RCW2; D3DU15; Q5BKZ6; Q8N3I9;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
read moreDT 13-NOV-2007, sequence version 2.
DT 22-JAN-2014, entry version 148.
DE RecName: Full=Mitogen-activated protein kinase kinase kinase 3;
DE EC=2.7.11.25;
DE AltName: Full=MAPK/ERK kinase kinase 3;
DE Short=MEK kinase 3;
DE Short=MEKK 3;
GN Name=MAP3K3; Synonyms=MAPKKK3, MEKK3;
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), AND FUNCTION.
RX PubMed=9006902; DOI=10.1074/jbc.272.5.2668;
RA Ellinger-Ziegelbauer H.C., Brown K., Kelly K., Siebenlist U.;
RT "Direct activation of the stress-activated protein kinase (SAPK) and
RT extracellular signal-regulated protein kinase (ERK) pathways by an
RT inducible mitogen-activated protein kinase/ERK kinase kinase 3 (MEKK)
RT derivative.";
RL J. Biol. Chem. 272:2668-2674(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Placenta;
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 [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Melanoma;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H.,
RA Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K.,
RA Ottenwaelder B., Poustka A., Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16625196; DOI=10.1038/nature04689;
RA Zody M.C., Garber M., Adams D.J., Sharpe T., Harrow J., Lupski J.R.,
RA Nicholson C., Searle S.M., Wilming L., Young S.K., Abouelleil A.,
RA Allen N.R., Bi W., Bloom T., Borowsky M.L., Bugalter B.E., Butler J.,
RA Chang J.L., Chen C.-K., Cook A., Corum B., Cuomo C.A., de Jong P.J.,
RA DeCaprio D., Dewar K., FitzGerald M., Gilbert J., Gibson R.,
RA Gnerre S., Goldstein S., Grafham D.V., Grocock R., Hafez N.,
RA Hagopian D.S., Hart E., Norman C.H., Humphray S., Jaffe D.B.,
RA Jones M., Kamal M., Khodiyar V.K., LaButti K., Laird G., Lehoczky J.,
RA Liu X., Lokyitsang T., Loveland J., Lui A., Macdonald P., Major J.E.,
RA Matthews L., Mauceli E., McCarroll S.A., Mihalev A.H., Mudge J.,
RA Nguyen C., Nicol R., O'Leary S.B., Osoegawa K., Schwartz D.C.,
RA Shaw-Smith C., Stankiewicz P., Steward C., Swarbreck D.,
RA Venkataraman V., Whittaker C.A., Yang X., Zimmer A.R., Bradley A.,
RA Hubbard T., Birren B.W., Rogers J., Lander E.S., Nusbaum C.;
RT "DNA sequence of human chromosome 17 and analysis of rearrangement in
RT the human lineage.";
RL Nature 440:1045-1049(2006).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Brain, and PNS;
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 [7]
RP PHOSPHORYLATION AT SER-166 AND SER-337 BY SGK1.
RX PubMed=12761204; DOI=10.1093/jb/mvg010;
RA Chun J., Kwon T., Kim D.J., Park I., Chung G., Lee E.J., Hong S.K.,
RA Chang S.I., Kim H.Y., Kang S.S.;
RT "Inhibition of mitogen-activated kinase kinase kinase 3 activity
RT through phosphorylation by the serum- and glucocorticoid-induced
RT kinase 1.";
RL J. Biochem. 133:103-108(2003).
RN [8]
RP FUNCTION, AND INTERACTION WITH MAP2K5.
RX PubMed=12912994; DOI=10.1074/jbc.C300313200;
RA Nakamura K., Johnson G.L.;
RT "PB1 domains of MEKK2 and MEKK3 interact with the MEK5 PB1 domain for
RT activation of the ERK5 pathway.";
RL J. Biol. Chem. 278:36989-36992(2003).
RN [9]
RP FUNCTION, AND INTERACTION WITH TRAF6.
RX PubMed=14661019; DOI=10.1038/ni1014;
RA Huang Q., Yang J., Lin Y., Walker C., Cheng J., Liu Z.G., Su B.;
RT "Differential regulation of interleukin 1 receptor and Toll-like
RT receptor signaling by MEKK3.";
RL Nat. Immunol. 5:98-103(2004).
RN [10]
RP FUNCTION, AND INTERACTION WITH TRAF7.
RX PubMed=14743216; DOI=10.1038/ncb1086;
RA Bouwmeester T., Bauch A., Ruffner H., Angrand P.-O., Bergamini G.,
RA Croughton K., Cruciat C., Eberhard D., Gagneur J., Ghidelli S.,
RA Hopf C., Huhse B., Mangano R., Michon A.-M., Schirle M., Schlegl J.,
RA Schwab M., Stein M.A., Bauer A., Casari G., Drewes G., Gavin A.-C.,
RA Jackson D.B., Joberty G., Neubauer G., Rick J., Kuster B.,
RA Superti-Furga G.;
RT "A physical and functional map of the human TNF-alpha/NF-kappa B
RT signal transduction pathway.";
RL Nat. Cell Biol. 6:97-105(2004).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-250; SER-337 AND
RP SER-340, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of
RT the kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-250; SER-337 AND
RP SER-340, AND MASS SPECTROMETRY.
RX PubMed=19369195; DOI=10.1074/mcp.M800588-MCP200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [13]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-337 AND SER-340, AND
RP MASS SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [14]
RP VARIANT [LARGE SCALE ANALYSIS] MET-281.
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: Component of a protein kinase signal transduction
CC cascade. Mediates activation of the NF-kappa-B, AP1 and DDIT3
CC transcriptional regulators.
CC -!- CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein.
CC -!- COFACTOR: Magnesium.
CC -!- ENZYME REGULATION: Activated by phosphorylation on Thr-530 (By
CC similarity).
CC -!- SUBUNIT: Binds both upstream activators and downstream substrates
CC in multimolecular complexes. Part of a complex with MAP2K3, RAC1
CC and CCM2. Interacts with MAP2K5 and SPAG9.
CC -!- INTERACTION:
CC Q6Q0C0:TRAF7; NbExp=3; IntAct=EBI-307281, EBI-307556;
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q99759-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q99759-2; Sequence=VSP_035967;
CC -!- PTM: Phosphorylation at Ser-166 and Ser-337 by SGK1 inhibits its
CC activity.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. STE Ser/Thr
CC protein kinase family. MAP kinase kinase kinase subfamily.
CC -!- SIMILARITY: Contains 1 OPR domain.
CC -!- SIMILARITY: Contains 1 protein kinase domain.
CC -----------------------------------------------------------------------
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DR EMBL; U78876; AAB41729.1; -; mRNA.
DR EMBL; AK315305; BAG37709.1; -; mRNA.
DR EMBL; AL834303; CAD38973.1; -; mRNA.
DR EMBL; AC046185; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471109; EAW94297.1; -; Genomic_DNA.
DR EMBL; CH471109; EAW94298.1; -; Genomic_DNA.
DR EMBL; CH471109; EAW94299.1; -; Genomic_DNA.
DR EMBL; BC090859; AAH90859.1; -; mRNA.
DR EMBL; BC093672; AAH93672.1; -; mRNA.
DR EMBL; BC093674; AAH93674.1; -; mRNA.
DR RefSeq; NP_002392.2; NM_002401.3.
DR RefSeq; NP_976226.1; NM_203351.1.
DR UniGene; Hs.29282; -.
DR PDB; 2C60; X-ray; 1.25 A; A=37-124.
DR PDB; 2JRH; NMR; -; A=42-126.
DR PDB; 2O2V; X-ray; 1.83 A; B=37-124.
DR PDB; 2PPH; NMR; -; A=42-126.
DR PDBsum; 2C60; -.
DR PDBsum; 2JRH; -.
DR PDBsum; 2O2V; -.
DR PDBsum; 2PPH; -.
DR ProteinModelPortal; Q99759; -.
DR SMR; Q99759; 43-122, 336-624.
DR DIP; DIP-27521N; -.
DR IntAct; Q99759; 13.
DR MINT; MINT-272157; -.
DR STRING; 9606.ENSP00000354927; -.
DR BindingDB; Q99759; -.
DR ChEMBL; CHEMBL5970; -.
DR GuidetoPHARMACOLOGY; 2078; -.
DR PhosphoSite; Q99759; -.
DR DMDM; 160332306; -.
DR PaxDb; Q99759; -.
DR PRIDE; Q99759; -.
DR DNASU; 4215; -.
DR Ensembl; ENST00000361357; ENSP00000354927; ENSG00000198909.
DR Ensembl; ENST00000361733; ENSP00000354485; ENSG00000198909.
DR Ensembl; ENST00000579585; ENSP00000461988; ENSG00000198909.
DR GeneID; 4215; -.
DR KEGG; hsa:4215; -.
DR UCSC; uc002jbg.3; human.
DR CTD; 4215; -.
DR GeneCards; GC17P061699; -.
DR HGNC; HGNC:6855; MAP3K3.
DR HPA; CAB007764; -.
DR MIM; 602539; gene.
DR neXtProt; NX_Q99759; -.
DR PharmGKB; PA30599; -.
DR eggNOG; COG0515; -.
DR HOGENOM; HOG000049130; -.
DR HOVERGEN; HBG006303; -.
DR KO; K04421; -.
DR OMA; QALHSIM; -.
DR OrthoDB; EOG747PHJ; -.
DR BRENDA; 2.7.12.2; 2681.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; Q99759; -.
DR ChiTaRS; MAP3K3; human.
DR EvolutionaryTrace; Q99759; -.
DR GeneWiki; MAP3K3; -.
DR GenomeRNAi; 4215; -.
DR NextBio; 16621; -.
DR PRO; PR:Q99759; -.
DR ArrayExpress; Q99759; -.
DR Bgee; Q99759; -.
DR CleanEx; HS_MAP3K3; -.
DR Genevestigator; Q99759; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0004709; F:MAP kinase kinase kinase activity; TAS:ProtInc.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0043123; P:positive regulation of I-kappaB kinase/NF-kappaB cascade; IEP:UniProtKB.
DR GO; GO:0046777; P:protein autophosphorylation; IDA:MGI.
DR InterPro; IPR011009; Kinase-like_dom.
DR InterPro; IPR000270; OPR_PB1.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR002290; Ser/Thr_dual-sp_kinase_dom.
DR Pfam; PF00564; PB1; 1.
DR Pfam; PF00069; Pkinase; 1.
DR SMART; SM00666; PB1; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; FALSE_NEG.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; FALSE_NEG.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; ATP-binding; Complete proteome;
KW Kinase; Magnesium; Metal-binding; Nucleotide-binding; Phosphoprotein;
KW Polymorphism; Reference proteome; Serine/threonine-protein kinase;
KW Transferase.
FT CHAIN 1 626 Mitogen-activated protein kinase kinase
FT kinase 3.
FT /FTId=PRO_0000086245.
FT DOMAIN 44 123 OPR.
FT DOMAIN 362 622 Protein kinase.
FT NP_BIND 368 376 ATP (By similarity).
FT ACT_SITE 489 489 Proton acceptor (By similarity).
FT BINDING 391 391 ATP (By similarity).
FT MOD_RES 166 166 Phosphoserine; by SGK1.
FT MOD_RES 250 250 Phosphoserine.
FT MOD_RES 337 337 Phosphoserine; by SGK1.
FT MOD_RES 340 340 Phosphoserine.
FT VAR_SEQ 42 42 Q -> QKKHNSSSSALLNSPTVTTSSCAGASEKKKFL (in
FT isoform 2).
FT /FTId=VSP_035967.
FT VARIANT 281 281 V -> M (in dbSNP:rs36109904).
FT /FTId=VAR_040685.
FT VARIANT 325 325 A -> G (in dbSNP:rs34042309).
FT /FTId=VAR_037275.
FT VARIANT 435 435 A -> G (in dbSNP:rs9910858).
FT /FTId=VAR_037276.
FT CONFLICT 135 135 G -> E (in Ref. 1; AAB41729).
FT STRAND 45 51
FT STRAND 54 60
FT HELIX 66 77
FT STRAND 82 86
FT STRAND 91 93
FT HELIX 97 109
FT TURN 111 114
FT STRAND 115 121
SQ SEQUENCE 626 AA; 70898 MW; 28129168A57571DD CRC64;
MDEQEALNSI MNDLVALQMN RRHRMPGYET MKNKDTGHSN RQSDVRIKFE HNGERRIIAF
SRPVKYEDVE HKVTTVFGQP LDLHYMNNEL SILLKNQDDL DKAIDILDRS SSMKSLRILL
LSQDRNHNSS SPHSGVSRQV RIKASQSAGD INTIYQPPEP RSRHLSVSSQ NPGRSSPPPG
YVPERQQHIA RQGSYTSINS EGEFIPETSE QCMLDPLSSA ENSLSGSCQS LDRSADSPSF
RKSRMSRAQS FPDNRQEYSD RETQLYDKGV KGGTYPRRYH VSVHHKDYSD GRRTFPRIRR
HQGNLFTLVP SSRSLSTNGE NMGLAVQYLD PRGRLRSADS ENALSVQERN VPTKSPSAPI
NWRRGKLLGQ GAFGRVYLCY DVDTGRELAS KQVQFDPDSP ETSKEVSALE CEIQLLKNLQ
HERIVQYYGC LRDRAEKTLT IFMEYMPGGS VKDQLKAYGA LTESVTRKYT RQILEGMSYL
HSNMIVHRDI KGANILRDSA GNVKLGDFGA SKRLQTICMS GTGMRSVTGT PYWMSPEVIS
GEGYGRKADV WSLGCTVVEM LTEKPPWAEY EAMAAIFKIA TQPTNPQLPS HISEHGRDFL
RRIFVEARQR PSAEELLTHH FAQLMY
//
MIM
602539
*RECORD*
*FIELD* NO
602539
*FIELD* TI
*602539 MITOGEN-ACTIVATED KINASE KINASE KINASE 3; MAP3K3
;;MAP/ERK KINASE KINASE 3; MEKK3;;
read moreMAPKKK3
*FIELD* TX
CLONING
Ellinger-Ziegelbauer et al. (1997) cloned a human kinase cDNA from an
activated peripheral blood T lymphocyte cDNA library and found that it
encodes the homolog of mouse Mekk3. Human MEKK3 (MAP3K3) is a 626-amino
acid polypeptide that is 96.5% identical to mouse Mekk3. Its catalytic
domain is closely related to those of several other kinases, including
mouse Mekk2 (MAP3K2; 609487), tobacco NPK, and yeast Ste11. Northern
blot analysis revealed a 4.6-kb MEKK3 transcript that appears to be
ubiquitously expressed.
GENE FUNCTION
Ellinger-Ziegelbauer et al. (1997) showed that MEKK3 directly regulates
the stress-activated protein kinase (SAPK) and extracellular
signal-regulated protein kinase (ERK) pathways by activating SEK
(601335) and MEK1/2 (176872, 601263), respectively; it does not regulate
the p38 pathway (see 600289). In cotransfection assays, MEKK3 enhanced
transcription from a nuclear factor kappa-B (NFKB; 164011,
164012)-dependent reporter gene, consistent with a role in the SAPK
pathway.
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, which activates p38 in response 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 (MAP2K3; 602315), 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.
Channavajhala et al. (2005) showed that cotransfection of KSR2 (610737)
with MEKK3 in HEK293T cells significantly reduced MEKK3-mediated ERK
activation but did not affect ERK activation by other MAP3Ks. KSR2 also
significantly reduced MEKK3-induced NF-kappa-B activation to near
background levels in the IL1B (147720)-mediated proinflammatory pathway
and downregulated MEKK3-induced IL8 (146930) production in response to
IL1B stimulation. Channavajhala et al. (2005) concluded that KSR2
specifically regulates the activity of MEKK3 and COT (MAP3K8; 191195)
but not other members of the MAP3K family.
MAPPING
MAP3K3 is contiguously distal to LYK5 (608626) on chromosome 17
(Puffenberger et al., 2007).
ANIMAL MODEL
The early development of blood vessels consists of 2 phases,
vasculogenesis and angiogenesis, which involve distinct and overlapping
molecular regulators. To define the intracellular signal transduction
pathways involved in these processes, Yang et al. (2000) disrupted the
Mekk3 gene in mice. Mekk3 -/- embryos died at approximately embryonic
day (E) 11, displaying disruption of blood vessel development and the
structural integrity of the yolk sac. Angiogenesis was blocked at
approximately E9.5 in mutant embryos. Mekk3 disruption did not alter the
expression of the genes encoding Vegf1 (VEGF; 192240), angiopoietin
(ANGPT1; 601667), or their receptors. The development of embryonic, but
not maternal, blood vessels in the placentas of Mekk3 -/- embryos was
impaired, revealing an intrinsic defect in Mekk3 -/- endothelial cells.
Moreover, Mekk3 activated myocyte-specific enhancer factor 2C (MEF2C;
600662), a transcription factor crucial for early embryonic
cardiovascular development through the p38 mitogen-activated protein
kinase cascade. Yang et al. (2000) concluded that Mekk3 is necessary for
blood vessel development and may be a possible target for drugs that
control angiogenesis.
*FIELD* RF
1. Channavajhala, P. L.; Rao, V. R.; Spaulding, V.; Lin, L. L.; Zhang,
Y. G.: hKSR-2 inhibits MEKK3-activated MAP kinase and NF-kappa-B
pathways in inflammation. Biochem. Biophys. Res. Commun. 334: 1214-1218,
2005.
2. Ellinger-Ziegelbauer, H.; Brown, K.; Kelly, K.; Siebenlist, U.
: Direct activation of the stress-activated protein kinase (SAPK)
and extracellular signal-regulated protein kinase (ERK) pathways by
an inducible mitogen-activated protein kinase/ERK kinase kinase 3
(MEKK) derivative. J. Biol. Chem. 272: 2668-2674, 1997.
3. Puffenberger, E. G.; Strauss, K. A.; Ramsey, K. E.; Craig, D. W.;
Stephan, D. A.; Robinson, D. L.; Hendrickson, C. L.; Gottlieb, S.;
Ramsay, D. A.; Siu, V. M.; Heuer, G. G.; Crino, P. B.; Morton, D.
H.: Polyhydramnios, megalencephaly and symptomatic epilepsy caused
by a homozygous 7-kilobase deletion in LYK5. Brain 130: 1929-1941,
2007.
4. 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.
5. Yang, J.; Boerm, M.; McCarty, M.; Bucana, C.; Fidler, I. J.; Zhuang,
Y.; Su, B.: Mekk3 is essential for early embryonic cardiovascular
development. Nature Genet. 24: 309-313, 2000.
*FIELD* CN
Patricia A. Hartz - updated: 2/24/2009
Victor A. McKusick - updated: 6/6/2007
Jennifer L. Goldstein - updated: 1/31/2007
Victor A. McKusick - updated: 3/1/2000
*FIELD* CD
Jennifer P. Macke: 4/21/1998
*FIELD* ED
alopez: 05/13/2009
mgross: 2/24/2009
alopez: 6/6/2007
terry: 6/6/2007
wwang: 1/31/2007
mgross: 7/21/2005
alopez: 3/1/2000
terry: 3/1/2000
mgross: 9/15/1999
psherman: 6/3/1998
dholmes: 4/29/1998
*RECORD*
*FIELD* NO
602539
*FIELD* TI
*602539 MITOGEN-ACTIVATED KINASE KINASE KINASE 3; MAP3K3
;;MAP/ERK KINASE KINASE 3; MEKK3;;
read moreMAPKKK3
*FIELD* TX
CLONING
Ellinger-Ziegelbauer et al. (1997) cloned a human kinase cDNA from an
activated peripheral blood T lymphocyte cDNA library and found that it
encodes the homolog of mouse Mekk3. Human MEKK3 (MAP3K3) is a 626-amino
acid polypeptide that is 96.5% identical to mouse Mekk3. Its catalytic
domain is closely related to those of several other kinases, including
mouse Mekk2 (MAP3K2; 609487), tobacco NPK, and yeast Ste11. Northern
blot analysis revealed a 4.6-kb MEKK3 transcript that appears to be
ubiquitously expressed.
GENE FUNCTION
Ellinger-Ziegelbauer et al. (1997) showed that MEKK3 directly regulates
the stress-activated protein kinase (SAPK) and extracellular
signal-regulated protein kinase (ERK) pathways by activating SEK
(601335) and MEK1/2 (176872, 601263), respectively; it does not regulate
the p38 pathway (see 600289). In cotransfection assays, MEKK3 enhanced
transcription from a nuclear factor kappa-B (NFKB; 164011,
164012)-dependent reporter gene, consistent with a role in the SAPK
pathway.
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, which activates p38 in response 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 (MAP2K3; 602315), 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.
Channavajhala et al. (2005) showed that cotransfection of KSR2 (610737)
with MEKK3 in HEK293T cells significantly reduced MEKK3-mediated ERK
activation but did not affect ERK activation by other MAP3Ks. KSR2 also
significantly reduced MEKK3-induced NF-kappa-B activation to near
background levels in the IL1B (147720)-mediated proinflammatory pathway
and downregulated MEKK3-induced IL8 (146930) production in response to
IL1B stimulation. Channavajhala et al. (2005) concluded that KSR2
specifically regulates the activity of MEKK3 and COT (MAP3K8; 191195)
but not other members of the MAP3K family.
MAPPING
MAP3K3 is contiguously distal to LYK5 (608626) on chromosome 17
(Puffenberger et al., 2007).
ANIMAL MODEL
The early development of blood vessels consists of 2 phases,
vasculogenesis and angiogenesis, which involve distinct and overlapping
molecular regulators. To define the intracellular signal transduction
pathways involved in these processes, Yang et al. (2000) disrupted the
Mekk3 gene in mice. Mekk3 -/- embryos died at approximately embryonic
day (E) 11, displaying disruption of blood vessel development and the
structural integrity of the yolk sac. Angiogenesis was blocked at
approximately E9.5 in mutant embryos. Mekk3 disruption did not alter the
expression of the genes encoding Vegf1 (VEGF; 192240), angiopoietin
(ANGPT1; 601667), or their receptors. The development of embryonic, but
not maternal, blood vessels in the placentas of Mekk3 -/- embryos was
impaired, revealing an intrinsic defect in Mekk3 -/- endothelial cells.
Moreover, Mekk3 activated myocyte-specific enhancer factor 2C (MEF2C;
600662), a transcription factor crucial for early embryonic
cardiovascular development through the p38 mitogen-activated protein
kinase cascade. Yang et al. (2000) concluded that Mekk3 is necessary for
blood vessel development and may be a possible target for drugs that
control angiogenesis.
*FIELD* RF
1. Channavajhala, P. L.; Rao, V. R.; Spaulding, V.; Lin, L. L.; Zhang,
Y. G.: hKSR-2 inhibits MEKK3-activated MAP kinase and NF-kappa-B
pathways in inflammation. Biochem. Biophys. Res. Commun. 334: 1214-1218,
2005.
2. Ellinger-Ziegelbauer, H.; Brown, K.; Kelly, K.; Siebenlist, U.
: Direct activation of the stress-activated protein kinase (SAPK)
and extracellular signal-regulated protein kinase (ERK) pathways by
an inducible mitogen-activated protein kinase/ERK kinase kinase 3
(MEKK) derivative. J. Biol. Chem. 272: 2668-2674, 1997.
3. Puffenberger, E. G.; Strauss, K. A.; Ramsey, K. E.; Craig, D. W.;
Stephan, D. A.; Robinson, D. L.; Hendrickson, C. L.; Gottlieb, S.;
Ramsay, D. A.; Siu, V. M.; Heuer, G. G.; Crino, P. B.; Morton, D.
H.: Polyhydramnios, megalencephaly and symptomatic epilepsy caused
by a homozygous 7-kilobase deletion in LYK5. Brain 130: 1929-1941,
2007.
4. 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.
5. Yang, J.; Boerm, M.; McCarty, M.; Bucana, C.; Fidler, I. J.; Zhuang,
Y.; Su, B.: Mekk3 is essential for early embryonic cardiovascular
development. Nature Genet. 24: 309-313, 2000.
*FIELD* CN
Patricia A. Hartz - updated: 2/24/2009
Victor A. McKusick - updated: 6/6/2007
Jennifer L. Goldstein - updated: 1/31/2007
Victor A. McKusick - updated: 3/1/2000
*FIELD* CD
Jennifer P. Macke: 4/21/1998
*FIELD* ED
alopez: 05/13/2009
mgross: 2/24/2009
alopez: 6/6/2007
terry: 6/6/2007
wwang: 1/31/2007
mgross: 7/21/2005
alopez: 3/1/2000
terry: 3/1/2000
mgross: 9/15/1999
psherman: 6/3/1998
dholmes: 4/29/1998