UniProtKB - P52564 (MP2K6_HUMAN)
Dual specificity mitogen-activated protein kinase kinase 6
MAP2K6
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.
8 PublicationsCatalytic activityi
Activity regulationi
Sites
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Binding sitei | 82 | ATPPROSITE-ProRule annotation | 1 | |
Active sitei | 179 | Proton acceptorPROSITE-ProRule annotation | 1 |
Regions
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Nucleotide bindingi | 59 – 67 | ATPPROSITE-ProRule annotation | 9 |
GO - Molecular functioni
- ATP binding Source: UniProtKB-KW
- identical protein binding Source: IntAct
- MAP kinase kinase activity Source: UniProtKB
- phosphatase activator activity Source: Ensembl
- protein kinase binding Source: UniProtKB
- protein serine/threonine kinase activator activity Source: Ensembl
- protein serine/threonine kinase activity Source: Reactome
- protein serine kinase activity Source: RHEA
- protein tyrosine kinase activity Source: UniProtKB-KW
GO - Biological processi
- apoptotic process Source: UniProtKB-KW
- bone development Source: Ensembl
- cardiac muscle contraction Source: Ensembl
- cellular response to sorbitol Source: Ensembl
- cellular senescence Source: Reactome
- DNA damage induced protein phosphorylation Source: ProtInc
- MAPK cascade Source: GO_Central
- negative regulation of cold-induced thermogenesis Source: YuBioLab
- nucleotide-binding oligomerization domain containing signaling pathway Source: Reactome
- osteoblast differentiation Source: Ensembl
- ovulation cycle process Source: Ensembl
- positive regulation of apoptotic process Source: Ensembl
- positive regulation of MAP kinase activity Source: Ensembl
- positive regulation of nitric-oxide synthase biosynthetic process Source: Ensembl
- positive regulation of prostaglandin secretion Source: Ensembl
- regulation of cell cycle Source: ProtInc
- regulation of signal transduction by p53 class mediator Source: Reactome
- response to ischemia Source: Ensembl
- response to xenobiotic stimulus Source: Ensembl
- signal transduction Source: ProtInc
- stress-activated MAPK cascade Source: UniProtKB
Keywordsi
Molecular function | Kinase, Serine/threonine-protein kinase, Transferase, Tyrosine-protein kinase |
Biological process | Apoptosis, Stress response, Transcription, Transcription regulation |
Ligand | ATP-binding, Nucleotide-binding |
Enzyme and pathway databases
BRENDAi | 2.7.12.2, 2681 |
PathwayCommonsi | P52564 |
Reactomei | R-HSA-168638, NOD1/2 Signaling Pathway R-HSA-2559580, Oxidative Stress Induced Senescence R-HSA-450302, activated TAK1 mediates p38 MAPK activation R-HSA-5210891, Uptake and function of anthrax toxins [P52564-1] R-HSA-525793, Myogenesis R-HSA-6811555, PI5P Regulates TP53 Acetylation R-HSA-9020702, Interleukin-1 signaling |
SignaLinki | P52564 |
SIGNORi | P52564 |
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 Stress-activated protein kinase kinase 3 Short name: SAPK kinase 3 Short name: SAPKK-3 Short name: SAPKK3 |
Gene namesi | Name:MAP2K6 Synonyms:MEK6, MKK6, PRKMK6, SKK3 |
Organismi | Homo sapiens (Human) |
Taxonomic identifieri | 9606 [NCBI] |
Taxonomic lineagei | Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo |
Proteomesi |
|
Organism-specific databases
HGNCi | HGNC:6846, MAP2K6 |
MIMi | 601254, gene |
neXtProti | NX_P52564 |
VEuPathDBi | HostDB:ENSG00000108984 |
Subcellular locationi
Nucleus
- Nucleus 1 Publication
Cytoplasm and Cytosol
- Cytoplasm 1 Publication
Cytoskeleton
- cytoskeleton 1 Publication
Note: Binds to microtubules.
Cytoskeleton
- cytoskeleton Source: UniProtKB-SubCell
Cytosol
- cytosol Source: HPA
Nucleus
- nucleoplasm Source: HPA
Keywords - Cellular componenti
Cytoplasm, Cytoskeleton, NucleusPathology & Biotechi
Mutagenesis
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Mutagenesisi | 207 | S → A: Inactivation. | 1 | |
Mutagenesisi | 207 | S → E: Constitutive activation according to PubMed:8622669, but not to PubMed:8621675. | 1 | |
Mutagenesisi | 211 | T → A: Inactivation. | 1 | |
Mutagenesisi | 211 | T → E: Constitutive activation according to PubMed:8622669, but not to PubMed:8621675. | 1 |
Organism-specific databases
DisGeNETi | 5608 |
OpenTargetsi | ENSG00000108984 |
PharmGKBi | PA30591 |
Miscellaneous databases
Pharosi | P52564, Tchem |
Chemistry databases
ChEMBLi | CHEMBL2171 |
DrugBanki | DB12010, Fostamatinib |
DrugCentrali | P52564 |
GuidetoPHARMACOLOGYi | 2067 |
Genetic variation databases
BioMutai | MAP2K6 |
DMDMi | 1709088 |
PTM / Processingi
Molecule processing
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
ChainiPRO_0000086386 | 1 – 334 | Dual specificity mitogen-activated protein kinase kinase 6Add BLAST | 334 |
Amino acid modifications
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Modified residuei | 207 | (Microbial infection) O-acetylserine; by Yersinia YopJ; alternate2 Publications | 1 | |
Modified residuei | 207 | Phosphoserine; by MAP3K; alternate1 Publication | 1 | |
Modified residuei | 211 | (Microbial infection) O-acetylthreonine; by Yersinia YopJ; alternate2 Publications | 1 | |
Modified residuei | 211 | Phosphothreonine; by MAP3K; alternate1 Publication | 1 |
Post-translational modificationi
Sites
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Sitei | 14 – 15 | Cleavage; by anthrax lethal factor | 2 |
Keywords - PTMi
Acetylation, PhosphoproteinProteomic databases
CPTACi | CPTAC-820 CPTAC-821 |
EPDi | P52564 |
jPOSTi | P52564 |
MassIVEi | P52564 |
MaxQBi | P52564 |
PaxDbi | P52564 |
PeptideAtlasi | P52564 |
PRIDEi | P52564 |
ProteomicsDBi | 56487 [P52564-1] 56488 [P52564-2] |
PTM databases
GlyGeni | P52564, 1 site, 1 O-linked glycan (1 site) |
iPTMneti | P52564 |
MetOSitei | P52564 |
PhosphoSitePlusi | P52564 |
Expressioni
Tissue specificityi
Inductioni
Gene expression databases
Bgeei | ENSG00000108984, Expressed in quadriceps femoris and 219 other tissues |
ExpressionAtlasi | P52564, baseline and differential |
Genevisiblei | P52564, HS |
Organism-specific databases
HPAi | ENSG00000108984, Tissue enhanced (skeletal) |
Interactioni
Subunit structurei
Dimer.
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.
Interacts with EIF2AK2/PKR.
By similarity4 Publications(Microbial infection) Interacts with Yersinia YopJ.
1 PublicationBinary interactionsi
P52564
With | #Exp. | IntAct |
---|---|---|
LRRK2 [Q5S007] | 4 | EBI-448135,EBI-5323863 |
NFE2L2 [Q16236] | 5 | EBI-448135,EBI-2007911 |
PICK1 [Q9NRD5] | 3 | EBI-448135,EBI-79165 |
WFS1 [O76024] | 3 | EBI-448135,EBI-720609 |
MAP2K6 - isoform 1 [P52564-1]
With | #Exp. | IntAct |
---|---|---|
itself | 3 | EBI-15750978,EBI-15750978 |
GO - Molecular functioni
- identical protein binding Source: IntAct
- protein kinase binding Source: UniProtKB
Protein-protein interaction databases
BioGRIDi | 111594, 50 interactors |
DIPi | DIP-31346N |
ELMi | P52564 |
IntActi | P52564, 15 interactors |
MINTi | P52564 |
STRINGi | 9606.ENSP00000468348 |
Chemistry databases
BindingDBi | P52564 |
Miscellaneous databases
RNActi | P52564, protein |
Structurei
Secondary structure
3D structure databases
SMRi | P52564 |
ModBasei | Search... |
PDBe-KBi | Search... |
Miscellaneous databases
EvolutionaryTracei | P52564 |
Family & Domainsi
Domains and Repeats
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Domaini | 53 – 314 | Protein kinasePROSITE-ProRule annotationAdd BLAST | 262 |
Region
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Regioni | 1 – 34 | DisorderedSequence analysisAdd BLAST | 34 | |
Regioni | 4 – 19 | D domainBy similarityAdd BLAST | 16 | |
Regioni | 311 – 334 | DVD domainAdd BLAST | 24 |
Compositional bias
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Compositional biasi | 20 – 34 | Polar residuesSequence analysisAdd BLAST | 15 |
Domaini
Sequence similaritiesi
Phylogenomic databases
eggNOGi | KOG0984, Eukaryota |
GeneTreei | ENSGT00940000157836 |
HOGENOMi | CLU_000288_63_23_1 |
InParanoidi | P52564 |
OMAi | YPKVFRH |
PhylomeDBi | P52564 |
Family and domain databases
DisProti | DP01342 |
IDEALi | IID00455 |
InterProi | View protein in InterPro IPR011009, Kinase-like_dom_sf IPR000719, Prot_kinase_dom IPR017441, Protein_kinase_ATP_BS IPR008271, Ser/Thr_kinase_AS |
Pfami | View protein in Pfam PF00069, Pkinase, 1 hit |
SMARTi | View protein in SMART SM00220, S_TKc, 1 hit |
SUPFAMi | SSF56112, SSF56112, 1 hit |
PROSITEi | View protein in PROSITE PS00107, PROTEIN_KINASE_ATP, 1 hit PS50011, PROTEIN_KINASE_DOM, 1 hit PS00108, PROTEIN_KINASE_ST, 1 hit |
s (2+)i Sequence
Sequence statusi: Complete.
This entry describes 2 produced by isoformsialternative splicing. AlignAdd to basketThis entry has 2 described isoforms and 3 potential isoforms that are computationally mapped.Show allAlign All
This isoform has been chosen as the sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry. canonicali
10 20 30 40 50
MSQSKGKKRN PGLKIPKEAF EQPQTSSTPP RDLDSKACIS IGNQNFEVKA
60 70 80 90 100
DDLEPIMELG RGAYGVVEKM RHVPSGQIMA VKRIRATVNS QEQKRLLMDL
110 120 130 140 150
DISMRTVDCP FTVTFYGALF REGDVWICME LMDTSLDKFY KQVIDKGQTI
160 170 180 190 200
PEDILGKIAV SIVKALEHLH SKLSVIHRDV KPSNVLINAL GQVKMCDFGI
210 220 230 240 250
SGYLVDSVAK TIDAGCKPYM APERINPELN QKGYSVKSDI WSLGITMIEL
260 270 280 290 300
AILRFPYDSW GTPFQQLKQV VEEPSPQLPA DKFSAEFVDF TSQCLKKNSK
310 320 330
ERPTYPELMQ HPFFTLHESK GTDVASFVKL ILGD
Computationally mapped potential isoform sequencesi
There are 3 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basketK7EIW3 | K7EIW3_HUMAN | Dual-specificity mitogen-activated ... | MAP2K6 | 128 | Annotation score: | ||
K7ELM6 | K7ELM6_HUMAN | Dual-specificity mitogen-activated ... | MAP2K6 | 84 | Annotation score: | ||
A0A0A0MRF7 | A0A0A0MRF7_HUMAN | Dual-specificity mitogen-activated ... | MAP2K6 | 68 | Annotation score: |
Experimental Info
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Sequence conflicti | 125 | V → M in AAB03705 (PubMed:8621675).Curated | 1 | |
Sequence conflicti | 125 | V → M in AAB03708 (PubMed:8621675).Curated | 1 |
Alternative sequence
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Alternative sequenceiVSP_004882 | 1 – 56 | Missing in isoform 2. 1 PublicationAdd BLAST | 56 |
Sequence databases
Select the link destinations: EMBLi GenBanki DDBJi Links Updated | U39657 mRNA Translation: AAC50389.1 U39656 mRNA Translation: AAC50388.1 U49732 mRNA Translation: AAB05035.1 U39065 mRNA Translation: AAB03705.1 U39064 mRNA Translation: AAB03708.1 D87905 mRNA Translation: BAA13496.1 X96757 mRNA Translation: CAA65532.1 BC012009 mRNA Translation: AAH12009.1 |
CCDSi | CCDS11686.1 [P52564-1] CCDS82194.1 [P52564-2] |
PIRi | S71631 |
RefSeqi | NP_002749.2, NM_002758.3 [P52564-1] |
Genome annotation databases
Ensembli | ENST00000589647; ENSP00000467213; ENSG00000108984 [P52564-2] ENST00000590474; ENSP00000468348; ENSG00000108984 ENST00000613873; ENSP00000477701; ENSG00000108984 [P52564-2] |
GeneIDi | 5608 |
KEGGi | hsa:5608 |
MANE-Selecti | ENST00000590474.7; ENSP00000468348.1; NM_002758.4; NP_002749.2 |
UCSCi | uc002jij.4, human [P52564-1] |
Keywords - Coding sequence diversityi
Alternative splicingSimilar proteinsi
Cross-referencesi
Sequence databases
Select the link destinations: EMBLi GenBanki DDBJi Links Updated | U39657 mRNA Translation: AAC50389.1 U39656 mRNA Translation: AAC50388.1 U49732 mRNA Translation: AAB05035.1 U39065 mRNA Translation: AAB03705.1 U39064 mRNA Translation: AAB03708.1 D87905 mRNA Translation: BAA13496.1 X96757 mRNA Translation: CAA65532.1 BC012009 mRNA Translation: AAH12009.1 |
CCDSi | CCDS11686.1 [P52564-1] CCDS82194.1 [P52564-2] |
PIRi | S71631 |
RefSeqi | NP_002749.2, NM_002758.3 [P52564-1] |
3D structure databases
Select the link destinations: PDBei RCSB PDBi PDBji Links Updated | PDB entry | Method | Resolution (Å) | Chain | Positions | PDBsum |
2Y8O | X-ray | 1.95 | B | 4-17 | [»] | |
3ENM | X-ray | 2.35 | A/B/C/D | 45-332 | [»] | |
3FME | X-ray | 2.26 | A | 47-334 | [»] | |
3VN9 | X-ray | 2.60 | A | 1-334 | [»] | |
5ETF | X-ray | 2.40 | B | 4-17 | [»] | |
SMRi | P52564 | |||||
ModBasei | Search... | |||||
PDBe-KBi | Search... |
Protein-protein interaction databases
BioGRIDi | 111594, 50 interactors |
DIPi | DIP-31346N |
ELMi | P52564 |
IntActi | P52564, 15 interactors |
MINTi | P52564 |
STRINGi | 9606.ENSP00000468348 |
Chemistry databases
BindingDBi | P52564 |
ChEMBLi | CHEMBL2171 |
DrugBanki | DB12010, Fostamatinib |
DrugCentrali | P52564 |
GuidetoPHARMACOLOGYi | 2067 |
PTM databases
GlyGeni | P52564, 1 site, 1 O-linked glycan (1 site) |
iPTMneti | P52564 |
MetOSitei | P52564 |
PhosphoSitePlusi | P52564 |
Genetic variation databases
BioMutai | MAP2K6 |
DMDMi | 1709088 |
Proteomic databases
CPTACi | CPTAC-820 CPTAC-821 |
EPDi | P52564 |
jPOSTi | P52564 |
MassIVEi | P52564 |
MaxQBi | P52564 |
PaxDbi | P52564 |
PeptideAtlasi | P52564 |
PRIDEi | P52564 |
ProteomicsDBi | 56487 [P52564-1] 56488 [P52564-2] |
Protocols and materials databases
Antibodypediai | 3570, 874 antibodies from 41 providers |
DNASUi | 5608 |
Genome annotation databases
Ensembli | ENST00000589647; ENSP00000467213; ENSG00000108984 [P52564-2] ENST00000590474; ENSP00000468348; ENSG00000108984 ENST00000613873; ENSP00000477701; ENSG00000108984 [P52564-2] |
GeneIDi | 5608 |
KEGGi | hsa:5608 |
MANE-Selecti | ENST00000590474.7; ENSP00000468348.1; NM_002758.4; NP_002749.2 |
UCSCi | uc002jij.4, human [P52564-1] |
Organism-specific databases
CTDi | 5608 |
DisGeNETi | 5608 |
GeneCardsi | MAP2K6 |
HGNCi | HGNC:6846, MAP2K6 |
HPAi | ENSG00000108984, Tissue enhanced (skeletal) |
MIMi | 601254, gene |
neXtProti | NX_P52564 |
OpenTargetsi | ENSG00000108984 |
PharmGKBi | PA30591 |
VEuPathDBi | HostDB:ENSG00000108984 |
GenAtlasi | Search... |
Phylogenomic databases
eggNOGi | KOG0984, Eukaryota |
GeneTreei | ENSGT00940000157836 |
HOGENOMi | CLU_000288_63_23_1 |
InParanoidi | P52564 |
OMAi | YPKVFRH |
PhylomeDBi | P52564 |
Enzyme and pathway databases
BRENDAi | 2.7.12.2, 2681 |
PathwayCommonsi | P52564 |
Reactomei | R-HSA-168638, NOD1/2 Signaling Pathway R-HSA-2559580, Oxidative Stress Induced Senescence R-HSA-450302, activated TAK1 mediates p38 MAPK activation R-HSA-5210891, Uptake and function of anthrax toxins [P52564-1] R-HSA-525793, Myogenesis R-HSA-6811555, PI5P Regulates TP53 Acetylation R-HSA-9020702, Interleukin-1 signaling |
SignaLinki | P52564 |
SIGNORi | P52564 |
Miscellaneous databases
BioGRID-ORCSi | 5608, 9 hits in 1074 CRISPR screens |
ChiTaRSi | MAP2K6, human |
EvolutionaryTracei | P52564 |
GeneWikii | MAP2K6 |
GenomeRNAii | 5608 |
Pharosi | P52564, Tchem |
PROi | PR:P52564 |
RNActi | P52564, protein |
SOURCEi | Search... |
Gene expression databases
Bgeei | ENSG00000108984, Expressed in quadriceps femoris and 219 other tissues |
ExpressionAtlasi | P52564, baseline and differential |
Genevisiblei | P52564, HS |
Family and domain databases
DisProti | DP01342 |
IDEALi | IID00455 |
InterProi | View protein in InterPro IPR011009, Kinase-like_dom_sf IPR000719, Prot_kinase_dom IPR017441, Protein_kinase_ATP_BS IPR008271, Ser/Thr_kinase_AS |
Pfami | View protein in Pfam PF00069, Pkinase, 1 hit |
SMARTi | View protein in SMART SM00220, S_TKc, 1 hit |
SUPFAMi | SSF56112, SSF56112, 1 hit |
PROSITEi | View protein in PROSITE PS00107, PROTEIN_KINASE_ATP, 1 hit PS50011, PROTEIN_KINASE_DOM, 1 hit PS00108, PROTEIN_KINASE_ST, 1 hit |
MobiDBi | Search... |
Entry informationi
Entry namei | MP2K6_HUMAN | |
Accessioni | P52564Primary (citable) accession number: P52564 | |
Entry historyi | Integrated into UniProtKB/Swiss-Prot: | October 1, 1996 |
Last sequence update: | October 1, 1996 | |
Last modified: | February 23, 2022 | |
This is version 207 of the entry and version 1 of the sequence. See complete history. | ||
Entry statusi | Reviewed (UniProtKB/Swiss-Prot) | |
Annotation program | Chordata Protein Annotation Program | |
Disclaimer | Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care. |
Miscellaneousi
Keywords - Technical termi
3D-structure, Reference proteomeDocuments
- Human and mouse protein kinases
Human and mouse protein kinases: classification and index - Human chromosome 17
Human chromosome 17: entries, gene names and cross-references to MIM - MIM cross-references
Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot - PDB cross-references
Index of Protein Data Bank (PDB) cross-references - SIMILARITY comments
Index of protein domains and families