DUSP4

Summary

DUSP4 (dual specificity phosphatase 4, HGNC:3070) is a protein-coding gene on chromosome 8p12, encoding Dual specificity protein phosphatase 4 (Q13115). Regulates mitogenic signal transduction by dephosphorylating both Thr and Tyr residues on MAP kinases ERK1 and ERK2.

The protein encoded by this gene is a member of the dual specificity protein phosphatase subfamily. These phosphatases inactivate their target kinases by dephosphorylating both the phosphoserine/threonine and phosphotyrosine residues. They negatively regulate members of the mitogen-activated protein (MAP) kinase superfamily (MAPK/ERK, SAPK/JNK, p38), which are associated with cellular proliferation and differentiation. Different members of the family of dual specificity phosphatases show distinct substrate specificities for various MAP kinases, different tissue distribution and subcellular localization, and different modes of inducibility of their expression by extracellular stimuli. This gene product inactivates ERK1, ERK2 and JNK, is expressed in a variety of tissues, and is localized in the nucleus. Two alternatively spliced transcript variants, encoding distinct isoforms, have been observed for this gene. In addition, multiple polyadenylation sites have been reported.

Source: NCBI Gene 1846 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 59 total
• Druggable target: yes
• MANE Select transcript: NM_001394

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3070
Approved symbol	DUSP4
Name	dual specificity phosphatase 4
Location	8p12
Locus type	gene with protein product
Status	Approved
Aliases	HVH2, MKP-2, TYP
Ensembl gene	ENSG00000120875
Ensembl biotype	protein_coding
OMIM	602747
Entrez	1846

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000240100, ENST00000240101

RefSeq mRNA: 2 — MANE Select: NM_001394 NM_001394, NM_057158

CCDS: CCDS6072, CCDS6073

Canonical transcript exons

ENST00000240100 — 4 exons

Exon	Start	End
ENSE00000429120	29338282	29338501
ENSE00000687534	29340098	29340243
ENSE00003992628	29333064	29337411
ENSE00003992634	29349846	29350684

Expression profiles

Bgee: expression breadth ubiquitous, 220 present calls, max score 97.11.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 18.5051 / max 471.8245, expressed in 1316 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
92563	15.8481	1265
92564	2.6569	813

Top tissues by expression

280 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
pigmented layer of retina	UBERON:0001782	97.11	gold quality
buccal mucosa cell	CL:0002336	97.01	gold quality
mammary duct	UBERON:0001765	94.22	gold quality
seminal vesicle	UBERON:0000998	94.19	gold quality
epithelium of mammary gland	UBERON:0003244	94.15	gold quality
eye	UBERON:0000970	91.61	gold quality
palpebral conjunctiva	UBERON:0001812	90.12	gold quality
sperm	CL:0000019	89.53	gold quality
mammary gland	UBERON:0001911	89.42	gold quality
thoracic mammary gland	UBERON:0005200	89.32	gold quality
cortical plate	UBERON:0005343	88.54	gold quality
trachea	UBERON:0003126	88.43	gold quality
male germ cell	CL:0000015	88.19	gold quality
mucosa of urinary bladder	UBERON:0001259	87.91	gold quality
nipple	UBERON:0002030	86.34	gold quality
body of pancreas	UBERON:0001150	85.82	gold quality
bronchial epithelial cell	CL:0002328	85.72	gold quality
body of stomach	UBERON:0001161	85.46	gold quality
pancreatic ductal cell	CL:0002079	85.13	silver quality
amniotic fluid	UBERON:0000173	85.07	gold quality
pancreas	UBERON:0001264	84.89	gold quality
bronchus	UBERON:0002185	84.47	gold quality
epithelium of bronchus	UBERON:0002031	84.37	gold quality
stomach	UBERON:0000945	84.17	gold quality
islet of Langerhans	UBERON:0000006	84.06	gold quality
cardia of stomach	UBERON:0001162	83.86	gold quality
parotid gland	UBERON:0001831	83.52	silver quality
placenta	UBERON:0001987	83.32	gold quality
nasal cavity mucosa	UBERON:0001826	83.17	gold quality
nasal cavity epithelium	UBERON:0005384	82.06	silver quality

Single-cell (SCXA)

Detected in 14 experiment(s), a significant marker in 10.

Experiment	Marker?	Max mean expression
E-HCAD-29	yes	511.74
E-MTAB-7008	yes	306.04
E-MTAB-8142	yes	37.27
E-CURD-46	yes	21.31
E-MTAB-8410	yes	21.15
E-MTAB-5061	yes	18.17
E-CURD-122	yes	13.65
E-HCAD-1	yes	12.64
E-HCAD-5	yes	8.84
E-CURD-95	no	946.65
E-GEOD-111727	no	910.35
E-GEOD-86618	no	147.40
E-CURD-120	no	30.05
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CREM, E2F1, EGR1, FOXO1, HOXA10, TP53

miRNA regulators (miRDB)

151 targeting DUSP4, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-518D-5P	100.00	67.51	979
HSA-MIR-518E-5P	100.00	67.66	954
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-519A-5P	100.00	67.66	954
HSA-MIR-519B-5P	100.00	67.66	954
HSA-MIR-519C-5P	100.00	67.66	954
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-522-5P	100.00	67.66	954
HSA-MIR-523-5P	100.00	67.66	954
HSA-MIR-526A-5P	100.00	67.51	979
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-5680	99.91	69.83	3421

Literature-anchored findings (GeneRIF, showing 40)

• Results demonstrate the in vivo specificity of MKP-2 for JNK and not ERK and show that nuclear-targeted JNK is involved in genotoxic stress-induced apoptosis. (PMID:16038800)
• MKP2-mediated inactivation of nuclear extracellular signal-regulated protein kinase ERK2 represents a key event in the establishment of replicative cell senescence. (PMID:17145763)
• E2F-1 is a transcriptional activator of MKP-2 and MKP-2 is an essential cell death mediator in the E2F-1 pathway (PMID:17452331)
• a novel, stimulus-specific, and phosphatase-specific mechanism of ERK2 regulation in the nucleus by DUSP1, -2, and -4. (PMID:18178562)
• Crystal structure of the catalytic domain of human MKP-2 reveals a 24-mer assembly. (PMID:19415758)
• Results show that DUSP4 is involved in negative feedback control of EGFR signaling, and provide functional validation for its role as a growth suppressor in EGFR-mutant lung adenocarcinoma. (PMID:19525976)
• The occurrence of a novel splice variant of MKP-2 which is unable to bind ERK and may be significant in the dysregulation of MAP kinase activity in certain disease states. (PMID:19843478)
• MKP-2 as a common epigenetically silenced gene in glioma, the inactivation of which may play a significant role in glioma development. (PMID:20124482)
• presence of activating KRAS mutations is significantly correlated to an upregulation of 13 genes (adjusted P-value <0.05), among them DUSP4, a MAP-kinase phosphatase, and SMYD3, a histone methyltransferase (PMID:20725992)
• Over-expression of MKP-2 had different effects upon the expression of inflammatory proteins due to a reciprocal effect upon JNK and NFkappaB signalling, and also prevented TNF-alpha-mediated endothelial cell death (PMID:20860659)
• MKP-2 is phosphorylated by ERK and that such phosphorylation leads to stabilization of MKP-2 protein. (PMID:21084841)
• DUSP4 functions as part of a negative feedback mechanism in the control of the duration and magnitude of nuclear ERK activation during intestinal tumorigenesis. (PMID:22430215)
• Increased DUSP4 expression in activated T cells in the elderly in part accounts for defective adaptive immune responses. (PMID:22434910)
• High DUSP4 is associated with microsatellite instability in colorectal cancer and causes increased cell proliferation. (PMID:22965873)
• Dusp4 mediates cardiomyopathy caused by LMNA gene mutation. (PMID:23048029)
• MKP2 is a negative regulator of VRK1-mediated histone H3 phosphorylation. (PMID:23223570)
• There was no significant correlation between DUSP4 expression and KRAS mutation. (PMID:23749251)
• DUSP4 attenuates ERK signaling and reduces cell viability, suggesting that the novel crosstalk between NFkappaB and mitogen activated protein kinase pathways contributes to cell survival. (PMID:23812841)
• high DUSP4 expression was associated with a worse overall survival and with clinical characteristics typical for BRAF mutant patients (PMID:23875912)
• Enforced expression of DUSP4 reduced the CD44(+)/CD24(-) population in multiple BLBC cell lines in a MEK-dependent manner, limiting tumor formation of claudin-low SUM159PT cells in mice. (PMID:23966295)
• Increased DUSP4 expression is associated with papillary thyroid carcinoma. (PMID:24222120)
• DUSP1, DUSP4, and DUSP5 differentially modulate endothelial MAPK signaling pathways downstream of Tie-2 receptors. (PMID:24308939)
• Data suggest that MKP-2 rather than MKP-1 is tamoxifen-regulated and that the elevated expression of MKP-2 in MCF7-TAMR cells potentially functions to restore tamoxifen sensitivity. (PMID:24658355)
• Instead, autophagic cell death was the major consequence, and our investigation of mechanisms suggested it is mediated via the dual specificity phosphatase-4 (DUSP4) dependent ERK inactivation pathway (PMID:25027955)
• MKP-1 and MKP-2 stability is regulated by ERK-mediated phosphorylation through a degradation pathway independent of polyubiquitination (PMID:25204653)
• Low DUSP4 expression levels predict recurrence and mortality in triple-negative breast cancer patients (PMID:25281216)
• Data indicate that normalization of dual-specific phosphatase 4 (DUSP4) expression using a specific siRNA improved CD4(+) T-cell activity in idiopathic CD4 lymphopenia (ICL). (PMID:25733583)
• Ectopic expression of wild-type DUSP4, but not of a phosphatase-deficient mutant, dephosphorylates c-JUN N-terminal kinase (JNK) and induces apoptosis in DLBCL cells. (PMID:25847947)
• Our findings demonstrate a genetic mechanism by which pancreatic precursor lesions progress to invasive carcinomas and highlight DUSP4 as a novel invasion suppressor (PMID:26941286)
• Results show that DUSP4 gene is under-expressed in ER-negative breast cancer and is deleted in approximately 50 % of breast cancers. Induced DUSP4 expression suppresses both in vitro and in vivo growths of breast cancer cells suggesting that DUSP4 is a critical regulator of the growth and invasion of triple-negative breast cancer cells. (PMID:27393618)
• This study was aimed to investigate the correlation of dual-specificity phosphatase 4 (DUSP4) expression with clinicopathologic features and overall survival in patients with GC and explore the effects of sanguinarine on tumour growth and invasion in GC cells (SGC-7901 and HGC-27) and underlying molecular mechanisms (PMID:27957827)
• DUSP4 is crucial in regulating corticosteroid sensitivity. (PMID:28283554)
• Study revealed that DUSP4 expression was apparently downregulated in the deep region of colorectal cancer (CRC) tissues compared with the superficial region, and that ERK phosphorylation was conversely increased in the deep region relative to the superficial region. Also, downregulation of DUSP4 in CRC might promote cell proliferation and invasiveness through activation of ERK. (PMID:29150975)
• The expression of miR-122-5p in GC tissues and cells was significantly down-regulated, whereas DUSP4 expression was up-regulated. MiR-122-5p restrained migration and invasion abilities of GC cells by repressing DUSP4. (PMID:29509059)
• show that a high GFAP-delta/alpha ratio induces the expression of the dual-specificity phosphatase 4 (DUSP4) in focal adhesions. By focusing on pathways up- and downstream of DUSP4 that are involved in the cell-extracellular matrix interaction, we show that a high GFAP-delta/alpha ratio equips glioma cells to better invade the brain (PMID:31480854)
• It findings identify the CREMalpha/DUSP4 axis as a promising candidate in the search for biomarkers and therapeutic targets in systemic lupus erythematosus. (PMID:31653682)
• miR-137 alleviates doxorubicin resistance in breast cancer through inhibition of epithelial-mesenchymal transition by targeting DUSP4. (PMID:31801953)
• Dual-specificity protein phosphatase DUSP4 regulates response to MEK inhibition in BRAF wild-type melanoma. (PMID:31839677)
• DUSP4 is involved in the enhanced proliferation and survival of DUSP4-overexpressing cancer cells. (PMID:32505357)
• Expression of DUSP4 transcript variants as a potential biomarker for colorectal cancer. (PMID:32613839)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	dusp4	ENSDARG00000044688
mus_musculus	Dusp4	ENSMUSG00000031530
rattus_norvegicus	Dusp4	ENSRNOG00000011921

Paralogs (31): DUSP13B (ENSG00000079393), DUSP12 (ENSG00000081721), SSH1 (ENSG00000084112), DUSP3 (ENSG00000108861), PTPMT1 (ENSG00000110536), DUSP16 (ENSG00000111266), EPM2A (ENSG00000112425), DUSP22 (ENSG00000112679), DUSP1 (ENSG00000120129), STYXL1 (ENSG00000127952), DUSP9 (ENSG00000130829), DUSP26 (ENSG00000133878), DUSP5 (ENSG00000138166), DUSP6 (ENSG00000139318), SSH2 (ENSG00000141298), DUSP10 (ENSG00000143507), DUSP15 (ENSG00000149599), DUSP2 (ENSG00000158050), KASH5 (ENSG00000161609), DUSP19 (ENSG00000162999), DUSP7 (ENSG00000164086), DUSP18 (ENSG00000167065), SSH3 (ENSG00000172830), DUSP8 (ENSG00000184545), DUSP28 (ENSG00000188542), DUSP29 (ENSG00000188716), DUSP21 (ENSG00000189037), STYX (ENSG00000198252), STYXL2 (ENSG00000198842), DUSP14 (ENSG00000276023), DUSP13A (ENSG00000293543)

Protein

Protein identifiers

Dual specificity protein phosphatase 4 — Q13115 (reviewed: Q13115)

Alternative names: Dual specificity protein phosphatase hVH2, Mitogen-activated protein kinase phosphatase 2

All UniProt accessions (1): Q13115

UniProt curated annotations — full annotation on UniProt →

Function. Regulates mitogenic signal transduction by dephosphorylating both Thr and Tyr residues on MAP kinases ERK1 and ERK2.

Subunit / interactions. Hollow spherical complex composed of 24 subunits with pseudooctahedral symmetry, has a tetramer as the basic unit.

Subcellular location. Nucleus.

Post-translational modifications. Phosphorylation in the C-terminus by ERK1/2 inhibits proteasomal degradation and stabilizes the protein.

Miscellaneous. Does not bind to JNK or ERK, and is more susceptible to proteasomal degradation.

Similarity. Belongs to the protein-tyrosine phosphatase family. Non-receptor class dual specificity subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q13115-1	1, MKP-2-L	yes
Q13115-2	2, MKP-2-S

RefSeq proteins (2): NP_001385, NP_476499 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000340	Dual-sp_phosphatase_cat-dom	Domain
IPR000387	Tyr_Pase_dom	Domain
IPR001763	Rhodanese-like_dom	Domain
IPR003595	Tyr_Pase_cat	Domain
IPR008343	MKP	Family
IPR016130	Tyr_Pase_AS	Active_site
IPR020422	TYR_PHOSPHATASE_DUAL_dom	Domain
IPR029021	Prot-tyrosine_phosphatase-like	Homologous_superfamily
IPR036873	Rhodanese-like_dom_sf	Homologous_superfamily

Pfam: PF00581, PF00782

Catalyzed reactions (Rhea), 3 shown:

• O-phospho-L-tyrosyl-[protein] + H2O = L-tyrosyl-[protein] + phosphate (RHEA:10684)
• O-phospho-L-seryl-[protein] + H2O = L-seryl-[protein] + phosphate (RHEA:20629)
• O-phospho-L-threonyl-[protein] + H2O = L-threonyl-[protein] + phosphate (RHEA:47004)

UniProt features (26 total): strand 7, helix 6, modified residue 3, turn 2, domain 2, splice variant 2, initiator methionine 1, chain 1, sequence conflict 1, active site 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
3EZZ	X-RAY DIFFRACTION	2.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13115-F1	78.78	0.53

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 280 (phosphocysteine intermediate)

Post-translational modifications (3): 2, 386, 391

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-112409	RAF-independent MAPK1/3 activation
R-HSA-202670	ERKs are inactivated
R-HSA-5675221	Negative regulation of MAPK pathway

MSigDB gene sets: 427 (showing top): BROWNE_HCMV_INFECTION_30MIN_DN, LEE_SP4_THYMOCYTE, GOBP_NEGATIVE_REGULATION_OF_ERK1_AND_ERK2_CASCADE, FREAC2_01, REACTOME_INNATE_IMMUNE_SYSTEM, BENPORATH_ES_WITH_H3K27ME3, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_FORMATION_OF_PRIMARY_GERM_LAYER, KEGG_MAPK_SIGNALING_PATHWAY, GCANCTGNY_MYOD_Q6, SHEPARD_CRASH_AND_BURN_MUTANT_UP, RIZKI_TUMOR_INVASIVENESS_3D_DN, NAGASHIMA_NRG1_SIGNALING_UP, AAAYRNCTG_UNKNOWN, CAGCTG_AP4_Q5

GO Biological Process (6): endoderm formation (GO:0001706), signal transduction (GO:0007165), dephosphorylation (GO:0016311), negative regulation of MAPK cascade (GO:0043409), negative regulation of ERK1 and ERK2 cascade (GO:0070373), protein dephosphorylation (GO:0006470)

GO Molecular Function (10): phosphoprotein phosphatase activity (GO:0004721), protein tyrosine phosphatase activity (GO:0004725), protein tyrosine/threonine phosphatase activity (GO:0008330), phosphatase activity (GO:0016791), MAP kinase tyrosine/serine/threonine phosphatase activity (GO:0017017), MAP kinase serine/threonine phosphatase activity (GO:1990439), protein serine/threonine phosphatase activity (GO:0004722), protein binding (GO:0005515), hydrolase activity (GO:0016787), MAP kinase phosphatase activity (GO:0033549)

GO Cellular Component (3): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
MAPK1/MAPK3 signaling	1
ERK/MAPK targets	1
RAF/MAP kinase cascade	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
phosphoprotein phosphatase activity	4
MAP kinase phosphatase activity	2
cellular anatomical structure	2
formation of primary germ layer	1
endoderm development	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
phosphate-containing compound metabolic process	1
MAPK cascade	1
regulation of MAPK cascade	1
negative regulation of intracellular signal transduction	1
negative regulation of MAPK cascade	1
ERK1 and ERK2 cascade	1
regulation of ERK1 and ERK2 cascade	1
dephosphorylation	1
protein modification process	1
phosphatase activity	1
catalytic activity, acting on a protein	1
phosphoric ester hydrolase activity	1
protein tyrosine/serine/threonine phosphatase activity	1
protein serine/threonine phosphatase activity	1
binding	1
catalytic activity	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

2028 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DUSP4	MAPK3	P27361	734
DUSP4	PTPN21	Q16825	697
DUSP4	EGR1	P18146	628
DUSP4	MAPK9	P45984	571
DUSP4	PTGDS	P41222	569
DUSP4	MAP2K2	P36507	566
DUSP4	ETS1	P14921	564
DUSP4	BCL2	P10415	560
DUSP4	SPRY2	O43597	558
DUSP4	SPRY4	Q9C004	552
DUSP4	HPGDS	O60760	549
DUSP4	PTPN11	Q06124	541
DUSP4	DUSP12	Q9UNI6	541
DUSP4	RPS6KA2	Q15349	509
DUSP4	DUSP6	Q16828	501

IntAct

49 interactions, top by confidence:

A	B	Type	Score
MAPK1	DUSP4	psi-mi:“MI:0915”(physical association)	0.810
DUSP4	MAPK1	psi-mi:“MI:0914”(association)	0.810
DUSP4	MAPK1	psi-mi:“MI:0915”(physical association)	0.810
MAPK9	DUSP4	psi-mi:“MI:0915”(physical association)	0.660
DUSP4	MAPK9	psi-mi:“MI:2364”(proximity)	0.660
DUSP4	TEPSIN	psi-mi:“MI:0915”(physical association)	0.560
DUSP4	ZNF426	psi-mi:“MI:0915”(physical association)	0.560
TRAF1	DUSP4	psi-mi:“MI:0915”(physical association)	0.560
DUSP4	LZTS2	psi-mi:“MI:0915”(physical association)	0.560
DUSP4	GORASP2	psi-mi:“MI:0915”(physical association)	0.560
DUSP4	LYSMD2	psi-mi:“MI:0915”(physical association)	0.560
DUSP4	ZNF655	psi-mi:“MI:0915”(physical association)	0.560
DUSP4	NOXA1	psi-mi:“MI:0915”(physical association)	0.560
DUSP4	LYSMD1	psi-mi:“MI:0915”(physical association)	0.560
DUSP4	PLEKHF2	psi-mi:“MI:0915”(physical association)	0.560
HSPB8	VWA8	psi-mi:“MI:0914”(association)	0.530
DUSP4	CRMP1	psi-mi:“MI:0915”(physical association)	0.370
DUSP4	MYO1C	psi-mi:“MI:0914”(association)	0.350
PTPN12	PRPSAP2	psi-mi:“MI:0914”(association)	0.350
MAPK1	SEC16A	psi-mi:“MI:0914”(association)	0.350
DUSP4	PSMD11	psi-mi:“MI:0914”(association)	0.350
PTPN12	HSPB1	psi-mi:“MI:0914”(association)	0.350
DUSP4	H3-7	psi-mi:“MI:0914”(association)	0.350
EEF1AKMT3	SMCHD1	psi-mi:“MI:0914”(association)	0.350
DUSP4	TRAF1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (140): MAPK3 (Affinity Capture-Western), MAPK8 (Affinity Capture-Western), MAPK9 (Co-localization), EIF3C (Affinity Capture-MS), MAPK1 (Affinity Capture-MS), DUSP4 (Affinity Capture-MS), MAPK3 (Affinity Capture-MS), MAPK1 (Affinity Capture-MS), WDR34 (Affinity Capture-MS), COA7 (Affinity Capture-MS), NME2P1 (Affinity Capture-MS), ABHD14B (Affinity Capture-MS), VPS29 (Affinity Capture-MS), PRDX5 (Affinity Capture-MS), PPIA (Affinity Capture-MS)

ESM2 similar proteins: O43304, O54838, O75038, O95382, P0C591, P0C592, P0C594, P0C595, P0C596, P28562, P28563, Q05922, Q05923, Q13115, Q14451, Q16690, Q16828, Q16829, Q17QJ3, Q2KJ36, Q4RQD3, Q561R2, Q5FVI9, Q5R6H6, Q60806, Q61152, Q62767, Q63340, Q64346, Q64623, Q68J44, Q6B8I0, Q6PAT0, Q8BFV3, Q8BK84, Q90W58, Q91790, Q91Z46, Q99952, Q99956

Diamond homologs: A0A7H0DN78, P07239, P0C597, P0C598, P0C5A0, P0C5A1, P0DOQ5, P0DOQ6, P20495, P28191, P28562, P28563, P29074, P51452, P80994, Q05923, Q13115, Q16690, Q16828, Q2KJ36, Q4RQD3, Q54R42, Q54T76, Q5RD73, Q62767, Q64346, Q64623, Q6B8I0, Q6B8I1, Q84JU4, Q85297, Q8BFV3, Q90W58, Q91790, Q99956, Q9D0T2, Q9DBB1, Q9J592, Q9M8K7, Q9PW71

SIGNOR signaling

10 interactions.

A	Effect	B	Mechanism
DUSP4	down-regulates	MAPK14	dephosphorylation
DUSP4	down-regulates	MAPK8	dephosphorylation
DUSP4	down-regulates	MAPK1	dephosphorylation
DUSP4	down-regulates	MAPK9	dephosphorylation
DUSP4	“down-regulates activity”	MAPK3	dephosphorylation
DUSP4	“down-regulates activity”	MAPK1	dephosphorylation
DUSP4	“down-regulates activity”	Gbeta	dephosphorylation
DUSP4	“down-regulates activity”	ERK1/2	dephosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

59 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	48
Likely benign	5
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

605 predictions. Top by Δscore:

Variant	Effect	Δscore
8:29337407:GGCAT:G	acceptor_gain	1.0000
8:29337408:GCAT:G	acceptor_gain	1.0000
8:29337409:CAT:C	acceptor_gain	1.0000
8:29337409:CATC:C	acceptor_gain	1.0000
8:29337410:AT:A	acceptor_gain	1.0000
8:29337412:C:CC	acceptor_gain	1.0000
8:29337412:CTGG:C	acceptor_loss	1.0000
8:29337419:C:CT	acceptor_gain	1.0000
8:29338277:CCTA:C	donor_loss	1.0000
8:29338278:CTA:C	donor_loss	1.0000
8:29338279:TACC:T	donor_loss	1.0000
8:29338280:A:AC	donor_gain	1.0000
8:29338281:C:CC	donor_gain	1.0000
8:29338281:CCGAT:C	donor_gain	1.0000
8:29338299:T:TA	donor_gain	1.0000
8:29338300:C:A	donor_gain	1.0000
8:29338497:CCCCC:C	acceptor_gain	1.0000
8:29338498:CCCC:C	acceptor_gain	1.0000
8:29338498:CCCCC:C	acceptor_gain	1.0000
8:29338499:CCC:C	acceptor_gain	1.0000
8:29338499:CCCC:C	acceptor_gain	1.0000
8:29338500:CCC:C	acceptor_gain	1.0000
8:29340093:TCTA:T	donor_loss	1.0000
8:29340094:CTACC:C	donor_loss	1.0000
8:29340095:TACCT:T	donor_loss	1.0000
8:29340097:C:CG	donor_loss	1.0000
8:29340240:CCGC:C	acceptor_gain	1.0000
8:29340241:CGC:C	acceptor_gain	1.0000
8:29340241:CGCC:C	acceptor_gain	1.0000
8:29340241:CGCCT:C	acceptor_loss	1.0000

AlphaMissense

2554 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:29337228:A:G	L328P	1.000
8:29337231:A:G	L327P	1.000
8:29337231:A:T	L327Q	1.000
8:29337242:G:C	F323L	1.000
8:29337242:G:T	F323L	1.000
8:29337243:A:C	F323C	1.000
8:29337243:A:G	F323S	1.000
8:29337244:A:C	F323V	1.000
8:29337244:A:G	F323L	1.000
8:29337244:A:T	F323I	1.000
8:29337251:G:C	N320K	1.000
8:29337251:G:T	N320K	1.000
8:29337255:G:A	P319L	1.000
8:29337255:G:C	P319R	1.000
8:29337255:G:T	P319H	1.000
8:29337256:G:A	P319S	1.000
8:29337256:G:C	P319A	1.000
8:29337256:G:T	P319T	1.000
8:29337261:A:T	I317N	1.000
8:29337271:G:T	R314S	1.000
8:29337282:A:T	V310D	1.000
8:29337290:G:C	F307L	1.000
8:29337290:G:T	F307L	1.000
8:29337292:A:G	F307L	1.000
8:29337327:A:G	L295P	1.000
8:29337331:A:C	Y294D	1.000
8:29337333:G:T	A293D	1.000
8:29337336:A:G	L292P	1.000
8:29337338:G:C	C291W	1.000
8:29337339:C:T	C291Y	1.000

dbSNP variants (sampled 300 via entrez): RS1000900931 (8:29347303 T>C), RS1000933015 (8:29347004 C>G,T), RS1001117235 (8:29339785 C>A,T), RS1001321093 (8:29332823 AAAG>A), RS1001507715 (8:29338153 A>G), RS1001604988 (8:29344336 A>C,G), RS1001610985 (8:29343851 C>G), RS1001753445 (8:29350186 G>A,C), RS1001765216 (8:29349019 C>T), RS1001901244 (8:29345877 C>G,T), RS1001998907 (8:29342175 G>A), RS1002010889 (8:29348339 C>T), RS1002060361 (8:29343506 G>GTGTC), RS1002105836 (8:29348101 C>T), RS1002163813 (8:29334450 G>A)

Disease associations

OMIM: gene MIM:602747 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST000635_16	Response to statin therapy	3.000000e-08
GCST004844_2	Gestational age at birth (maternal effect)	2.000000e-06
GCST004845_2	Spontaneous preterm birth (maternal effect)	2.000000e-08
GCST007981_2	Postoperative complication after cardiac surgery	6.000000e-06
GCST011957_27	Prostate cancer	5.000000e-09

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0005112	gestational age
EFO:0005939	parental genotype effect measurement
EFO:0006917	spontaneous preterm birth
EFO:0005323	post-operative sign or symptom
EFO:0009951	response to surgery

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2146343 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

1 potent at pChembl≥5 of 3 total, top 1 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.64	IC50	2290	nM	CHEMBL2146956

PubChem BioAssay actives

1 with measured affinity, of 7 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
6-pyrazin-2-yl-3-quinolin-2-yl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole	687366: Inhibition of MKP2	ic50	2.2900	uM

CTD chemical–gene interactions

113 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression, increases methylation	8
Estradiol	affects cotreatment, increases expression, decreases expression	6
trichostatin A	affects cotreatment, decreases expression, affects expression	4
Doxorubicin	increases expression, affects expression	4
(+)-JQ1 compound	affects cotreatment, affects expression, decreases expression	3
Benzo(a)pyrene	increases expression, increases methylation	3
Mitoxantrone	affects response to substance, increases expression	3
Particulate Matter	increases abundance, increases expression	3
mono-(2-ethylhexyl)phthalate	increases abundance, increases methylation, increases expression	2
sodium arsenite	decreases methylation, decreases expression	2
Panobinostat	affects cotreatment, decreases expression	2
Air Pollutants	increases expression, increases abundance	2
Daunorubicin	increases expression	2
Etoposide	affects response to substance, increases expression	2
Formaldehyde	decreases expression, increases expression	2
Tetrachlorodibenzodioxin	affects cotreatment, increases expression	2
Cyclosporine	increases expression, decreases expression	2
Aflatoxin B1	increases expression	2
Asbestos, Crocidolite	affects expression, increases expression	2
GSK-J4	decreases expression	1
sotorasib	affects cotreatment, decreases expression	1
daidzein	decreases expression	1
methylmercuric chloride	increases expression	1
bisphenol A	increases expression	1
lead acetate	increases expression	1
2,5,2’,5’-tetrachlorobiphenyl	increases expression	1
terbufos	increases methylation	1
beta-lapachone	increases expression	1
plumbagin	decreases reaction, increases cleavage, increases expression, decreases expression	1
afimoxifene	increases expression, affects reaction	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2148511	Binding	Inhibition of MKP2	Discovery of potent inhibitors of receptor protein tyrosine phosphatase sigma through the structure-based virtual screening. — Bioorg Med Chem Lett

Cellosaurus cell lines

7 cell lines: 6 cancer cell line, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B2MP	Abcam A-549 DUSP4 KO	Cancer cell line	Male
CVCL_B8EX	Abcam HCT 116 DUSP4 KO	Cancer cell line	Male
CVCL_B8V0	Abcam MCF-7 DUSP4 KO	Cancer cell line	Female
CVCL_D7P3	Ubigene A-549 DUSP4 KO	Cancer cell line	Male
CVCL_D8KI	Ubigene HCT 116 DUSP4 KO	Cancer cell line	Male
CVCL_D9DU	Ubigene HEK293 DUSP4 KO	Transformed cell line	Female
CVCL_E0C5	Ubigene HeLa DUSP4 KO	Cancer cell line	Female

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.