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   27-MAR-2024, entry version 191.
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,
RC   Spleen, 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; 10090-ENSMUSP00000002044; -.
DR   ProteomicsDB; 292067; -.
DR   Pumba; Q61084; -.
DR   Antibodypedia; 31306; 317 antibodies from 39 providers.
DR   DNASU; 26406; -.
DR   Ensembl; ENSMUST00000002044.10; ENSMUSP00000002044.10; ENSMUSG00000020700.12.
DR   GeneID; 26406; -.
DR   KEGG; mmu:26406; -.
DR   UCSC; uc007lyc.1; mouse.
DR   AGR; MGI:1346874; -.
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; ITTSPCA; -.
DR   OrthoDB; 145974at2759; -.
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 80 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 263 other cell types or tissues.
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:0016310; P:phosphorylation; IEA:UniProtKB-KW.
DR   GO; GO:0043123; P:positive regulation of canonical NF-kappaB signal transduction; IEA:Ensembl.
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:1900745; P:positive regulation of p38MAPK cascade; IDA:MGI.
DR   CDD; cd06405; PB1_Mekk2_3; 1.
DR   CDD; cd06625; STKc_MEKK3_like; 1.
DR   Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 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   PANTHER; PTHR48016; MAP KINASE KINASE KINASE SSK2-RELATED-RELATED; 1.
DR   PANTHER; PTHR48016:SF50; MITOGEN-ACTIVATED PROTEIN KINASE KINASE KINASE 19; 1.
DR   Pfam; PF00564; PB1; 1.
DR   Pfam; PF00069; Pkinase; 1.
DR   SMART; SM00666; PB1; 1.
DR   SMART; SM00220; S_TKc; 1.
DR   SUPFAM; SSF54277; CAD & PB1 domains; 1.
DR   SUPFAM; SSF56112; Protein kinase-like (PK-like); 1.
DR   PROSITE; PS51745; PB1; 1.
DR   PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR   Genevisible; Q61084; MM.
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
//