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P70236

- MP2K6_MOUSE

UniProt

P70236 - MP2K6_MOUSE

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Protein

Dual specificity mitogen-activated protein kinase kinase 6

Gene

Map2k6

Organism
Mus musculus (Mouse)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli

Functioni

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.7 Publications

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.

Enzyme regulationi

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/TAOK2.1 Publication

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Binding sitei82 – 821ATPPROSITE-ProRule annotation
Active sitei179 – 1791Proton acceptorPROSITE-ProRule annotation

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Nucleotide bindingi59 – 679ATPPROSITE-ProRule annotation

GO - Molecular functioni

  1. ATP binding Source: UniProtKB-KW
  2. MAP kinase kinase activity Source: Ensembl
  3. protein serine/threonine kinase activity Source: UniProtKB-KW
  4. protein tyrosine kinase activity Source: UniProtKB-KW

GO - Biological processi

  1. activation of MAPK activity Source: MGI
  2. apoptotic process Source: UniProtKB-KW
  3. cardiac muscle contraction Source: MGI
  4. cellular response to sorbitol Source: Ensembl
  5. MAPK cascade Source: MGI
  6. positive regulation of apoptotic process Source: Ensembl
  7. protein phosphorylation Source: MGI
  8. regulation of transcription, DNA-templated Source: UniProtKB-KW
  9. response to drug Source: Ensembl
  10. response to ischemia Source: Ensembl
  11. transcription, DNA-templated Source: UniProtKB-KW
Complete GO annotation...

Keywords - Molecular functioni

Kinase, Serine/threonine-protein kinase, Transferase, Tyrosine-protein kinase

Keywords - Biological processi

Apoptosis, Stress response, Transcription, Transcription regulation

Keywords - Ligandi

ATP-binding, Nucleotide-binding

Enzyme and pathway databases

BRENDAi2.7.12.2. 3474.
ReactomeiREACT_188970. Oxidative Stress Induced Senescence.
REACT_211125. NOD1/2 Signaling Pathway.
REACT_224208. Interleukin-1 signaling.

Names & Taxonomyi

Protein namesi
Recommended name:
Dual specificity mitogen-activated protein kinase kinase 6 (EC:2.7.12.2)
Short name:
MAP kinase kinase 6
Short name:
MAPKK 6
Alternative name(s):
MAPK/ERK kinase 6
Short name:
MEK 6
SAPKK3
Gene namesi
Name:Map2k6
Synonyms:Prkmk6, Sapkk3
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
ProteomesiUP000000589: Chromosome 11

Organism-specific databases

MGIiMGI:1346870. Map2k6.

Subcellular locationi

Nucleus By similarity. Cytoplasm By similarity. Cytoplasmcytoskeleton By similarity
Note: Binds to microtubules.By similarity

GO - Cellular componenti

  1. cytoskeleton Source: UniProtKB-KW
  2. cytosol Source: Reactome
  3. nucleus Source: UniProtKB-KW
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Cytoskeleton, Nucleus

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 334334Dual specificity mitogen-activated protein kinase kinase 6PRO_0000086387Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei207 – 2071Phosphoserine; by MAPK3Curated
Modified residuei211 – 2111Phosphothreonine; by MAPK3Curated

Post-translational modificationi

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.By similarity

Keywords - PTMi

Phosphoprotein

Proteomic databases

MaxQBiP70236.
PaxDbiP70236.
PRIDEiP70236.

PTM databases

PhosphoSiteiP70236.

Expressioni

Inductioni

MSAPK14 can negatively regulate the stability of the MAP2K6/MKK6 mRNA and thus control the steady-state concentration of one of its upstream activator.1 Publication

Gene expression databases

BgeeiP70236.
CleanExiMM_MAP2K6.
ExpressionAtlasiP70236. baseline and differential.
GenevestigatoriP70236.

Interactioni

Subunit structurei

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.By similarity

Protein-protein interaction databases

BioGridi204953. 2 interactions.
IntActiP70236. 1 interaction.
MINTiMINT-4102323.

Structurei

3D structure databases

ProteinModelPortaliP70236.
SMRiP70236. Positions 44-334.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini53 – 314262Protein kinasePROSITE-ProRule annotationAdd
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni4 – 1916D domainBy similarityAdd
BLAST
Regioni311 – 33424DVD domainBy similarityAdd
BLAST

Domaini

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).By similarity
The D domain (residues 4-19) contains a conserved docking site and is required for the binding to MAPK substrates.By similarity

Sequence similaritiesi

Contains 1 protein kinase domain.PROSITE-ProRule annotation

Phylogenomic databases

eggNOGiCOG0515.
HOGENOMiHOG000234206.
HOVERGENiHBG108518.
InParanoidiP70236.
KOiK04433.
OMAiDISMRAS.
OrthoDBiEOG7J9VPW.
PhylomeDBiP70236.
TreeFamiTF350701.

Family and domain databases

InterProiIPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR002290. Ser/Thr_dual-sp_kinase.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamiPF00069. Pkinase. 1 hit.
[Graphical view]
SMARTiSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF56112. SSF56112. 1 hit.
PROSITEiPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

P70236-1 [UniParc]FASTAAdd to Basket

« Hide

        10         20         30         40         50
MSQSKGKKRN PGLKIPKEAF EQPQTSSTPP RDLDSKACIS IGNQNFEVKA
60 70 80 90 100
DDLEPIVELG RGAYGVVEKM RHVPSGQIMA VKRIRATVNS QEQKRLLMDL
110 120 130 140 150
DVSMRTVDCP FTVTFYGALF REGDVWICME LMDTSLDKFY KQVIDKGQTI
160 170 180 190 200
PEDILGKIAV SIVKALEHLH SKLSVIHRDV KPSNVLINTL GQVKMCDFGI
210 220 230 240 250
SGYLVDSVAK TIDAGCKPYM APERINPELN QKGYSVKSDI WSLGITMIEL
260 270 280 290 300
AILRFPYDSW GTPFQQLKQV VEEPSPQLPA DKFSADFVDF TSQCLKKNSK
310 320 330
ERPTYPELMQ HPFFTVHESK AADVASFVKL ILGD
Length:334
Mass (Da):37,432
Last modified:February 1, 1997 - v1
Checksum:i62CEF6C28AF50BAC
GO

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
X97052 mRNA. Translation: CAA65764.1.
BC075652 mRNA. Translation: AAH75652.1.
CCDSiCCDS25592.1.
PIRiS71632.
RefSeqiNP_036073.1. NM_011943.2.
UniGeneiMm.14487.

Genome annotation databases

EnsembliENSMUST00000020949; ENSMUSP00000020949; ENSMUSG00000020623.
GeneIDi26399.
KEGGimmu:26399.
UCSCiuc007mdr.1. mouse.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
X97052 mRNA. Translation: CAA65764.1 .
BC075652 mRNA. Translation: AAH75652.1 .
CCDSi CCDS25592.1.
PIRi S71632.
RefSeqi NP_036073.1. NM_011943.2.
UniGenei Mm.14487.

3D structure databases

ProteinModelPortali P70236.
SMRi P70236. Positions 44-334.
ModBasei Search...
MobiDBi Search...

Protein-protein interaction databases

BioGridi 204953. 2 interactions.
IntActi P70236. 1 interaction.
MINTi MINT-4102323.

PTM databases

PhosphoSitei P70236.

Proteomic databases

MaxQBi P70236.
PaxDbi P70236.
PRIDEi P70236.

Protocols and materials databases

Structural Biology Knowledgebase Search...

Genome annotation databases

Ensembli ENSMUST00000020949 ; ENSMUSP00000020949 ; ENSMUSG00000020623 .
GeneIDi 26399.
KEGGi mmu:26399.
UCSCi uc007mdr.1. mouse.

Organism-specific databases

CTDi 5608.
MGIi MGI:1346870. Map2k6.

Phylogenomic databases

eggNOGi COG0515.
HOGENOMi HOG000234206.
HOVERGENi HBG108518.
InParanoidi P70236.
KOi K04433.
OMAi DISMRAS.
OrthoDBi EOG7J9VPW.
PhylomeDBi P70236.
TreeFami TF350701.

Enzyme and pathway databases

BRENDAi 2.7.12.2. 3474.
Reactomei REACT_188970. Oxidative Stress Induced Senescence.
REACT_211125. NOD1/2 Signaling Pathway.
REACT_224208. Interleukin-1 signaling.

Miscellaneous databases

NextBioi 304355.
PROi P70236.
SOURCEi Search...

Gene expression databases

Bgeei P70236.
CleanExi MM_MAP2K6.
ExpressionAtlasi P70236. baseline and differential.
Genevestigatori P70236.

Family and domain databases

InterProi IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR002290. Ser/Thr_dual-sp_kinase.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view ]
Pfami PF00069. Pkinase. 1 hit.
[Graphical view ]
SMARTi SM00220. S_TKc. 1 hit.
[Graphical view ]
SUPFAMi SSF56112. SSF56112. 1 hit.
PROSITEi PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view ]
ProtoNeti Search...

Publicationsi

« Hide 'large scale' publications
  1. "Purification and cDNA cloning of SAPKK3, the major activator of RK/p38 in stress- and cytokine-stimulated monocytes and epithelial cells."
    Cuenda A., Alonso G., Morrice N., Jones M., Meier R., Cohen P., Nebreda A.R.
    EMBO J. 15:4156-4164(1996) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA].
  2. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
    The MGC Project Team
    Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
    Strain: C57BL/6.
    Tissue: Eye.
  3. "Differential involvement of p38 mitogen-activated protein kinase kinases MKK3 and MKK6 in T-cell apoptosis."
    Tanaka N., Kamanaka M., Enslen H., Dong C., Wysk M., Davis R.J., Flavell R.A.
    EMBO Rep. 3:785-791(2002) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION IN REGULATION OF T-CELL APOPTOSIS.
  4. "Involvement of MKK6 in TCRalphabeta(int)CD69lo: a target population for apoptotic cell death in thymocytes."
    Suzuki H., Wu J., Hossain K., Ohhata T., Du J., Akhand A.A., Hayakawa A., Kimura H., Hagiwara M., Nakashima I.
    FASEB J. 17:1538-1540(2003) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION IN REGULATION OF T-CELL APOPTOSIS.
  5. Cited for: FUNCTION OF THE P38 MAP KINASE SIGNAL TRANSDUCTION PATHWAY.
  6. "Negative feedback regulation of MKK6 mRNA stability by p38alpha mitogen-activated protein kinase."
    Ambrosino C., Mace G., Galban S., Fritsch C., Vintersten K., Black E., Gorospe M., Nebreda A.R.
    Mol. Cell. Biol. 23:370-381(2003) [PubMed] [Europe PMC] [Abstract]
    Cited for: INDUCTION.
  7. "Activation of mitogen-activated protein kinase kinase (MKK) 3 and MKK6 by type I interferons."
    Li Y., Batra S., Sassano A., Majchrzak B., Levy D.E., Gaestel M., Fish E.N., Davis R.J., Platanias L.C.
    J. Biol. Chem. 280:10001-10010(2005) [PubMed] [Europe PMC] [Abstract]
    Cited for: ENZYME REGULATION, FUNCTION OF THE P38 MAP KINASE SIGNAL TRANSDUCTION PATHWAY.
  8. "Osteoclast differentiation requires TAK1 and MKK6 for NFATc1 induction and NF-kappaB transactivation by RANKL."
    Huang H., Ryu J., Ha J., Chang E.J., Kim H.J., Kim H.M., Kitamura T., Lee Z.H., Kim H.H.
    Cell Death Differ. 13:1879-1891(2006) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION OF THE P38 MAP KINASE SIGNAL TRANSDUCTION PATHWAY.
  9. "Constitutive activation of MKK6 in chondrocytes of transgenic mice inhibits proliferation and delays endochondral bone formation."
    Zhang R., Murakami S., Coustry F., Wang Y., de Crombrugghe B.
    Proc. Natl. Acad. Sci. U.S.A. 103:365-370(2006) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION OF THE P38 MAP KINASE SIGNAL TRANSDUCTION PATHWAY.
  10. Cited for: FUNCTION.
  11. Cited for: REVIEW ON ENZYME REGULATION, REVIEW ON FUNCTION.

Entry informationi

Entry nameiMP2K6_MOUSE
AccessioniPrimary (citable) accession number: P70236
Entry historyi
Integrated into UniProtKB/Swiss-Prot: July 15, 1998
Last sequence update: February 1, 1997
Last modified: October 29, 2014
This is version 120 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  3. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3