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P70236 (MP2K6_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 114. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (3) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Dual specificity mitogen-activated protein kinase kinase 6

Short name=MAP kinase kinase 6
Short name=MAPKK 6
EC=2.7.12.2
Alternative name(s):
MAPK/ERK kinase 6
Short name=MEK 6
SAPKK3
Gene names
Name:Map2k6
Synonyms:Prkmk6, Sapkk3
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

Sequence length334 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

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. Ref.3 Ref.4 Ref.5 Ref.7 Ref.8 Ref.9 Ref.10

Catalytic activity

ATP + a protein = ADP + a phosphoprotein.

Enzyme 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. Ref.7

Subunit structure

Dimer By similarity. Interacts (via its D domain) with its substrates MAPK11, MAPK12, MAPK13 and MAPK14 By similarity. 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 By similarity. Interacts with DCTN1 By similarity. Interacts with EIF2AK2/PKR By similarity.

Subcellular location

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

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. Ref.6 Ref.7

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.

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

Post-translational modification

Weakly autophosphorylated By similarity. 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.

Sequence similarities

Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase subfamily.

Contains 1 protein kinase domain.

Ontologies

Keywords
   Biological processApoptosis
Stress response
Transcription
Transcription regulation
   Cellular componentCytoplasm
Cytoskeleton
Nucleus
   LigandATP-binding
Nucleotide-binding
   Molecular functionKinase
Serine/threonine-protein kinase
Transferase
Tyrosine-protein kinase
   PTMPhosphoprotein
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processMAPK cascade

Inferred from physical interaction PubMed 12556533. Source: MGI

activation of MAPK activity

Inferred from direct assay PubMed 14744933PubMed 15767678. Source: MGI

apoptotic process

Inferred from electronic annotation. Source: UniProtKB-KW

cardiac muscle contraction

Inferred from mutant phenotype PubMed 11593045. Source: MGI

cellular response to sorbitol

Inferred from electronic annotation. Source: Ensembl

positive regulation of apoptotic process

Inferred from electronic annotation. Source: Ensembl

protein phosphorylation

Inferred from direct assay PubMed 12213961PubMed 14744933. Source: MGI

regulation of transcription, DNA-templated

Inferred from electronic annotation. Source: UniProtKB-KW

response to drug

Inferred from electronic annotation. Source: Ensembl

response to ischemia

Inferred from electronic annotation. Source: Ensembl

transcription, DNA-templated

Inferred from electronic annotation. Source: UniProtKB-KW

   Cellular_componentcytoplasm

Inferred from Biological aspect of Ancestor. Source: RefGenome

cytoskeleton

Inferred from electronic annotation. Source: UniProtKB-SubCell

cytosol

Traceable author statement. Source: Reactome

nucleus

Inferred from electronic annotation. Source: UniProtKB-SubCell

   Molecular_functionATP binding

Inferred from electronic annotation. Source: UniProtKB-KW

MAP kinase kinase activity

Inferred from Biological aspect of Ancestor. Source: RefGenome

protein tyrosine kinase activity

Inferred from electronic annotation. Source: UniProtKB-KW

receptor signaling protein serine/threonine kinase activity

Inferred from Biological aspect of Ancestor. Source: RefGenome

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 334334Dual specificity mitogen-activated protein kinase kinase 6
PRO_0000086387

Regions

Domain53 – 314262Protein kinase
Nucleotide binding59 – 679ATP By similarity
Region4 – 1916D domain By similarity
Region311 – 33424DVD domain By similarity

Sites

Active site1791Proton acceptor By similarity
Binding site821ATP By similarity

Amino acid modifications

Modified residue2071Phosphoserine; by MAPK3 Probable
Modified residue2111Phosphothreonine; by MAPK3 Probable

Sequences

Sequence LengthMass (Da)Tools
P70236 [UniParc].

Last modified February 1, 1997. Version 1.
Checksum: 62CEF6C28AF50BAC

FASTA33437,432
        10         20         30         40         50         60 
MSQSKGKKRN PGLKIPKEAF EQPQTSSTPP RDLDSKACIS IGNQNFEVKA DDLEPIVELG 

        70         80         90        100        110        120 
RGAYGVVEKM RHVPSGQIMA VKRIRATVNS QEQKRLLMDL DVSMRTVDCP FTVTFYGALF 

       130        140        150        160        170        180 
REGDVWICME LMDTSLDKFY KQVIDKGQTI PEDILGKIAV SIVKALEHLH SKLSVIHRDV 

       190        200        210        220        230        240 
KPSNVLINTL GQVKMCDFGI SGYLVDSVAK TIDAGCKPYM APERINPELN QKGYSVKSDI 

       250        260        270        280        290        300 
WSLGITMIEL AILRFPYDSW GTPFQQLKQV VEEPSPQLPA DKFSADFVDF TSQCLKKNSK 

       310        320        330 
ERPTYPELMQ HPFFTVHESK AADVASFVKL ILGD 

« Hide

References

« Hide 'large scale' references
[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]"Mechanism of p38 MAP kinase activation in vivo."
Brancho D., Tanaka N., Jaeschke A., Ventura J.J., Kelkar N., Tanaka Y., Kyuuma M., Takeshita T., Flavell R.A., Davis R.J.
Genes Dev. 17:1969-1978(2003) [PubMed] [Europe PMC] [Abstract]
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]"Differential activation of p38MAPK isoforms by MKK6 and MKK3."
Remy G., Risco A.M., Inesta-Vaquera F.A., Gonzalez-Teran B., Sabio G., Davis R.J., Cuenda A.
Cell. Signal. 22:660-667(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[11]"Signaling by dual specificity kinases."
Dhanasekaran N., Premkumar Reddy E.
Oncogene 17:1447-1455(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW ON ENZYME REGULATION, REVIEW ON FUNCTION.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
X97052 mRNA. Translation: CAA65764.1.
BC075652 mRNA. Translation: AAH75652.1.
PIRS71632.
RefSeqNP_036073.1. NM_011943.2.
UniGeneMm.14487.

3D structure databases

ProteinModelPortalP70236.
SMRP70236. Positions 44-334.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid204953. 2 interactions.
IntActP70236. 1 interaction.
MINTMINT-4102323.

PTM databases

PhosphoSiteP70236.

Proteomic databases

PaxDbP70236.
PRIDEP70236.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000020949; ENSMUSP00000020949; ENSMUSG00000020623.
GeneID26399.
KEGGmmu:26399.
UCSCuc007mdr.1. mouse.

Organism-specific databases

CTD5608.
MGIMGI:1346870. Map2k6.

Phylogenomic databases

eggNOGCOG0515.
HOGENOMHOG000234206.
HOVERGENHBG108518.
InParanoidP70236.
KOK04433.
OMADISMRAS.
OrthoDBEOG7J9VPW.
PhylomeDBP70236.
TreeFamTF350701.

Enzyme and pathway databases

BRENDA2.7.12.2. 3474.
ReactomeREACT_188576. Developmental Biology.

Gene expression databases

ArrayExpressP70236.
BgeeP70236.
CleanExMM_MAP2K6.
GenevestigatorP70236.

Family and domain databases

InterProIPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR002290. Ser/Thr_dual-sp_kinase_dom.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamPF00069. Pkinase. 1 hit.
[Graphical view]
SMARTSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMSSF56112. SSF56112. 1 hit.
PROSITEPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

NextBio304355.
PROP70236.
SOURCESearch...

Entry information

Entry nameMP2K6_MOUSE
AccessionPrimary (citable) accession number: P70236
Entry history
Integrated into UniProtKB/Swiss-Prot: July 15, 1998
Last sequence update: February 1, 1997
Last modified: April 16, 2014
This is version 114 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

Human and mouse protein kinases

Human and mouse protein kinases: classification and index

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot