Detailed entry information

Protein Information (annotations from UniProt)

Database IDHIV0005633
UniProt IDP45985
Primary gene name(s)MAP2K4
Synonym gene name(s)JNKK1, MEK4, MKK4, PRKMK4, SEK1, SERK1, SKK1
Protein nameDual specificity mitogen-activated protein kinase kinase 4
Protein functionDual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. Essential component of the stress-activated protein kinase/c-Jun N-terminal kinase, SAP/JNK signaling pathway. With MAP2K7/MKK7, is the one of the only known kinase to directly activate the stress-activated protein kinase/c-Jun N-terminal kinases MAPK8/JNK1, MAPK9/JNK2 and MAPK10/JNK3. MAP2K4/MKK4 and MAP2K7/MKK7 both activate the JNKs by phosphorylation, but they differ in their preference for the phosphorylation site in the Thr-Pro-Tyr motif. MAP2K4 shows preference for phosphorylation of the Tyr residue and MAP2K7/MKK7 for the Thr residue. The phosphorylation of the Thr residue by MAP2K7/MKK7 seems to be the prerequisite for JNK activation at least in response to proinflammatory cytokines, while other stimuli activate both MAP2K4/MKK4 and MAP2K7/MKK7 which synergistically phosphorylate JNKs. MAP2K4 is required for maintaining peripheral lymphoid homeostasis. The MKK/JNK signaling pathway is also involved in mitochondrial death signaling pathway, including the release cytochrome c, leading to apoptosis. Whereas MAP2K7/MKK7 exclusively activates JNKs, MAP2K4/MKK4 additionally activates the p38 MAPKs MAPK11, MAPK12, MAPK13 and MAPK14. {ECO:0000269|PubMed:7716521}.
Subcellular locationCytoplasm {ECO:0000250}. Nucleus {ECO:0000250}.
ECO codeClick here for more information.
Amino acid sequence
FASTA format: P45985
Gene Ontology
(Biological Process)
Complete annatation
apoptotic process [GO:0006915];
cell growth involved in cardiac muscle cell development [GO:0061049];
cellular response to mechanical stimulus [GO:0071260];
cellular response to sorbitol [GO:0072709];
Fc-epsilon receptor signaling pathway [GO:0038095];
JNK cascade [GO:0007254];
negative regulation of motor neuron apoptotic process [GO:2000672];
positive regulation of DNA replication [GO:0045740];
positive regulation of neuron apoptotic process [GO:0043525];
positive regulation of nitric-oxide synthase biosynthetic process [GO:0051770];
positive regulation of smooth muscle cell apoptotic process [GO:0034393];
proteolysis in other organism [GO:0035897];
response to wounding [GO:0009611];
signal transduction [GO:0007165]
Gene Ontology
(Molecular Function)
Complete annatation
ATP binding [GO:0005524];
protein kinase activity [GO:0004672];
protein tyrosine kinase activity [GO:0004713];
receptor signaling protein serine/threonine kinase activity [GO:0004702]
Gene Ontology
(Cellular Component)
Complete annatation
cytoplasm [GO:0005737];
cytosol [GO:0005829];
nucleus [GO:0005634]
Protein-protein interaction112315
Phylogenetic treeP45985
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. CD30.5510221590889840.09351280265021910.166697216031236
AZA vs. DISU-0.08607997402638090.7345568023679680.974560663114398
AZA vs. IL70.4463369292807940.02117949038842740.465222860423355
AZA vs. SAHA0.09625995750000470.6942951771337720.913326250119074
DISU vs. CD3-0.6491669707496180.07473932201122380.148415299696639
DISU vs. IL70.5235540220111760.03855427820288970.257855254617818
DISU vs. SAHA0.1835196722648060.5304119003470990.842077083127686
DMSO vs. AZA-0.03017915087903330.858356884305831
DMSO vs. CD3-0.5928745550212240.06474229495943910.119673947676558
DMSO vs. DISU0.05409778447435970.8251271168652680.98057019242518
DMSO vs. IL70.4837615047445760.007593130346946640.181404817718258
DMSO vs. SAHA0.1199511237586830.6123055979321020.871830776400222
HIV vs. Mock in Activation-0.0486350368851650.9377528854122480.999983755607037
HIV vs. Mock in Latency0.002747550243942480.986835224712810.999834320637052
IL7 vs. CD3-0.09668930064263070.7636790942972130.843068671039152
SAHA vs. CD3-0.4794434548737570.175734003284170.273331760707239
SAHA vs. IL7-0.3530980445064160.1492408845467790.365441373238815
(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 -0.326012 0.0833365
(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
1.016 1 1.138 1.195 1.071
(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
3ALN X-ray 2.3Å A/B/C=80-399.
3ALO X-ray 2.6Å A=80-399.
3VUT X-ray 3.5Å A/B=80-399.

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

not found

Metabolic/Signalling Pathway       (annotations from KEGG database)      top

Pathway Accession Number Description
hsa04010 MAPK signaling pathway - Homo sapiens (human)
hsa04012 ErbB signaling pathway - 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)
hsa04912 GnRH signaling pathway - Homo sapiens (human)
hsa05120 Epithelial cell signaling in Helicobacter pylori infection - Homo sapiens (human)
hsa05142 Chagas disease (American trypanosomiasis) - Homo sapiens (human)
hsa05161 Hepatitis B - Homo sapiens (human)
hsa05164 Influenza A - Homo sapiens (human)
hsa05166 HTLV-I infection - Homo sapiens (human)
hsa05169 Epstein-Barr virus infection - Homo sapiens (human)