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 04-NOV-2026, entry version 195. 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=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + CC H(+); 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=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + CC ADP + H(+); Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060, Rhea:RHEA- CC COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, ChEBI:CHEBI:30616, CC ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; EC=2.7.12.2; CC -!- CATALYTIC ACTIVITY: CC Reaction=L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + CC ADP + H(+); Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA- CC COMP:20101, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858, CC ChEBI:CHEBI:61978, 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|UniProtKB:P52564}. CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000250|UniProtKB:P52564}. Cytoplasm CC {ECO:0000250|UniProtKB:P52564}. Cytoplasm, cytoskeleton CC {ECO:0000250|UniProtKB:P52564}. Note=Binds to microtubules. CC {ECO:0000250|UniProtKB:P52564}. 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|UniProtKB:P52564}. CC -!- PTM: In response to genotoxic stress, MAP3K-phosphorylated MAP2K6 is CC ubiquitinated and degraded by the SCF(FBXO31) complex. CC {ECO:0000250|UniProtKB:P52564}. CC -!- SIMILARITY: Belongs to the protein kinase superfamily. STE Ser/Thr CC protein kinase family. MAP kinase kinase subfamily. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- 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_011943.3. DR AlphaFoldDB; P70236; -. DR SMR; P70236; -. DR BioGRID; 204953; 17. DR FunCoup; P70236; 2788. DR STRING; 10090.ENSMUSP00000020949; -. DR GlyGen; P70236; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; P70236; -. DR PhosphoSitePlus; P70236; -. DR jPOST; P70236; -. DR PaxDb; 10090-ENSMUSP00000020949; -. DR PeptideAtlas; P70236; -. DR ProteomicsDB; 252602; -. DR Pumba; P70236; -. DR Antibodypedia; 3570; 994 antibodies from 45 providers. DR DNASU; 26399; -. DR Ensembl; ENSMPUT00000014439; ENSMPUP00000014211; ENSMPUG00000014320. DR Ensembl; ENSMUST00000020949.12; ENSMUSP00000020949.6; ENSMUSG00000020623.12. DR GeneID; 26399; -. DR KEGG; mmu:26399; -. DR UCSC; uc007mdr.1; mouse. DR AGR; MGI:1346870; -. DR CTD; 5608; -. DR MGI; MGI:1346870; Map2k6. DR VEuPathDB; HostDB:ENSMUSG00000020623; -. DR eggNOG; KOG0984; Eukaryota. DR GeneTree; ENSGT00940000157836; -. DR InParanoid; P70236; -. DR OMA; AAMCKQV; -. DR OrthoDB; 10252354at2759; -. DR PhylomeDB; P70236; -. 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 Reactome; R-MMU-9833482; PKR-mediated signaling. DR BioGRID-ORCS; 26399; 4 hits in 78 CRISPR screens. DR PRO; PR:P70236; -. DR Proteomes; UP000000589; Chromosome 11. DR RNAct; P70236; protein. DR Bgee; ENSMUSG00000020623; Expressed in cortical plate and 212 other cell types or tissues. DR ExpressionAtlas; P70236; baseline and differential. DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB. DR GO; GO:0005856; C:cytoskeleton; IEA:UniProtKB-SubCell. DR GO; GO:0005829; C:cytosol; ISO:GO_Central. DR GO; GO:0005654; C:nucleoplasm; ISO:GO_Central. DR GO; GO:0005634; C:nucleus; ISS:UniProtKB. DR GO; GO:0005524; F:ATP binding; IEA:InterPro. DR GO; GO:0042802; F:identical protein binding; ISO:GO_Central. DR GO; GO:0004708; F:MAP kinase kinase activity; IMP:MGI. DR GO; GO:0019901; F:protein kinase binding; ISO:GO_Central. DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA. DR GO; GO:0004713; F:protein tyrosine kinase activity; IEA:RHEA. DR GO; GO:0060348; P:bone development; IMP:MGI. DR GO; GO:0060048; P:cardiac muscle contraction; IMP:MGI. DR GO; GO:0071493; P:cellular response to UV-B; ISO:GO_Central. 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:1904784; P:NLRP1 inflammasome complex assembly; ISO:GO_Central. DR GO; GO:0001649; P:osteoblast differentiation; IMP:MGI. DR GO; GO:0038066; P:p38MAPK cascade; ISO:GO_Central. DR GO; GO:0043065; P:positive regulation of apoptotic process; ISO:GO_Central. 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:0032308; P:positive regulation of prostaglandin secretion; ISO:GO_Central. DR GO; GO:0001934; P:positive regulation of protein phosphorylation; ISO:GO_Central. DR GO; GO:0051604; P:protein maturation; ISO:GO_Central. DR GO; GO:0006468; P:protein phosphorylation; IDA:MGI. DR GO; GO:0070269; P:pyroptotic inflammatory response; ISO:GO_Central. DR GO; GO:0051403; P:stress-activated MAPK cascade; ISO:GO_Central. DR GO; GO:0031098; P:stress-activated protein kinase signaling cascade; ISO:GO_Central. DR CDD; cd06617; PKc_MKK3_6; 1. DR FunFam; 3.30.200.20:FF:000040; Dual specificity mitogen-activated protein kinase kinase; 1. DR FunFam; 1.10.510.10:FF:000158; Dual specificity mitogen-activated protein kinase kinase 6; 1. DR Gene3D; 3.30.200.20; Phosphorylase Kinase, domain 1; 1. DR Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1. 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 PANTHER; PTHR48013; DUAL SPECIFICITY MITOGEN-ACTIVATED PROTEIN KINASE KINASE 5-RELATED; 1. DR PANTHER; PTHR48013:SF12; DUAL SPECIFICITY MITOGEN-ACTIVATED PROTEIN KINASE KINASE 6; 1. DR Pfam; PF00069; Pkinase; 1. DR PIRSF; PIRSF000654; Integrin-linked_kinase; 1. DR SMART; SM00220; S_TKc; 1. DR SUPFAM; SSF56112; Protein kinase-like (PK-like); 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; KW Ubl conjugation. 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 1..11 FT /note="Basic 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" FT MOD_RES 211 FT /note="Phosphothreonine; by MAPK3" FT /evidence="ECO:0000250|UniProtKB:P52564" 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 //