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Dual specificity mitogen-activated protein kinase kinase 6 (MAP kinase kinase 6) (MAPKK 6) (EC 2.7.12.2) (MAPK/ERK kinase 6) (MEK 6) (SAPKK3)

 MP2K6_MOUSE             Reviewed;         334 AA.
P70236;
15-JUL-1998, integrated into UniProtKB/Swiss-Prot.
01-FEB-1997, sequence version 1.
12-SEP-2018, entry version 154.
RecName: Full=Dual specificity mitogen-activated protein kinase kinase 6;
Short=MAP kinase kinase 6;
Short=MAPKK 6;
EC=2.7.12.2;
AltName: Full=MAPK/ERK kinase 6;
Short=MEK 6;
AltName: Full=SAPKK3;
Name=Map2k6; Synonyms=Prkmk6, Sapkk3;
Mus musculus (Mouse).
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha;
Muroidea; Muridae; Murinae; Mus; Mus.
NCBI_TaxID=10090;
[1]
NUCLEOTIDE SEQUENCE [MRNA].
PubMed=8861944;
Cuenda A., Alonso G., Morrice N., Jones M., Meier R., Cohen P.,
Nebreda A.R.;
"Purification and cDNA cloning of SAPKK3, the major activator of
RK/p38 in stress- and cytokine-stimulated monocytes and epithelial
cells.";
EMBO J. 15:4156-4164(1996).
[2]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
STRAIN=C57BL/6J; TISSUE=Eye;
PubMed=15489334; DOI=10.1101/gr.2596504;
The MGC Project Team;
"The status, quality, and expansion of the NIH full-length cDNA
project: the Mammalian Gene Collection (MGC).";
Genome Res. 14:2121-2127(2004).
[3]
FUNCTION IN REGULATION OF T-CELL APOPTOSIS.
PubMed=12151339; DOI=10.1093/embo-reports/kvf153;
Tanaka N., Kamanaka M., Enslen H., Dong C., Wysk M., Davis R.J.,
Flavell R.A.;
"Differential involvement of p38 mitogen-activated protein kinase
kinases MKK3 and MKK6 in T-cell apoptosis.";
EMBO Rep. 3:785-791(2002).
[4]
FUNCTION IN REGULATION OF T-CELL APOPTOSIS.
PubMed=12824301; DOI=10.1096/fj.02-0869fje;
Suzuki H., Wu J., Hossain K., Ohhata T., Du J., Akhand A.A.,
Hayakawa A., Kimura H., Hagiwara M., Nakashima I.;
"Involvement of MKK6 in TCRalphabeta(int)CD69lo: a target population
for apoptotic cell death in thymocytes.";
FASEB J. 17:1538-1540(2003).
[5]
FUNCTION OF THE P38 MAP KINASE SIGNAL TRANSDUCTION PATHWAY.
PubMed=12893778; DOI=10.1101/gad.1107303;
Brancho D., Tanaka N., Jaeschke A., Ventura J.J., Kelkar N.,
Tanaka Y., Kyuuma M., Takeshita T., Flavell R.A., Davis R.J.;
"Mechanism of p38 MAP kinase activation in vivo.";
Genes Dev. 17:1969-1978(2003).
[6]
INDUCTION.
PubMed=12482988; DOI=10.1128/MCB.23.1.370-381.2003;
Ambrosino C., Mace G., Galban S., Fritsch C., Vintersten K., Black E.,
Gorospe M., Nebreda A.R.;
"Negative feedback regulation of MKK6 mRNA stability by p38alpha
mitogen-activated protein kinase.";
Mol. Cell. Biol. 23:370-381(2003).
[7]
ACTIVITY REGULATION, AND FUNCTION OF THE P38 MAP KINASE SIGNAL
TRANSDUCTION PATHWAY.
PubMed=15644321; DOI=10.1074/jbc.M410972200;
Li Y., Batra S., Sassano A., Majchrzak B., Levy D.E., Gaestel M.,
Fish E.N., Davis R.J., Platanias L.C.;
"Activation of mitogen-activated protein kinase kinase (MKK) 3 and
MKK6 by type I interferons.";
J. Biol. Chem. 280:10001-10010(2005).
[8]
FUNCTION OF THE P38 MAP KINASE SIGNAL TRANSDUCTION PATHWAY.
PubMed=16498455; DOI=10.1038/sj.cdd.4401882;
Huang H., Ryu J., Ha J., Chang E.J., Kim H.J., Kim H.M., Kitamura T.,
Lee Z.H., Kim H.H.;
"Osteoclast differentiation requires TAK1 and MKK6 for NFATc1
induction and NF-kappaB transactivation by RANKL.";
Cell Death Differ. 13:1879-1891(2006).
[9]
FUNCTION OF THE P38 MAP KINASE SIGNAL TRANSDUCTION PATHWAY.
PubMed=16387856; DOI=10.1073/pnas.0507979103;
Zhang R., Murakami S., Coustry F., Wang Y., de Crombrugghe B.;
"Constitutive activation of MKK6 in chondrocytes of transgenic mice
inhibits proliferation and delays endochondral bone formation.";
Proc. Natl. Acad. Sci. U.S.A. 103:365-370(2006).
[10]
IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
TISSUE=Brain, Heart, Lung, and Spleen;
PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
"A tissue-specific atlas of mouse protein phosphorylation and
expression.";
Cell 143:1174-1189(2010).
[11]
FUNCTION.
PubMed=20004242; DOI=10.1016/j.cellsig.2009.11.020;
Remy G., Risco A.M., Inesta-Vaquera F.A., Gonzalez-Teran B., Sabio G.,
Davis R.J., Cuenda A.;
"Differential activation of p38MAPK isoforms by MKK6 and MKK3.";
Cell. Signal. 22:660-667(2010).
[12]
REVIEW ON ACTIVITY REGULATION, AND REVIEW ON FUNCTION.
PubMed=9779990; DOI=10.1038/sj.onc.1202251;
Dhanasekaran N., Premkumar Reddy E.;
"Signaling by dual specificity kinases.";
Oncogene 17:1447-1455(1998).
-!- FUNCTION: Dual specificity protein kinase which acts as an
essential component of the MAP kinase signal transduction pathway.
With MAP3K3/MKK3, catalyzes the concomitant phosphorylation of a
threonine and a tyrosine residue in the MAP kinases p38 MAPK11,
MAPK12, MAPK13 and MAPK14 and plays an important role in the
regulation of cellular responses to cytokines and all kinds of
stresses. Especially, MAP2K3/MKK3 and MAP2K6/MKK6 are both
essential for the activation of MAPK11 and MAPK13 induced by
environmental stress, whereas MAP2K6/MKK6 is the major MAPK11
activator in response to TNF. MAP2K6/MKK6 also phosphorylates and
activates PAK6. The p38 MAP kinase signal transduction pathway
leads to direct activation of transcription factors. Nuclear
targets of p38 MAP kinase include the transcription factors ATF2
and ELK1. Within the p38 MAPK signal transduction pathway,
MAP3K6/MKK6 mediates phosphorylation of STAT4 through MAPK14
activation, and is therefore required for STAT4 activation and
STAT4-regulated gene expression in response to IL-12 stimulation.
The pathway is also crucial for IL-6-induced SOCS3 expression and
down-regulation of IL-6-mediated gene induction; and for IFNG-
dependent gene transcription. Has a role in osteoclast
differentiation through NF-kappa-B transactivation by TNFSF11, and
in endochondral ossification and since SOX9 is another likely
downstream target of the p38 MAPK pathway. MAP2K6/MKK6 mediates
apoptotic cell death in thymocytes. Acts also as a regulator for
melanocytes dendricity, through the modulation of Rho family
GTPases. {ECO:0000269|PubMed:12151339,
ECO:0000269|PubMed:12824301, ECO:0000269|PubMed:12893778,
ECO:0000269|PubMed:15644321, ECO:0000269|PubMed:16387856,
ECO:0000269|PubMed:16498455, ECO:0000269|PubMed:20004242}.
-!- CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein.
-!- ACTIVITY REGULATION: Activated by dual phosphorylation on Ser-207
and Thr-211 in response to a variety of cellular stresses,
including UV radiation, osmotic shock, hypoxia, inflammatory
cytokines, interferon gamma (IFNG), and less often by growth
factors. MAP2K6/MKK6 is activated by the majority of M3Ks, such as
MAP3K5/ASK1, MAP3K1/MEKK1, MAP3K2/MEKK2, MAP3K3/MEKK3,
MAP3K4/MEKK4, MAP3K7/TAK1, MAP3K11/MLK3 and MAP3K17/TAOK2.
{ECO:0000269|PubMed:15644321}.
-!- SUBUNIT: Dimer. Interacts (via its D domain) with its substrates
MAPK11, MAPK12, MAPK13 and MAPK14. Interacts (via its DVD domain)
with MAP3Ks activators like MAP3K5/ASK1, MAP3K1/MEKK1,
MAP3K2/MEKK2, MAP3K3/MEKK3, MAP3K4/MEKK4, MAP3K7/TAK1,
MAP3K11/MLK3 and MAP3K17/TAOK2. Interacts with DCTN1. Interacts
with EIF2AK2/PKR. {ECO:0000250}.
-!- SUBCELLULAR LOCATION: Nucleus {ECO:0000250}. Cytoplasm
{ECO:0000250}. Cytoplasm, cytoskeleton {ECO:0000250}. Note=Binds
to microtubules. {ECO:0000250}.
-!- INDUCTION: MSAPK14 can negatively regulate the stability of the
MAP2K6/MKK6 mRNA and thus control the steady-state concentration
of one of its upstream activator. {ECO:0000269|PubMed:12482988}.
-!- DOMAIN: The DVD domain (residues 311-334) contains a conserved
docking site and is found in the mammalian MAP kinase kinases
(MAP2Ks). The DVD sites bind to their specific upstream MAP kinase
kinase kinases (MAP3Ks) and are essential for activation (By
similarity). {ECO:0000250}.
-!- DOMAIN: The D domain (residues 4-19) contains a conserved docking
site and is required for the binding to MAPK substrates.
{ECO:0000250}.
-!- PTM: Weakly autophosphorylated. Phosphorylated at Ser-207 and Thr-
211 by the majority of M3Ks, such as MAP3K5/ASK1, MAP3K1/MEKK1,
MAP3K2/MEKK2, MAP3K3/MEKK3, MAP3K4/MEKK4, MAP3K7/TAK1,
MAP3K11/MLK3 and MAP3K17/TAOK2. {ECO:0000250}.
-!- SIMILARITY: Belongs to the protein kinase superfamily. STE Ser/Thr
protein kinase family. MAP kinase kinase subfamily. {ECO:0000305}.
-----------------------------------------------------------------------
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EMBL; X97052; CAA65764.1; -; mRNA.
EMBL; BC075652; AAH75652.1; -; mRNA.
CCDS; CCDS25592.1; -.
PIR; S71632; S71632.
RefSeq; NP_036073.1; NM_011943.2.
UniGene; Mm.14487; -.
ProteinModelPortal; P70236; -.
SMR; P70236; -.
BioGrid; 204953; 3.
IntAct; P70236; 1.
MINT; P70236; -.
STRING; 10090.ENSMUSP00000020949; -.
iPTMnet; P70236; -.
PhosphoSitePlus; P70236; -.
EPD; P70236; -.
PaxDb; P70236; -.
PeptideAtlas; P70236; -.
PRIDE; P70236; -.
Ensembl; ENSMUST00000020949; ENSMUSP00000020949; ENSMUSG00000020623.
GeneID; 26399; -.
KEGG; mmu:26399; -.
UCSC; uc007mdr.1; mouse.
CTD; 5608; -.
MGI; MGI:1346870; Map2k6.
eggNOG; KOG0984; Eukaryota.
eggNOG; ENOG410XT3F; LUCA.
GeneTree; ENSGT00760000119199; -.
HOGENOM; HOG000234206; -.
HOVERGEN; HBG108518; -.
InParanoid; P70236; -.
KO; K04433; -.
OMA; WGTPFEQ; -.
OrthoDB; EOG091G0A9H; -.
PhylomeDB; P70236; -.
TreeFam; TF350701; -.
BRENDA; 2.7.12.2; 3474.
Reactome; R-MMU-168638; NOD1/2 Signaling Pathway.
Reactome; R-MMU-2559580; Oxidative Stress Induced Senescence.
Reactome; R-MMU-450302; activated TAK1 mediates p38 MAPK activation.
Reactome; R-MMU-6811555; PI5P Regulates TP53 Acetylation.
Reactome; R-MMU-9020702; Interleukin-1 signaling.
PRO; PR:P70236; -.
Proteomes; UP000000589; Chromosome 11.
Bgee; ENSMUSG00000020623; Expressed in 249 organ(s), highest expression level in cochlea.
CleanEx; MM_MAP2K6; -.
ExpressionAtlas; P70236; baseline and differential.
Genevisible; P70236; MM.
GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
GO; GO:0005856; C:cytoskeleton; IEA:UniProtKB-SubCell.
GO; GO:0005829; C:cytosol; ISO:MGI.
GO; GO:0005634; C:nucleus; ISO:MGI.
GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
GO; GO:0042802; F:identical protein binding; ISO:MGI.
GO; GO:0004708; F:MAP kinase kinase activity; ISO:MGI.
GO; GO:0019901; F:protein kinase binding; ISO:MGI.
GO; GO:0004674; F:protein serine/threonine kinase activity; IBA:GO_Central.
GO; GO:0004713; F:protein tyrosine kinase activity; IEA:UniProtKB-KW.
GO; GO:0000187; P:activation of MAPK activity; IDA:MGI.
GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
GO; GO:0060048; P:cardiac muscle contraction; IMP:MGI.
GO; GO:0072709; P:cellular response to sorbitol; IEA:Ensembl.
GO; GO:0000165; P:MAPK cascade; IPI:MGI.
GO; GO:0120163; P:negative regulation of cold-induced thermogenesis; IMP:YuBioLab.
GO; GO:0022602; P:ovulation cycle process; IEA:Ensembl.
GO; GO:0043065; P:positive regulation of apoptotic process; ISO:MGI.
GO; GO:0051770; P:positive regulation of nitric-oxide synthase biosynthetic process; ISO:MGI.
GO; GO:0032308; P:positive regulation of prostaglandin secretion; ISO:MGI.
GO; GO:0001934; P:positive regulation of protein phosphorylation; ISO:MGI.
GO; GO:0006468; P:protein phosphorylation; IDA:MGI.
GO; GO:0042981; P:regulation of apoptotic process; IBA:GO_Central.
GO; GO:0007346; P:regulation of mitotic cell cycle; IBA:GO_Central.
GO; GO:0006355; P:regulation of transcription, DNA-templated; IEA:UniProtKB-KW.
GO; GO:0042493; P:response to drug; IEA:Ensembl.
GO; GO:0002931; P:response to ischemia; IEA:Ensembl.
GO; GO:0031098; P:stress-activated protein kinase signaling cascade; IBA:GO_Central.
GO; GO:0006351; P:transcription, DNA-templated; IEA:UniProtKB-KW.
InterPro; IPR011009; Kinase-like_dom_sf.
InterPro; IPR000719; Prot_kinase_dom.
InterPro; IPR017441; Protein_kinase_ATP_BS.
InterPro; IPR008271; Ser/Thr_kinase_AS.
Pfam; PF00069; Pkinase; 1.
SMART; SM00220; S_TKc; 1.
SUPFAM; SSF56112; SSF56112; 1.
PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
1: Evidence at protein level;
Apoptosis; ATP-binding; Complete proteome; Cytoplasm; Cytoskeleton;
Kinase; Nucleotide-binding; Nucleus; Phosphoprotein;
Reference proteome; Serine/threonine-protein kinase; Stress response;
Transcription; Transcription regulation; Transferase;
Tyrosine-protein kinase.
CHAIN 1 334 Dual specificity mitogen-activated
protein kinase kinase 6.
/FTId=PRO_0000086387.
DOMAIN 53 314 Protein kinase. {ECO:0000255|PROSITE-
ProRule:PRU00159}.
NP_BIND 59 67 ATP. {ECO:0000255|PROSITE-
ProRule:PRU00159}.
REGION 4 19 D domain. {ECO:0000250}.
REGION 311 334 DVD domain. {ECO:0000250}.
ACT_SITE 179 179 Proton acceptor. {ECO:0000255|PROSITE-
ProRule:PRU00159, ECO:0000255|PROSITE-
ProRule:PRU10027}.
BINDING 82 82 ATP. {ECO:0000255|PROSITE-
ProRule:PRU00159}.
MOD_RES 207 207 Phosphoserine; by MAPK3.
{ECO:0000250|UniProtKB:P52564,
ECO:0000305}.
MOD_RES 211 211 Phosphothreonine; by MAPK3.
{ECO:0000250|UniProtKB:P52564,
ECO:0000305}.
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


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