Detailed entry information

Protein Information (annotations from UniProt)

Database IDHIV0005635
UniProt IDP52564
Primary gene name(s)MAP2K6
Synonym gene name(s)MEK6, MKK6, PRKMK6, SKK3
Protein nameDual specificity mitogen-activated protein kinase kinase 6
Protein functionDual 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. {ECO:0000269|PubMed:10961885, ECO:0000269|PubMed:11727828, ECO:0000269|PubMed:15550393, ECO:0000269|PubMed:20869211, ECO:0000269|PubMed:8622669, ECO:0000269|PubMed:8626699, ECO:0000269|PubMed:8663074, ECO:0000269|PubMed:9218798}.
Subcellular locationNucleus {ECO:0000269|PubMed:9768359}. Cytoplasm {ECO:0000269|PubMed:9768359}. Cytoplasm, cytoskeleton {ECO:0000269|PubMed:9768359}. Note=Binds to microtubules.
ECO codeClick here for more information.
Amino acid sequence
FASTA format: P52564
Gene Ontology
(Biological Process)
Complete annatation
activation of MAPK activity [GO:0000187];
apoptotic process [GO:0006915];
cardiac muscle contraction [GO:0060048];
cell cycle arrest [GO:0007050];
cellular response to sorbitol [GO:0072709];
DNA damage induced protein phosphorylation [GO:0006975];
nucleotide-binding oligomerization domain containing signaling pathway [GO:0070423];
ovulation cycle process [GO:0022602];
positive regulation of apoptotic process [GO:0043065];
positive regulation of nitric-oxide synthase biosynthetic process [GO:0051770];
positive regulation of prostaglandin secretion [GO:0032308];
proteolysis in other organism [GO:0035897];
regulation of transcription, DNA-templated [GO:0006355];
response to drug [GO:0042493];
response to ischemia [GO:0002931];
signal transduction [GO:0007165];
transcription, DNA-templated [GO:0006351]
Gene Ontology
(Molecular Function)
Complete annatation
ATP binding [GO:0005524];
MAP kinase kinase activity [GO:0004708];
protein kinase binding [GO:0019901];
protein tyrosine kinase activity [GO:0004713];
receptor signaling protein serine/threonine kinase activity [GO:0004702]
Gene Ontology
(Cellular Component)
Complete annatation
cytoplasm [GO:0005737];
cytoskeleton [GO:0005856];
cytosol [GO:0005829];
nucleoplasm [GO:0005654]
Protein-protein interaction111594
Phylogenetic treeP52564
HIV replication factor status Zhou et al., Cell. Host. Microbe., 2008
Brass et al., Science, 2008
Smith et al., J. Immunol, 2010
gene status
Lu et al., J. Virol., 2011
      Folds changes 8h: unknown; Folds changes 16h: unknown; Tested: unknown;
Schoggins JW and Rice CM, Curr. Opin. Virol., 2011
      Targeted viruses: unknown
      Viral life cycle: unknown
      Mechanism related to antiviral activity: unknown
Anti-viral restriction factor Liu et al., Retrovirology, 2011
      unknown (Triplicates)

Gene Expression Profile       top

            Up-regulated;            Down-regulated

For brief introduction to each study, please go to the help page.

Gene expression during HIV latency

(1). Mohammadi et al., PLoS Pathog., 2014

Differentially expressed transcripts (Pairwise) during latency and subsequent viral reactivation using several agents - Primary CD4+ T-cell based model

DMSO: Dimethyl suloxyde (negative control) - 0.0033% final
SAHA: Vorinostat (Histone deacetylase inhibitor) - 0.5 μM
CD3: TCR Stimulation by IL-2+ antiCD3/anti-CD28 antibodies
IL7: Interleukin-7 based stimulation
DISU: Disulfiram (alcohol dehydrogenase inhibitor) - 0.5 μM
AZA: 5-azacytidine (AZA; DNA methylation inhibitor) - 1 μM
Experimental Condition Log2 Fold Change P value Adjusted P value
AZA vs. CD3-5.460837740087764.4409723143346e-073.72389129816428e-06
AZA vs. DISU-0.02286766366842910.9302443628599640.995042856396371
AZA vs. IL7-0.609680772435970.002827948763799330.157872858210175
AZA vs. SAHA-0.3117076065828950.2213307469556630.589713927268377
DISU vs. CD35.445634988956513.68264721828382e-073.94543171061907e-06
DISU vs. IL7-0.5952964535345190.02291641247388180.192245363407773
DISU vs. SAHA-0.2883163734696910.3326969180330580.712082843608644
DMSO vs. AZA-0.0773921817474750.6647424095915171
DMSO vs. CD35.373367018207857.72718405261941e-075.68686017355698e-06
DMSO vs. DISU-0.05569800660231760.8253837352961780.98057019242518
DMSO vs. IL7-0.5258906905197450.006068061953806050.161182383142331
DMSO vs. SAHA-0.241467007965430.3273847172589390.681399678747337
HIV vs. Mock in Activationunknownunknownunknown
HIV vs. Mock in Latency0.1171200592210510.5009211771220960.999834320637052
IL7 vs. CD34.865128633742935.76895247750286e-064.71456393132546e-05
SAHA vs. CD35.149250469463691.64556114290448e-061.26717457453094e-05
SAHA vs. IL70.2925406242541310.2609950506434740.506402290307599
(2). Iglesias-Ussel et al., J. Virol., 2013

Up and Downregulated transcripts during Latency (Latently infected CD4+ T cells vs Uninfected)- Primary CD4+Tcell based model
Log2 Fold Change P Value
unknown unknown

Gene expression during HIV infection and replication

(1). Imbeault et al., PloS Pathog., 2012

Transcriptomic profiling of HIV-1 infected CD4+ T cells - Primary CD4+ T cells
Experiment type Log2 Fold Change P Value Adjusted P Value
Infected vs. Mock unknown unknown unknown
Infected vs. Bystander unknown unknown unknown
(2). Lefebvre et al., J. Virol., 2011

Transcriptome analysis of T-cell line (Sup T1)
Log2 Fold Change unknown
(3). Li et al., J. Immunol., 2013

Lymphatic tissue
Acute Fold Change Acute P Value Asymt Fold Change Asypt P Value AIDS Fold Change AIDS P Value
unknown unknown unknown unknown unknown unknown
(4). Chang et al., MBio., 2011

Transcriptome analysis of T-cell line (Sup T1)

Derived from Sherrill-Mix et al., BMC Retrovirol., 2015 cross validation
Up-regulated (True) unknown
(5). Sherrill-Mix et al., BMC Retrovirol., 2015

Deep RNA-seq analysis of primary human T cell infected with low passage HIV isolate HIV89.6 - Primary CD4+ T cell based
Test Status Log2 Fold Change P Value
OK -0.555435 0.000305467
(6). Rotger et al., PLoS Pathog., 2010

Genome-wide mRNA expression of CD4+ T cells from HIV-infected patient
(Genes differentially expressed (at adjusted p<0.01) according to the empirical Bayes approach)
Log2 Fold Change P Value
unknown unknown

Proteomic/Transcriptomics studies indicating differentially expressed genes mediated by HIV

(1). Greenwood et al., Elife, 2016

Activated (CD3/CD28) Primary human CD4+ T cells infected with pNL4-3-dE-EGFP. The table shows the complete (unfiltered) TMT (tandem mass tag)-based proteomic time course dataset
6 h 24 h 48 h 72 h RTi
0.951 1.134 1.241 1.325 1.346
(2). Navare et al., Virology, 2012

SUP-T1 cell line
FC-4hpi P-value FC-8hpi P-value FC-20hpi P-value Category
unknown unknown unknown unknown unknown unknown unknown
(3). Hyrcza et al., J. Virolo., 2007

Primary human CD4+ and CD8+ T Cells
Affymetrix Prob ID Fold Change In CD8? Category
unknown unknown unknown unknown

Protein Overview       top

Drug-protein Interaction       (annotations from DrugBank)      top

not found

Protein Secondary Structure       (annotations from PDB)      top

PDB Accession Method Resolution Chain Structure Preview
2Y8O X-ray 1.9Å B=4-17.
3ENM X-ray 2.3Å A/B/C/D=45-332.
3FME X-ray 2.2Å A=47-334.
3VN9 X-ray 2.6Å A=1-334.

HIV-1 Interaction       (annotations from NCBI HIV-1 Interaction Database)      top

HIV Partner Interaction Type PubMed
Tat activates 23535064
Tat interacts with 23535064

Metabolic/Signalling Pathway       (annotations from KEGG database)      top

Pathway Accession Number Description
hsa04010 MAPK signaling pathway - Homo sapiens (human)
hsa04015 Rap1 signaling pathway - Homo sapiens (human)
hsa04380 Osteoclast differentiation - Homo sapiens (human)
hsa04620 Toll-like receptor signaling pathway - Homo sapiens (human)
hsa04664 Fc epsilon RI signaling pathway - Homo sapiens (human)
hsa04668 TNF signaling pathway - Homo sapiens (human)
hsa04750 Inflammatory mediator regulation of TRP channels - Homo sapiens (human)
hsa04912 GnRH signaling pathway - Homo sapiens (human)
hsa05014 Amyotrophic lateral sclerosis (ALS) - Homo sapiens (human)
hsa05145 Toxoplasmosis - Homo sapiens (human)
hsa05164 Influenza A - Homo sapiens (human)
hsa05169 Epstein-Barr virus infection - Homo sapiens (human)