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Protein

Dual specificity mitogen-activated protein kinase kinase 6

Gene

MAP2K6

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: 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.8 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/TAOK2.3 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei82ATPPROSITE-ProRule annotation1
Active sitei179Proton acceptorPROSITE-ProRule annotation1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi59 – 67ATPPROSITE-ProRule annotation9

GO - Molecular functioni

  • ATP binding Source: UniProtKB-KW
  • identical protein binding Source: IntAct
  • MAP kinase kinase activity Source: Reactome
  • protein kinase binding Source: UniProtKB
  • protein serine/threonine kinase activity Source: GO_Central
  • protein tyrosine kinase activity Source: UniProtKB-KW

GO - Biological processi

Keywordsi

Molecular functionKinase, Serine/threonine-protein kinase, Transferase, Tyrosine-protein kinase
Biological processApoptosis, Stress response, Transcription, Transcription regulation
LigandATP-binding, Nucleotide-binding

Enzyme and pathway databases

BRENDAi2.7.12.2. 2681.
ReactomeiR-HSA-168638. NOD1/2 Signaling Pathway.
R-HSA-2559580. Oxidative Stress Induced Senescence.
R-HSA-375170. CDO in myogenesis.
R-HSA-446652. Interleukin-1 family signaling.
R-HSA-450302. activated TAK1 mediates p38 MAPK activation.
R-HSA-5210891. Uptake and function of anthrax toxins.
R-HSA-6811555. PI5P Regulates TP53 Acetylation.
SignaLinkiP52564.
SIGNORiP52564.

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
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 17

Organism-specific databases

EuPathDBiHostDB:ENSG00000108984.13.
HGNCiHGNC:6846. MAP2K6.

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cytoplasm, Cytoskeleton, Nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi207S → A: Inactivation. 1
Mutagenesisi207S → E: Constitutive activation according to PubMed:8622669, but not to PubMed:8621675. 1
Mutagenesisi211T → A: Inactivation. 1
Mutagenesisi211T → E: Constitutive activation according to PubMed:8622669, but not to PubMed:8621675. 1

Organism-specific databases

DisGeNETi5608.
OpenTargetsiENSG00000108984.
PharmGKBiPA30591.

Chemistry databases

ChEMBLiCHEMBL2171.
GuidetoPHARMACOLOGYi2067.

Polymorphism and mutation databases

BioMutaiMAP2K6.
DMDMi1709088.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000863861 – 334Dual specificity mitogen-activated protein kinase kinase 6Add BLAST334

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei207O-acetylserine; by Yersinia yopJ; alternate1 Publication1
Modified residuei207Phosphoserine; by MAP3K; alternate1 Publication1
Modified residuei211O-acetylthreonine; by Yersinia yopJ; alternate1 Publication1
Modified residuei211Phosphothreonine; by MAP3K; alternate1 Publication1

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/TAOK2.1 Publication
Acetylation of Ser-207 and Thr-211 by Yersinia yopJ prevents phosphorylation and activation, thus blocking the MAPK signaling pathway.1 Publication

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei14 – 15Cleavage; by anthrax lethal factor2

Keywords - PTMi

Acetylation, Phosphoprotein

Proteomic databases

EPDiP52564.
MaxQBiP52564.
PaxDbiP52564.
PeptideAtlasiP52564.
PRIDEiP52564.

PTM databases

iPTMnetiP52564.
PhosphoSitePlusiP52564.

Miscellaneous databases

PMAP-CutDBiP52564.

Expressioni

Tissue specificityi

Isoform 2 is only expressed in skeletal muscle. Isoform 1 is expressed in skeletal muscle, heart, and in lesser extent in liver or pancreas.1 Publication

Inductioni

Strongly activated by UV, anisomycin, and osmotic shock but not by phorbol esters, NGF or EGF.

Gene expression databases

BgeeiENSG00000108984.
CleanExiHS_MAP2K6.
ExpressionAtlasiP52564. baseline and differential.
GenevisibleiP52564. HS.

Organism-specific databases

HPAiCAB007744.
HPA031134.

Interactioni

Subunit structurei

Dimer. Interacts with Yersinia yopJ. 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

Binary interactionsi

Show more details

GO - Molecular functioni

  • identical protein binding Source: IntAct
  • protein kinase binding Source: UniProtKB

Protein-protein interaction databases

BioGridi111594. 27 interactors.
DIPiDIP-31346N.
ELMiP52564.
IntActiP52564. 12 interactors.
MINTiMINT-3019559.
STRINGi9606.ENSP00000468348.

Chemistry databases

BindingDBiP52564.

Structurei

Secondary structure

1334
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi50 – 52Combined sources3
Beta strandi53 – 61Combined sources9
Beta strandi63 – 72Combined sources10
Turni73 – 76Combined sources4
Beta strandi77 – 84Combined sources8
Helixi90 – 104Combined sources15
Turni110 – 112Combined sources3
Beta strandi115 – 120Combined sources6
Beta strandi122 – 130Combined sources9
Beta strandi133 – 135Combined sources3
Helixi136 – 145Combined sources10
Helixi152 – 172Combined sources21
Helixi182 – 184Combined sources3
Beta strandi185 – 187Combined sources3
Beta strandi193 – 195Combined sources3
Helixi201 – 203Combined sources3
Helixi207 – 212Combined sources6
Helixi222 – 225Combined sources4
Helixi236 – 252Combined sources17
Helixi263 – 272Combined sources10
Turni280 – 282Combined sources3
Helixi285 – 294Combined sources10
Helixi299 – 301Combined sources3
Helixi305 – 308Combined sources4
Helixi312 – 319Combined sources8
Helixi324 – 332Combined sources9

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
2Y8OX-ray1.95B4-17[»]
3ENMX-ray2.35A/B/C/D45-332[»]
3FMEX-ray2.26A47-334[»]
3VN9X-ray2.60A1-334[»]
5ETFX-ray2.40B4-17[»]
ProteinModelPortaliP52564.
SMRiP52564.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP52564.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini53 – 314Protein kinasePROSITE-ProRule annotationAdd BLAST262

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni4 – 19D domainBy similarityAdd BLAST16
Regioni311 – 334DVD domainAdd BLAST24

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

Sequence similaritiesi

Phylogenomic databases

eggNOGiKOG0984. Eukaryota.
ENOG410XT3F. LUCA.
GeneTreeiENSGT00760000119199.
HOGENOMiHOG000234206.
HOVERGENiHBG108518.
InParanoidiP52564.
KOiK04433.
OMAiWGTPFEQ.
OrthoDBiEOG091G0A9H.
PhylomeDBiP52564.

Family and domain databases

InterProiView protein in InterPro
IPR011009. Kinase-like_dom_sf.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR008271. Ser/Thr_kinase_AS.
PfamiView protein in Pfam
PF00069. Pkinase. 1 hit.
SMARTiView protein in SMART
SM00220. S_TKc. 1 hit.
SUPFAMiSSF56112. SSF56112. 1 hit.
PROSITEiView protein in PROSITE
PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.

Sequences (2)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: P52564-1) [UniParc]FASTAAdd to basket
Also known as: MKK6b

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        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
Length:334
Mass (Da):37,492
Last modified:October 1, 1996 - v1
Checksum:i4ECA8014522216AF
GO
Isoform 2 (identifier: P52564-2) [UniParc]FASTAAdd to basket
Also known as: MKK6

The sequence of this isoform differs from the canonical sequence as follows:
     1-56: Missing.

Show »
Length:278
Mass (Da):31,339
Checksum:i1EE7FC1B26B11AE4
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti125V → M in AAB03705 (PubMed:8621675).Curated1
Sequence conflicti125V → M in AAB03708 (PubMed:8621675).Curated1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0048821 – 56Missing in isoform 2. 1 PublicationAdd BLAST56

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.
CCDSiCCDS11686.1. [P52564-1]
CCDS82194.1. [P52564-2]
PIRiS71631.
RefSeqiNP_002749.2. NM_002758.3. [P52564-1]
UniGeneiHs.463978.
Hs.49329.

Genome annotation databases

EnsembliENST00000589647; ENSP00000467213; ENSG00000108984. [P52564-2]
ENST00000590474; ENSP00000468348; ENSG00000108984. [P52564-1]
ENST00000613873; ENSP00000477701; ENSG00000108984. [P52564-2]
GeneIDi5608.
KEGGihsa:5608.
UCSCiuc002jij.4. human. [P52564-1]

Keywords - Coding sequence diversityi

Alternative splicing

Similar proteinsi

Entry informationi

Entry nameiMP2K6_HUMAN
AccessioniPrimary (citable) accession number: P52564
Entry historyiIntegrated into UniProtKB/Swiss-Prot: October 1, 1996
Last sequence update: October 1, 1996
Last modified: November 22, 2017
This is version 181 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny 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, Complete proteome, Reference proteome

Documents

  1. Human chromosome 17
    Human chromosome 17: entries, gene names and cross-references to MIM
  2. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  3. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  4. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  5. SIMILARITY comments
    Index of protein domains and families