M3K3_MOUSE
ID M3K3_MOUSE Reviewed; 626 AA.
AC Q61084;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1996, sequence version 1.
DT 03-AUG-2022, entry version 182.
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=Mekk3;
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], AND FUNCTION.
RC TISSUE=Brain;
RX PubMed=8621389; DOI=10.1074/jbc.271.10.5361;
RA Blank J.L., Gerwins P., Elliott E.M., Sather S., Johnson G.L.;
RT "Molecular cloning of mitogen-activated protein/ERK kinase kinases (MEKK) 2
RT and 3. Regulation of sequential phosphorylation pathways involving mitogen-
RT activated protein kinase and c-Jun kinase.";
RL J. Biol. Chem. 271:5361-5368(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=FVB/N; 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 [3]
RP INTERACTION WITH SPAG9.
RX PubMed=12391307; DOI=10.1073/pnas.232310199;
RA Lee C.M., Onesime D., Reddy C.D., Dhanasekaran N., Reddy E.P.;
RT "JLP: a scaffolding protein that tethers JNK/p38MAPK signaling modules and
RT transcription factors.";
RL Proc. Natl. Acad. Sci. U.S.A. 99:14189-14194(2002).
RN [4]
RP INTERACTION WITH MAP2K3; 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 [5]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-337 AND SER-340, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=17242355; DOI=10.1073/pnas.0609836104;
RA Villen J., Beausoleil S.A., Gerber S.A., Gygi S.P.;
RT "Large-scale phosphorylation analysis of mouse liver.";
RL Proc. Natl. Acad. Sci. U.S.A. 104:1488-1493(2007).
RN [6]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-147; SER-166; SER-337 AND
RP SER-340, AND 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: Component of a protein kinase signal transduction cascade.
CC Mediates activation of the NF-kappa-B, AP1 and DDIT3 transcriptional
CC regulators. {ECO:0000269|PubMed:8621389}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-
CC [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA-
CC COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.25;
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-
CC threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060,
CC Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216;
CC EC=2.7.11.25;
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC -!- ACTIVITY REGULATION: Activated by phosphorylation on Thr-530.
CC {ECO:0000250}.
CC -!- SUBUNIT: Binds both upstream activators and downstream substrates in
CC multimolecular complexes. Part of a complex with MAP2K3, RAC1 and CCM2.
CC Interacts with MAP2K5 and SPAG9. {ECO:0000269|PubMed:12391307,
CC ECO:0000269|PubMed:14634666}.
CC -!- INTERACTION:
CC Q61084; Q9WVS7: Map2k5; NbExp=15; IntAct=EBI-446250, EBI-446144;
CC Q61084; P70196: Traf6; NbExp=5; IntAct=EBI-446250, EBI-448028;
CC -!- PTM: Phosphorylation at Ser-166 and Ser-337 by SGK1 inhibits its
CC activity. {ECO:0000250}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. STE Ser/Thr
CC protein kinase family. MAP kinase kinase kinase subfamily.
CC {ECO:0000305}.
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DR EMBL; U43187; AAB03535.1; -; mRNA.
DR EMBL; BC023781; AAH23781.1; -; mRNA.
DR CCDS; CCDS25548.1; -.
DR RefSeq; NP_036077.1; NM_011947.3.
DR AlphaFoldDB; Q61084; -.
DR BMRB; Q61084; -.
DR SMR; Q61084; -.
DR BioGRID; 204959; 4.
DR CORUM; Q61084; -.
DR IntAct; Q61084; 3.
DR MINT; Q61084; -.
DR STRING; 10090.ENSMUSP00000002044; -.
DR iPTMnet; Q61084; -.
DR PhosphoSitePlus; Q61084; -.
DR EPD; Q61084; -.
DR jPOST; Q61084; -.
DR MaxQB; Q61084; -.
DR PaxDb; Q61084; -.
DR PRIDE; Q61084; -.
DR ProteomicsDB; 292067; -.
DR Antibodypedia; 31306; 246 antibodies from 39 providers.
DR DNASU; 26406; -.
DR Ensembl; ENSMUST00000002044; ENSMUSP00000002044; ENSMUSG00000020700.
DR GeneID; 26406; -.
DR KEGG; mmu:26406; -.
DR UCSC; uc007lyc.1; mouse.
DR CTD; 4215; -.
DR MGI; MGI:1346874; Map3k3.
DR VEuPathDB; HostDB:ENSMUSG00000020700; -.
DR eggNOG; KOG0198; Eukaryota.
DR GeneTree; ENSGT00940000158767; -.
DR HOGENOM; CLU_029447_0_0_1; -.
DR InParanoid; Q61084; -.
DR OMA; DNRKECS; -.
DR OrthoDB; 55144at2759; -.
DR PhylomeDB; Q61084; -.
DR TreeFam; TF105113; -.
DR BRENDA; 2.7.12.2; 3474.
DR Reactome; R-MMU-9020702; Interleukin-1 signaling.
DR BioGRID-ORCS; 26406; 3 hits in 75 CRISPR screens.
DR ChiTaRS; Map3k3; mouse.
DR PRO; PR:Q61084; -.
DR Proteomes; UP000000589; Chromosome 11.
DR RNAct; Q61084; protein.
DR Bgee; ENSMUSG00000020700; Expressed in granulocyte and 259 other tissues.
DR Genevisible; Q61084; MM.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0004709; F:MAP kinase kinase kinase activity; IEA:UniProtKB-EC.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0004672; F:protein kinase activity; ISO:MGI.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; IBA:GO_Central.
DR GO; GO:0001568; P:blood vessel development; IMP:MGI.
DR GO; GO:0035556; P:intracellular signal transduction; ISO:MGI.
DR GO; GO:2000773; P:negative regulation of cellular senescence; ISO:MGI.
DR GO; GO:0090050; P:positive regulation of cell migration involved in sprouting angiogenesis; ISO:MGI.
DR GO; GO:0071864; P:positive regulation of cell proliferation in bone marrow; ISO:MGI.
DR GO; GO:0043123; P:positive regulation of I-kappaB kinase/NF-kappaB signaling; IEA:Ensembl.
DR GO; GO:1900745; P:positive regulation of p38MAPK cascade; IDA:MGI.
DR GO; GO:0046777; P:protein autophosphorylation; ISO:MGI.
DR CDD; cd06405; PB1_Mekk2_3; 1.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR000270; PB1_dom.
DR InterPro; IPR034879; PB1_MEKK2/3.
DR InterPro; IPR000719; Prot_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; PS51745; PB1; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
PE 1: Evidence at protein level;
KW ATP-binding; Kinase; Magnesium; Metal-binding; Nucleotide-binding;
KW Phosphoprotein; Reference proteome; Serine/threonine-protein kinase;
KW Transferase.
FT CHAIN 1..626
FT /note="Mitogen-activated protein kinase kinase kinase 3"
FT /id="PRO_0000086246"
FT DOMAIN 44..123
FT /note="PB1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01081"
FT DOMAIN 362..622
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 125..184
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 218..273
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 125..153
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 218..247
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 248..267
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 489
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 368..376
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 391
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOD_RES 147
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 166
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 250
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q99759"
FT MOD_RES 312
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q99759"
FT MOD_RES 337
FT /note="Phosphoserine; by SGK1"
FT /evidence="ECO:0007744|PubMed:17242355,
FT ECO:0007744|PubMed:21183079"
FT MOD_RES 340
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:17242355,
FT ECO:0007744|PubMed:21183079"
SQ SEQUENCE 626 AA; 70776 MW; 00EF2442C9E56E0B CRC64;
MDEQEALDSI MKDLVALQMS RRTRLSGYET MKNKDTGHPN RQSDVRIKFE HNGERRIIAF
SRPVRYEDVE HKVTTVFGQP LDLHYMNNEL SILLKNQDDL DKAIDILDRS SSMKSLRILL
LSQDRNHTSS SPHSGVSRQV RIKPSQSAGD INTIYQAPEP RSRHLSVSSQ NPGRSSPPPG
YVPERQQHIA RQGSYTSINS EGEFIPETSE QCMLDPLSSA ENSLSGSCQS LDRSADSPSF
RKSQMSRARS FPDNRKECSD RETQLYDKGV KGGTYPRRYH VSVHHKDYND GRRTFPRIRR
HQGNLFTLVP SSRSLSTNGE NMGVAVQYLD PRGRLRSADS ENALTVQERN VPTKSPSAPI
NWRRGKLLGQ GAFGRVYLCY DVDTGRELAS KQVQFDPDSP ETSKEVSALE CEIQLLKNLQ
HERIVQYYGC LRDRAEKILT IFMEYMPGGS VKDQLKAYGA LTESVTRKYT RQILEGMSYL
HSNMIVHRDI KGANILRDSA GNVKLGDFGA SKRLQTICMS GTGIRSVTGT PYWMSPEVIS
GEGYGRKADV WSLGCTVVEM LTEKPPWAEY EAMAAIFKIA TQPTNPQLPS HISEHGRDFL
RRIFVEARQR PSAEELLTHH FAQLVY
