MP2K6_MOUSE
ID MP2K6_MOUSE Reviewed; 334 AA.
AC P70236;
DT 15-JUL-1998, integrated into UniProtKB/Swiss-Prot.
DT 01-FEB-1997, sequence version 1.
DT 03-AUG-2022, entry version 176.
DE RecName: Full=Dual specificity mitogen-activated protein kinase kinase 6;
DE Short=MAP kinase kinase 6;
DE Short=MAPKK 6;
DE EC=2.7.12.2;
DE AltName: Full=MAPK/ERK kinase 6;
DE Short=MEK 6;
DE AltName: Full=SAPKK3;
GN Name=Map2k6; Synonyms=Prkmk6, Sapkk3;
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].
RX PubMed=8861944; DOI=10.1002/j.1460-2075.1996.tb00790.x;
RA Cuenda A., Alonso G., Morrice N., Jones M., Meier R., Cohen P.,
RA Nebreda A.R.;
RT "Purification and cDNA cloning of SAPKK3, the major activator of RK/p38 in
RT stress- and cytokine-stimulated monocytes and epithelial cells.";
RL EMBO J. 15:4156-4164(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Eye;
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 FUNCTION IN REGULATION OF T-CELL APOPTOSIS.
RX PubMed=12151339; DOI=10.1093/embo-reports/kvf153;
RA Tanaka N., Kamanaka M., Enslen H., Dong C., Wysk M., Davis R.J.,
RA Flavell R.A.;
RT "Differential involvement of p38 mitogen-activated protein kinase kinases
RT MKK3 and MKK6 in T-cell apoptosis.";
RL EMBO Rep. 3:785-791(2002).
RN [4]
RP FUNCTION IN REGULATION OF T-CELL APOPTOSIS.
RX PubMed=12824301; DOI=10.1096/fj.02-0869fje;
RA Suzuki H., Wu J., Hossain K., Ohhata T., Du J., Akhand A.A., Hayakawa A.,
RA Kimura H., Hagiwara M., Nakashima I.;
RT "Involvement of MKK6 in TCRalphabeta(int)CD69lo: a target population for
RT apoptotic cell death in thymocytes.";
RL FASEB J. 17:1538-1540(2003).
RN [5]
RP FUNCTION OF THE P38 MAP KINASE SIGNAL TRANSDUCTION PATHWAY.
RX PubMed=12893778; DOI=10.1101/gad.1107303;
RA Brancho D., Tanaka N., Jaeschke A., Ventura J.J., Kelkar N., Tanaka Y.,
RA Kyuuma M., Takeshita T., Flavell R.A., Davis R.J.;
RT "Mechanism of p38 MAP kinase activation in vivo.";
RL Genes Dev. 17:1969-1978(2003).
RN [6]
RP INDUCTION.
RX PubMed=12482988; DOI=10.1128/mcb.23.1.370-381.2003;
RA Ambrosino C., Mace G., Galban S., Fritsch C., Vintersten K., Black E.,
RA Gorospe M., Nebreda A.R.;
RT "Negative feedback regulation of MKK6 mRNA stability by p38alpha mitogen-
RT activated protein kinase.";
RL Mol. Cell. Biol. 23:370-381(2003).
RN [7]
RP ACTIVITY REGULATION, AND FUNCTION OF THE P38 MAP KINASE SIGNAL TRANSDUCTION
RP PATHWAY.
RX PubMed=15644321; DOI=10.1074/jbc.m410972200;
RA Li Y., Batra S., Sassano A., Majchrzak B., Levy D.E., Gaestel M.,
RA Fish E.N., Davis R.J., Platanias L.C.;
RT "Activation of mitogen-activated protein kinase kinase (MKK) 3 and MKK6 by
RT type I interferons.";
RL J. Biol. Chem. 280:10001-10010(2005).
RN [8]
RP FUNCTION OF THE P38 MAP KINASE SIGNAL TRANSDUCTION PATHWAY.
RX PubMed=16498455; DOI=10.1038/sj.cdd.4401882;
RA Huang H., Ryu J., Ha J., Chang E.J., Kim H.J., Kim H.M., Kitamura T.,
RA Lee Z.H., Kim H.H.;
RT "Osteoclast differentiation requires TAK1 and MKK6 for NFATc1 induction and
RT NF-kappaB transactivation by RANKL.";
RL Cell Death Differ. 13:1879-1891(2006).
RN [9]
RP FUNCTION OF THE P38 MAP KINASE SIGNAL TRANSDUCTION PATHWAY.
RX PubMed=16387856; DOI=10.1073/pnas.0507979103;
RA Zhang R., Murakami S., Coustry F., Wang Y., de Crombrugghe B.;
RT "Constitutive activation of MKK6 in chondrocytes of transgenic mice
RT inhibits proliferation and delays endochondral bone formation.";
RL Proc. Natl. Acad. Sci. U.S.A. 103:365-370(2006).
RN [10]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain, Heart, Lung, and Spleen;
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).
RN [11]
RP FUNCTION.
RX PubMed=20004242; DOI=10.1016/j.cellsig.2009.11.020;
RA Remy G., Risco A.M., Inesta-Vaquera F.A., Gonzalez-Teran B., Sabio G.,
RA Davis R.J., Cuenda A.;
RT "Differential activation of p38MAPK isoforms by MKK6 and MKK3.";
RL Cell. Signal. 22:660-667(2010).
RN [12]
RP REVIEW ON ACTIVITY REGULATION, AND REVIEW ON FUNCTION.
RX PubMed=9779990; DOI=10.1038/sj.onc.1202251;
RA Dhanasekaran N., Premkumar Reddy E.;
RT "Signaling by dual specificity kinases.";
RL Oncogene 17:1447-1455(1998).
CC -!- FUNCTION: Dual specificity protein kinase which acts as an essential
CC component of the MAP kinase signal transduction pathway. With
CC MAP3K3/MKK3, catalyzes the concomitant phosphorylation of a threonine
CC and a tyrosine residue in the MAP kinases p38 MAPK11, MAPK12, MAPK13
CC and MAPK14 and plays an important role in the regulation of cellular
CC responses to cytokines and all kinds of stresses. Especially,
CC MAP2K3/MKK3 and MAP2K6/MKK6 are both essential for the activation of
CC MAPK11 and MAPK13 induced by environmental stress, whereas MAP2K6/MKK6
CC is the major MAPK11 activator in response to TNF. MAP2K6/MKK6 also
CC phosphorylates and activates PAK6. The p38 MAP kinase signal
CC transduction pathway leads to direct activation of transcription
CC factors. Nuclear targets of p38 MAP kinase include the transcription
CC factors ATF2 and ELK1. Within the p38 MAPK signal transduction pathway,
CC MAP3K6/MKK6 mediates phosphorylation of STAT4 through MAPK14
CC activation, and is therefore required for STAT4 activation and STAT4-
CC regulated gene expression in response to IL-12 stimulation. The pathway
CC is also crucial for IL-6-induced SOCS3 expression and down-regulation
CC of IL-6-mediated gene induction; and for IFNG-dependent gene
CC transcription. Has a role in osteoclast differentiation through NF-
CC kappa-B transactivation by TNFSF11, and in endochondral ossification
CC and since SOX9 is another likely downstream target of the p38 MAPK
CC pathway. MAP2K6/MKK6 mediates apoptotic cell death in thymocytes. Acts
CC also as a regulator for melanocytes dendricity, through the modulation
CC of Rho family GTPases. {ECO:0000269|PubMed:12151339,
CC ECO:0000269|PubMed:12824301, ECO:0000269|PubMed:12893778,
CC ECO:0000269|PubMed:15644321, ECO:0000269|PubMed:16387856,
CC ECO:0000269|PubMed:16498455, ECO:0000269|PubMed:20004242}.
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=2.7.12.2;
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=2.7.12.2;
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl-
CC [protein]; Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA-
CC COMP:10137, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858,
CC ChEBI:CHEBI:82620, ChEBI:CHEBI:456216; EC=2.7.12.2;
CC -!- ACTIVITY REGULATION: Activated by dual phosphorylation on Ser-207 and
CC Thr-211 in response to a variety of cellular stresses, including UV
CC radiation, osmotic shock, hypoxia, inflammatory cytokines, interferon
CC gamma (IFNG), and less often by growth factors. MAP2K6/MKK6 is
CC activated by the majority of M3Ks, such as MAP3K5/ASK1, MAP3K1/MEKK1,
CC MAP3K2/MEKK2, MAP3K3/MEKK3, MAP3K4/MEKK4, MAP3K7/TAK1, MAP3K11/MLK3 and
CC MAP3K17/TAOK2. {ECO:0000269|PubMed:15644321}.
CC -!- SUBUNIT: Dimer. Interacts (via its D domain) with its substrates
CC MAPK11, MAPK12, MAPK13 and MAPK14. Interacts (via its DVD domain) with
CC MAP3Ks activators like MAP3K5/ASK1, MAP3K1/MEKK1, MAP3K2/MEKK2,
CC MAP3K3/MEKK3, MAP3K4/MEKK4, MAP3K7/TAK1, MAP3K11/MLK3 and
CC MAP3K17/TAOK2. Interacts with DCTN1. Interacts with EIF2AK2/PKR.
CC {ECO:0000250}.
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000250}. Cytoplasm {ECO:0000250}.
CC Cytoplasm, cytoskeleton {ECO:0000250}. Note=Binds to microtubules.
CC {ECO:0000250}.
CC -!- INDUCTION: MSAPK14 can negatively regulate the stability of the
CC MAP2K6/MKK6 mRNA and thus control the steady-state concentration of one
CC of its upstream activator. {ECO:0000269|PubMed:12482988}.
CC -!- DOMAIN: The DVD domain (residues 311-334) contains a conserved docking
CC site and is found in the mammalian MAP kinase kinases (MAP2Ks). The DVD
CC sites bind to their specific upstream MAP kinase kinase kinases
CC (MAP3Ks) and are essential for activation (By similarity).
CC {ECO:0000250}.
CC -!- DOMAIN: The D domain (residues 4-19) contains a conserved docking site
CC and is required for the binding to MAPK substrates. {ECO:0000250}.
CC -!- PTM: Weakly autophosphorylated. Phosphorylated at Ser-207 and Thr-211
CC by the majority of M3Ks, such as MAP3K5/ASK1, MAP3K1/MEKK1,
CC MAP3K2/MEKK2, MAP3K3/MEKK3, MAP3K4/MEKK4, MAP3K7/TAK1, MAP3K11/MLK3 and
CC MAP3K17/TAOK2. {ECO:0000250}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. STE Ser/Thr
CC protein kinase family. MAP kinase kinase subfamily. {ECO:0000305}.
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DR EMBL; X97052; CAA65764.1; -; mRNA.
DR EMBL; BC075652; AAH75652.1; -; mRNA.
DR CCDS; CCDS25592.1; -.
DR PIR; S71632; S71632.
DR RefSeq; NP_036073.1; NM_011943.2.
DR AlphaFoldDB; P70236; -.
DR SMR; P70236; -.
DR BioGRID; 204953; 16.
DR STRING; 10090.ENSMUSP00000020949; -.
DR iPTMnet; P70236; -.
DR PhosphoSitePlus; P70236; -.
DR EPD; P70236; -.
DR jPOST; P70236; -.
DR PaxDb; P70236; -.
DR PeptideAtlas; P70236; -.
DR PRIDE; P70236; -.
DR ProteomicsDB; 252602; -.
DR Antibodypedia; 3570; 891 antibodies from 41 providers.
DR DNASU; 26399; -.
DR Ensembl; ENSMUST00000020949; ENSMUSP00000020949; ENSMUSG00000020623.
DR GeneID; 26399; -.
DR KEGG; mmu:26399; -.
DR UCSC; uc007mdr.1; mouse.
DR CTD; 5608; -.
DR MGI; MGI:1346870; Map2k6.
DR VEuPathDB; HostDB:ENSMUSG00000020623; -.
DR eggNOG; KOG0984; Eukaryota.
DR GeneTree; ENSGT00940000157836; -.
DR InParanoid; P70236; -.
DR OMA; YTVQFYG; -.
DR OrthoDB; 688282at2759; -.
DR PhylomeDB; P70236; -.
DR TreeFam; TF350701; -.
DR BRENDA; 2.7.12.2; 3474.
DR Reactome; R-MMU-168638; NOD1/2 Signaling Pathway.
DR Reactome; R-MMU-2559580; Oxidative Stress Induced Senescence.
DR Reactome; R-MMU-450302; activated TAK1 mediates p38 MAPK activation.
DR Reactome; R-MMU-6811555; PI5P Regulates TP53 Acetylation.
DR Reactome; R-MMU-9020702; Interleukin-1 signaling.
DR BioGRID-ORCS; 26399; 4 hits in 73 CRISPR screens.
DR ChiTaRS; Map2k6; mouse.
DR PRO; PR:P70236; -.
DR Proteomes; UP000000589; Chromosome 11.
DR RNAct; P70236; protein.
DR Bgee; ENSMUSG00000020623; Expressed in cortical plate and 209 other tissues.
DR ExpressionAtlas; P70236; baseline and differential.
DR Genevisible; P70236; MM.
DR GO; GO:0005856; C:cytoskeleton; IEA:UniProtKB-SubCell.
DR GO; GO:0005829; C:cytosol; ISO:MGI.
DR GO; GO:0005654; C:nucleoplasm; ISO:MGI.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0042802; F:identical protein binding; ISO:MGI.
DR GO; GO:0004708; F:MAP kinase kinase activity; IMP:MGI.
DR GO; GO:0019211; F:phosphatase activator activity; IMP:MGI.
DR GO; GO:0019901; F:protein kinase binding; ISO:MGI.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0043539; F:protein serine/threonine kinase activator activity; IMP:MGI.
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:0006915; P:apoptotic process; IEA:UniProtKB-KW.
DR GO; GO:0060348; P:bone development; IMP:MGI.
DR GO; GO:0060048; P:cardiac muscle contraction; IMP:MGI.
DR GO; GO:0072709; P:cellular response to sorbitol; IEA:Ensembl.
DR GO; GO:0000165; P:MAPK cascade; IMP:MGI.
DR GO; GO:0120163; P:negative regulation of cold-induced thermogenesis; IMP:YuBioLab.
DR GO; GO:0001649; P:osteoblast differentiation; IMP:MGI.
DR GO; GO:0022602; P:ovulation cycle process; IEA:Ensembl.
DR GO; GO:0043065; P:positive regulation of apoptotic process; ISO:MGI.
DR GO; GO:0043406; P:positive regulation of MAP kinase activity; IDA:MGI.
DR GO; GO:0043410; P:positive regulation of MAPK cascade; IDA:MGI.
DR GO; GO:0051770; P:positive regulation of nitric-oxide synthase biosynthetic process; ISO:MGI.
DR GO; GO:0032308; P:positive regulation of prostaglandin secretion; ISO:MGI.
DR GO; GO:0001934; P:positive regulation of protein phosphorylation; ISO:MGI.
DR GO; GO:0006468; P:protein phosphorylation; IDA:MGI.
DR GO; GO:0002931; P:response to ischemia; IEA:Ensembl.
DR GO; GO:0009410; P:response to xenobiotic stimulus; IEA:Ensembl.
DR GO; GO:0051403; P:stress-activated MAPK cascade; ISO:MGI.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
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 Apoptosis; ATP-binding; Cytoplasm; Cytoskeleton; Kinase;
KW Nucleotide-binding; Nucleus; Phosphoprotein; Reference proteome;
KW Serine/threonine-protein kinase; Stress response; Transcription;
KW Transcription regulation; Transferase; Tyrosine-protein kinase.
FT CHAIN 1..334
FT /note="Dual specificity mitogen-activated protein kinase
FT kinase 6"
FT /id="PRO_0000086387"
FT DOMAIN 53..314
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 1..34
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 4..19
FT /note="D domain"
FT /evidence="ECO:0000250"
FT REGION 311..334
FT /note="DVD domain"
FT /evidence="ECO:0000250"
FT COMPBIAS 20..34
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 179
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10027"
FT BINDING 59..67
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 82
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOD_RES 207
FT /note="Phosphoserine; by MAPK3"
FT /evidence="ECO:0000250|UniProtKB:P52564, ECO:0000305"
FT MOD_RES 211
FT /note="Phosphothreonine; by MAPK3"
FT /evidence="ECO:0000250|UniProtKB:P52564, ECO:0000305"
SQ SEQUENCE 334 AA; 37432 MW; 62CEF6C28AF50BAC CRC64;
MSQSKGKKRN PGLKIPKEAF EQPQTSSTPP RDLDSKACIS IGNQNFEVKA DDLEPIVELG
RGAYGVVEKM RHVPSGQIMA VKRIRATVNS QEQKRLLMDL DVSMRTVDCP FTVTFYGALF
REGDVWICME LMDTSLDKFY KQVIDKGQTI PEDILGKIAV SIVKALEHLH SKLSVIHRDV
KPSNVLINTL GQVKMCDFGI SGYLVDSVAK TIDAGCKPYM APERINPELN QKGYSVKSDI
WSLGITMIEL AILRFPYDSW GTPFQQLKQV VEEPSPQLPA DKFSADFVDF TSQCLKKNSK
ERPTYPELMQ HPFFTVHESK AADVASFVKL ILGD
