M3K6_MOUSE
ID M3K6_MOUSE Reviewed; 1291 AA.
AC Q9WTR2; A2AE93; Q0VBN3;
DT 26-JUN-2007, integrated into UniProtKB/Swiss-Prot.
DT 26-JUN-2007, sequence version 4.
DT 03-AUG-2022, entry version 148.
DE RecName: Full=Mitogen-activated protein kinase kinase kinase 6;
DE EC=2.7.11.25;
DE AltName: Full=Apoptosis signal-regulating kinase 2;
GN Name=Map3k6 {ECO:0000312|MGI:MGI:1855691};
GN Synonyms=Ask2, Mapkkk6 {ECO:0000250|UniProtKB:O95382}, Mekk6;
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] {ECO:0000305}
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, ACTIVITY REGULATION, INTERACTION WITH
RP MAP3K5, PHOSPHORYLATION AT THR-807, AND MUTAGENESIS OF LYS-678.
RC TISSUE=Fibroblast {ECO:0000269|PubMed:17210579};
RX PubMed=17210579; DOI=10.1074/jbc.m607177200;
RA Takeda K., Shimozono R., Noguchi T., Umeda T., Morimoto Y., Naguro I.,
RA Tobiume K., Saitoh M., Matsuzawa A., Ichijo H.;
RT "Apoptosis signal-regulating kinase (ASK) 2 functions as a mitogen-
RT activated protein kinase kinase kinase in a heteromeric complex with
RT ASK1.";
RL J. Biol. Chem. 282:7522-7531(2007).
RN [2] {ECO:0000312|EMBL:CAM21067.1}
RP SEQUENCE REVISION TO 1003.
RC TISSUE=Fibroblast;
RA Saitoh M., Ichijo H.;
RL Submitted (JUL-2007) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=C57BL/6J;
RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112;
RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X.,
RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y.,
RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S.,
RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R.,
RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K.,
RA Eichler E.E., Ponting C.P.;
RT "Lineage-specific biology revealed by a finished genome assembly of the
RT mouse.";
RL PLoS Biol. 7:E1000112-E1000112(2009).
RN [4] {ECO:0000312|EMBL:AAI20566.1}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain {ECO:0000312|EMBL:AAI20566.1};
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Lung;
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 Activates the JNK, but not ERK or p38 kinase pathways.
CC {ECO:0000269|PubMed:17210579}.
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 Evidence={ECO:0000269|PubMed:17210579};
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; Evidence={ECO:0000269|PubMed:17210579};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000269|PubMed:17210579};
CC -!- ACTIVITY REGULATION: Activated by phosphorylation on Thr-807.
CC Catalytically active only when complexed with MAP3K5, with MAP3K5
CC supporting the stability and the active configuration of MAP3K6 and
CC MAP3K6 activating MAP3K5 by direct phosphorylation.
CC {ECO:0000269|PubMed:17210579}.
CC -!- SUBUNIT: Binds both upstream activators and downstream substrates in
CC multimolecular complexes. {ECO:0000269|PubMed:17210579}.
CC -!- INTERACTION:
CC Q9WTR2; Q99683: MAP3K5; Xeno; NbExp=3; IntAct=EBI-1254790, EBI-476263;
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; AB021861; BAA78532.4; -; mRNA.
DR EMBL; AL671882; CAM21067.1; -; Genomic_DNA.
DR EMBL; AL837525; CAM21067.1; JOINED; Genomic_DNA.
DR EMBL; AL837525; CAM18232.1; -; Genomic_DNA.
DR EMBL; AL671882; CAM18232.1; JOINED; Genomic_DNA.
DR EMBL; BC120565; AAI20566.1; -; mRNA.
DR EMBL; BC125577; AAI25578.1; -; mRNA.
DR CCDS; CCDS18744.1; -.
DR AlphaFoldDB; Q9WTR2; -.
DR SMR; Q9WTR2; -.
DR IntAct; Q9WTR2; 2.
DR STRING; 10090.ENSMUSP00000030677; -.
DR iPTMnet; Q9WTR2; -.
DR PhosphoSitePlus; Q9WTR2; -.
DR MaxQB; Q9WTR2; -.
DR PaxDb; Q9WTR2; -.
DR PRIDE; Q9WTR2; -.
DR ProteomicsDB; 292139; -.
DR MGI; MGI:1855691; Map3k6.
DR eggNOG; KOG4279; Eukaryota.
DR InParanoid; Q9WTR2; -.
DR PhylomeDB; Q9WTR2; -.
DR TreeFam; TF105115; -.
DR BRENDA; 2.7.11.25; 3474.
DR ChiTaRS; Map3k6; mouse.
DR PRO; PR:Q9WTR2; -.
DR Proteomes; UP000000589; Unplaced.
DR RNAct; Q9WTR2; protein.
DR GO; GO:0005524; F:ATP binding; ISO:MGI.
DR GO; GO:0000287; F:magnesium ion binding; ISO:MGI.
DR GO; GO:0004709; F:MAP kinase kinase kinase activity; ISO:MGI.
DR GO; GO:0004672; F:protein kinase activity; IBA:GO_Central.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0006468; P:protein phosphorylation; ISO:MGI.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR043969; MAP3K_PH.
DR InterPro; IPR025136; MAP3K_TRAF-bd.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR013761; SAM/pointed_sf.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR Pfam; PF19039; ASK_PH; 1.
DR Pfam; PF13281; MAP3K_TRAF_bd; 1.
DR Pfam; PF00069; Pkinase; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF47769; SSF47769; 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 ATP-binding; Coiled coil; Kinase; Magnesium; Metal-binding;
KW Nucleotide-binding; Phosphoprotein; Reference proteome;
KW Serine/threonine-protein kinase; Transferase.
FT CHAIN 1..1291
FT /note="Mitogen-activated protein kinase kinase kinase 6"
FT /id="PRO_0000291648"
FT DOMAIN 649..907
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 901..997
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1125..1160
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COILED 1006..1069
FT /evidence="ECO:0000255"
FT COILED 1164..1195
FT /evidence="ECO:0000255"
FT COMPBIAS 931..949
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1125..1139
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1140..1156
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 772
FT /note="Proton acceptor"
FT /evidence="ECO:0000250|UniProtKB:P28523,
FT ECO:0000255|PROSITE-ProRule:PRU00159, ECO:0000255|PROSITE-
FT ProRule:PRU10027"
FT BINDING 655..663
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:P28523,
FT ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 678
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000269|PubMed:17210579"
FT MOD_RES 807
FT /note="Phosphothreonine"
FT /evidence="ECO:0000269|PubMed:17210579"
FT MOD_RES 965
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O95382"
FT MOD_RES 985
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O95382"
FT MUTAGEN 678
FT /note="K->M: Loss of kinase activity."
FT /evidence="ECO:0000269|PubMed:17210579"
FT CONFLICT 7
FT /note="R -> G (in Ref. 3; CAM21067/CAM18232)"
FT /evidence="ECO:0000305"
FT CONFLICT 58
FT /note="P -> L (in Ref. 3; CAM21067/CAM18232)"
FT /evidence="ECO:0000305"
FT CONFLICT 550..552
FT /note="MSA -> VST (in Ref. 3; CAM21067/CAM18232)"
FT /evidence="ECO:0000305"
FT CONFLICT 559
FT /note="E -> D (in Ref. 3; CAM21067/CAM18232)"
FT /evidence="ECO:0000305"
FT CONFLICT 1114
FT /note="L -> M (in Ref. 3; CAM21067/CAM18232)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 1291 AA; 143055 MW; FC61A90935A7465D CRC64;
MAGPCPRAGV LERAGSCWQD PLAEALSRGR SSPAVTGRGC ARSRPLSVVY VLTREPGPGV
EPGSGTEAEP LPLRCLREAC AQLQGTRPPP QLRSLPFATL ALGDTAALDS FYNADVVVLE
VSSSLAQPSL FYHLGVRESF SMTNNVLLCS QAELPDLQAL REDVFQKNSD CVGSYTLIPY
VVTATGRVLC GDAGLLRGIA DGLVQAGAGT EALLTPLVGR LVRLLEATPT DSCGYFRETI
RQDIRQARER FSGQQLRQEL ARLQRRLDSV ELLSPDIVMN LLLSYRDVQD YSAIIELVET
LQALPTCDVA EQHNVCFHYT FALNRRNRPG DREKALAVLL PLVKYEGPVA PDLYCMCGRI
YKDMFFTSGF QNAGHLEQAY HWYRKAFDVE PSLHSGINAA VLLIAAGQHF EDSEELRLIG
MKLACLLARK GCVEKMQYYW DVGFYLGAQI LANDPIQVVL AAEQLYKLNA PIWYLVSVME
TFLLYQHFRP TPEPSGGPPL RAHFWLHFLL QSCQPFKMAP PQEDQCLVLV LEINKVLLPA
RLEIQGTDPM SAVTLSLLEP ETQEDPSSWT FPVTSICGIS TSKLDQRCCF LYALPPAQDV
QLCFPSVERC QRFCGLIQVL VMNPDSSAPT EEAEGAREVL EFDYEYSETG ERLVLGRGTY
GVVYAGRDRH TRVRIAIKEI PERDSRFSQP LHEEIALHKR LRHKNIVRYL GSASQGGYLK
IFMEEVPGGS LSSLLRSVWG PLKDNESTIS FYTRQILQGL SYLHENRIVH RDIKGDNVLI
NTFSGLLKIS DFGTSKRLAG ITPCTETFTG TLQYMAPEII DQGPRGYGKA ADIWSLGCTV
IEMATGRPPF HELGSPQAAM FQVGMYKVHP PVPGSLSAEA QAFLLRTFEP DPRLRASAQE
LLGDPFLQPG KRSRSPGSPR HTPRPSGAPS GPSSPSADSA TQSQTFPRPQ APSQHPPSPP
KRCLSYGDTS QLRVPEEPAA EEPASPEESS GLSLLHQESK RRAMLAAVLE QEVPTLAENL
LEQEQDSRLS KIHVELLLRC LGAQIHTPNR RQLAQELRTL QAQLRAQSLG PALLKGPLFA
FPDAVKQILR RRQIRPHWMF VLDSLLSRAV RAALAVLDAE SEKKAVLPRS EESSKEESQQ
KPQESQALQS QLPPEQGPPS LMVELGLLRA ETDRLRDLLA EKERECQALV QQALHRVHAE
TRKYAPASET PATLPKDQNL VRWLQELSVD PATIQTLLSH SFTLQTLLTC ATQDDLVYTR
IRGGMVCRIW RAILAQRAGA TSVTPVPRDA E
