DUSP6

Summary

DUSP6 (dual specificity phosphatase 6, HGNC:3072) is a protein-coding gene on chromosome 12q21.33, encoding Dual specificity protein phosphatase 6 (Q16828). Dual specificity protein phosphatase, which mediates dephosphorylation and inactivation of MAP kinases. In precision oncology, DUSP6 EXPRESSION confers sensitivity to Trametinib in Cancer (CIViC Level D).

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 ERK2, is expressed in a variety of tissues with the highest levels in heart and pancreas, and unlike most other members of this family, is localized in the cytoplasm. Mutations in this gene have been associated with congenital hypogonadotropic hypogonadism. Alternatively spliced transcript variants have been found for this gene.

Source: NCBI Gene 1848 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hypogonadotropic hypogonadism (Supportive, GenCC) — +2 more curated relationships
• GWAS associations: 5
• Clinical variants (ClinVar): 93 total — 1 pathogenic
• Phenotypes (HPO): 79
• Druggable target: yes
• Precision-oncology evidence (CIViC): 1 curated variant–drug association
• MANE Select transcript: NM_001946

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3072
Approved symbol	DUSP6
Name	dual specificity phosphatase 6
Location	12q21.33
Locus type	gene with protein product
Status	Approved
Aliases	MKP-3, PYST1
Ensembl gene	ENSG00000139318
Ensembl biotype	protein_coding
OMIM	602748
Entrez	1848

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 5 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000279488, ENST00000308385, ENST00000547140, ENST00000547291, ENST00000548755, ENST00000924807

RefSeq mRNA: 2 — MANE Select: NM_001946 NM_001946, NM_022652

CCDS: CCDS9033, CCDS9034

Canonical transcript exons

ENST00000279488 — 3 exons

Exon	Start	End
ENSE00002323215	89351640	89352501
ENSE00002366545	89347235	89349561
ENSE00003625718	89350588	89351025

Expression profiles

Bgee: expression breadth ubiquitous, 296 present calls, max score 99.11.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 34.2767 / max 918.8349, expressed in 1610 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
132446	24.3522	1577
132445	5.8995	1155
132444	3.1178	799
132442	0.4506	202
206829	0.3071	166
132443	0.1495	55

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
parotid gland	UBERON:0001831	99.11	gold quality
pericardium	UBERON:0002407	99.01	gold quality
monocyte	CL:0000576	98.85	gold quality
mononuclear cell	CL:0000842	98.78	gold quality
leukocyte	CL:0000738	98.76	gold quality
mammary duct	UBERON:0001765	98.73	gold quality
epithelium of mammary gland	UBERON:0003244	98.51	gold quality
visceral pleura	UBERON:0002401	98.50	gold quality
lower lobe of lung	UBERON:0008949	98.47	gold quality
pigmented layer of retina	UBERON:0001782	98.14	gold quality
retina	UBERON:0000966	98.11	gold quality
granulocyte	CL:0000094	97.79	gold quality
pleura	UBERON:0000977	97.77	gold quality
parietal pleura	UBERON:0002400	97.49	gold quality
trachea	UBERON:0003126	97.42	gold quality
skin of hip	UBERON:0001554	97.08	gold quality
gall bladder	UBERON:0002110	96.80	gold quality
mammary gland	UBERON:0001911	96.70	gold quality
thoracic mammary gland	UBERON:0005200	96.66	gold quality
mucosa of sigmoid colon	UBERON:0004993	96.61	gold quality
pylorus	UBERON:0001166	96.16	gold quality
upper leg skin	UBERON:0004262	96.07	gold quality
cervix squamous epithelium	UBERON:0006922	96.05	gold quality
mucosa of urinary bladder	UBERON:0001259	96.04	gold quality
layer of synovial tissue	UBERON:0007616	95.94	gold quality
synovial joint	UBERON:0002217	95.82	gold quality
bone marrow	UBERON:0002371	95.66	gold quality
urethra	UBERON:0000057	95.64	gold quality
germinal epithelium of ovary	UBERON:0001304	95.60	gold quality
dorsal root ganglion	UBERON:0000044	95.37	gold quality

Single-cell (SCXA)

Detected in 16 experiment(s), a significant marker in 13.

Experiment	Marker?	Max mean expression
E-MTAB-9221	yes	972.20
E-GEOD-149689	yes	960.52
E-MTAB-7381	yes	737.56
E-MTAB-9467	yes	30.67
E-GEOD-135922	yes	22.59
E-GEOD-93593	yes	14.92
E-MTAB-6701	yes	14.30
E-MTAB-8498	yes	12.19
E-CURD-112	yes	8.14
E-CURD-46	yes	6.33
E-MTAB-6678	yes	4.95
E-MTAB-9801	yes	4.60
E-CURD-10	no	759.66
E-MTAB-10596	no	549.07
E-MTAB-6524	no	255.91

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CTNNB1, ETS1, ETS2, ETV3, ETV4, F2RL1, FOXO3, MYB, WT1

miRNA regulators (miRDB)

130 targeting DUSP6, 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-8485	100.00	77.57	4731
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-4267	99.96	66.53	2368

Literature-anchored findings (GeneRIF, showing 40)

• Angiotensin II-induced upregulation of MAP kinase phosphatase-3 mRNA levels mediates endothelial cell apoptosis (PMID:11998972)
• Results show that DUSP6 exerts apparent tumor-suppressive effects in vitro and suggest that DUSP6 is a strong candidate tumor suppressor gene at 12q22 locus. (PMID:12759238)
• Constitutive induction of p-Erk1/2 accompanied by reduced activities of protein phosphatases 1 and 2A and MKP3 due to reactive oxygen species during cellular senescence. (PMID:12840032)
• Study gives first direct evidence that the N-terminal domain of MKP3 mediates intramolecular dephosphorylation between the monomeric form of phosphorylated extracellular signal-regulated kinase and a monomer of MKP3. (PMID:14690430)
• cytoplasmic localization of MKP3 is mediated by a chromosome region maintenance-1 (CRM1)-dependent nuclear export pathway; the ability of MKP3 to cause the cytoplasmic retention of ERK2 requires both a functional kinase interaction motif and NES (PMID:15269220)
• Hypermethylation with modification of histone deacetylation play an important role in transcriptional suppression of DUSP6 in human pancreatic cancer (PMID:15824892)
• Results suggest that the abrogation of DUSP6 is associated exclusively with progression from pancreatic intraepithelial neoplasia to the invasive ductal carcinoma. (PMID:15832194)
• Results demonstrate that in the Korean population DUSP6 may contribute to the etiology of bipolar disorder, but not schizophrenia. (PMID:16491131)
• These results suggest the existence of an ERK1/2-driven negative feed-back regulation of ERK5 signaling in epidermal growth factor-stimulated HK-2 cells, which is mediated by MKP-3, DUSP5 and/or MKP-1. (PMID:17131384)
• Nuclear matrix proteins such as mutant Pyst1 and nucleophosmin 1 were downregulated, whereas eIF6 and beta-tubulin were upregulated during cell differentiation in hepatocarcinoma cells. (PMID:17569113)
• even upon over-expression DUSP6 fails to inactivate ERK5, confirming that it is indeed an ERK1/2-specific DUSP (PMID:18280112)
• MKP3 can act to enhance DAT function and is a phosphatase involved in regulating dynamin-dependent endocysis (PMID:18434601)
• Loss of MKP3 mediated by oxidative stress enhances tumorigenicity and chemoresistance of ovarian cancer (PMID:18632752)
• WT1 transactivates another important negative regulator of the Ras/MAPK pathway, MAPK phosphatase 3 (MKP3). (PMID:18644985)
• mitogen-activated protein kinase phosphatase 3 activity is inhibited by interdomain binding (PMID:18694935)
• regulation of ERK1/2 by MKP-3 is countered by the complex regulation of MKP-3 by ERK1/2. (PMID:18771677)
• These results indicate that intron 1 of DUSP6 plays a crucial role in transcriptional regulation of DUSP6 in a feedback loop manner responding to MAPK1 via ETS2 in human cells. (PMID:18848526)
• Sphingosine-1-phosphate inhibits high glucose-mediated ERK1/2 action in endothelium through induction of MAP kinase phosphatase-3. (PMID:19091959)
• MKP3 is an important regulator of PDGF-induced Erk phosphorylation acting in both a rapid positive feed-forward and a later negative feed-back loop. (PMID:19106095)
• These results suggest that DUSP6 is a growth suppressor whose inactivation could promote the progression of lung cancer. (PMID:19608870)
• Dual specificity phosphatase 6 (DUSP6) is an ETS-regulated negative feedback mediator of oncogenic ERK signaling in lung cancer cells. (PMID:20097731)
• the differential up-regulation of MKP3 by Ets2 and of DUSP5 by c-Jun may converge in similar functional roles for these MAP kinase phosphatases in the growth arrest versus proliferation decisions of breast cancer cells (PMID:20554528)
• DUSP6 methylation is a rare event in endometrial cancer. Silencing of the DUSP6 phosphatase is unlikely to contribute to constitutive activation of the ERK kinase cascade in endometrial cancer. (PMID:20638106)
• This study shows that post-transcriptional regulation is a key process in the control of DUSP6 expression. (PMID:20665674)
• DUSP5 and DUSP6 selectively control ERK pathway activity and proliferation. (PMID:20806045)
• Loss of DUSP6 is associated with esophageal squamous cell carcinoma and nasopharyngeal carcinoma. (PMID:21387288)
• MKP3 not only controls the activities of ERK2 and p38alpha but also mediates cross-talk between these two MAPK pathways. (PMID:21454500)
• upregulation of DUSP6 exerts a tumor-promoting role in human glioblastomas exacerbating the malignant phenotype. (PMID:21499306)
• DUSP6 plays an important role in cancer resistance in different subtypes of non-small cell lung carcinoma. (PMID:21680106)
• Studies indicate that ERKs stimulate their own dephosphorylation by directly binding to phosphatases, such as MKP-3, and activating them. (PMID:22028468)
• DUSP6 plays an important role in the pathogenesis of bipolar disorder, particularly in women. (PMID:22155192)
• Studies identified a single gene DUSP6, whose expression was associated with sensitivity to GSK1120212. (PMID:22169769)
• DUSP6 is important in melanoma and it plays a different role in the distinct subtype of mouse melanoma compared with that in classic human melanoma. (PMID:22171919)
• caspase-3 cleavage of MKP3 down-regulates MKP3 full length and renders active MKP3 fragments, which may participate in novel regulatory pathways controlling the subcellular localization and activation of ERK1/2 during apoptosis. (PMID:22504224)
• A link between DUSP6 expression and high-risk features of papillary thyroid carcinoma suggested that DUSP6 is an important independent factor affecting the signaling pathways in established papillary thyroid carcinoma. (PMID:22535643)
• MESP2, HES7 and DUSP6 genes may not be involved in the etiopathogenesis of sporadic and non-syndromic CS in Chinese Han population. (PMID:22744456)
• Studies indicate that dual-specificity MAP kinase phosphatases (MKPs) DUSP6/MKP-3 and DUSP5 are localized in the cytoplasm and nuclear compartments. (PMID:22812510)
• ischemia/reperfusion inhibited eNOS expression by inactivation of ERK1/2, leading to decreased NO formation through a MKP-3-dependent mechanism in endothelial cells (PMID:22848708)
• study reports that naive CD4 T cells from elderly individuals have reduced signaling capacity of the ERK pathway; the underlying mechanism is an age-related decline in miR-181a expression and associated rise in levels of DUSP6 expression (PMID:23023500)
• The results provide insights on the modulatory role of p53 in the survival pathway by up-regulating DUSP6. (PMID:23108049)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	dusp6	ENSDARG00000070914
mus_musculus	Dusp6	ENSMUSG00000019960
rattus_norvegicus	Dusp6	ENSRNOG00000023896

Paralogs (31): DUSP13B (ENSG00000079393), DUSP12 (ENSG00000081721), SSH1 (ENSG00000084112), DUSP3 (ENSG00000108861), PTPMT1 (ENSG00000110536), DUSP16 (ENSG00000111266), EPM2A (ENSG00000112425), DUSP22 (ENSG00000112679), DUSP1 (ENSG00000120129), DUSP4 (ENSG00000120875), STYXL1 (ENSG00000127952), DUSP9 (ENSG00000130829), DUSP26 (ENSG00000133878), DUSP5 (ENSG00000138166), 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 6 — Q16828 (reviewed: Q16828)

Alternative names: Dual specificity protein phosphatase PYST1, Mitogen-activated protein kinase phosphatase 3

All UniProt accessions (3): Q16828, F8VW29, F8VZA4

UniProt curated annotations — full annotation on UniProt →

Function. Dual specificity protein phosphatase, which mediates dephosphorylation and inactivation of MAP kinases. Has a specificity for the ERK family. Plays an important role in alleviating chronic postoperative pain. Necessary for the normal dephosphorylation of the long-lasting phosphorylated forms of spinal MAPK1/3 and MAP kinase p38 induced by peripheral surgery, which drives the resolution of acute postoperative allodynia. Also important for dephosphorylation of MAPK1/3 in local wound tissue, which further contributes to resolution of acute pain. Promotes cell differentiation by regulating MAPK1/MAPK3 activity and regulating the expression of AP1 transcription factors.

Subunit / interactions. Interacts with MAPK1/ERK2.

Subcellular location. Cytoplasm.

Tissue specificity. Expressed in keratinocytes (at protein level).

Post-translational modifications. Ubiquitinated by the SCF(FBXO31) complex, leading to its proteasomal degradation.

Disease relevance. Hypogonadotropic hypogonadism 19 with or without anosmia (HH19) [MIM:615269] A disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic-pituitary axis. In some cases, it is associated with non-reproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss. Anosmia or hyposmia is related to the absence or hypoplasia of the olfactory bulbs and tracts. Hypogonadism is due to deficiency in gonadotropin-releasing hormone and probably results from a failure of embryonic migration of gonadotropin-releasing hormone-synthesizing neurons. In the presence of anosmia, idiopathic hypogonadotropic hypogonadism is referred to as Kallmann syndrome, whereas in the presence of a normal sense of smell, it has been termed normosmic idiopathic hypogonadotropic hypogonadism (nIHH). The disease is caused by variants affecting distinct genetic loci, including the gene represented in this entry. Some patients carrying mutations in DUSP6 also have a heterozygous mutation in another HH-associated gene including FGFR1 and SPRY4.

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

Isoforms (2)

UniProt ID	Names	Canonical?
Q16828-1	1	yes
Q16828-2	2, DUSP6-ALT

RefSeq proteins (2): NP_001937, NP_073143 (=MANE)

Domains & families (InterPro)

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

Pfam: PF00581, PF00782

Enzyme classification (BRENDA):

• EC 3.1.3.16 — protein-serine/threonine phosphatase (BRENDA: 92 organisms, 641 substrates, 468 inhibitors, 127 Km, 67 kcat entries)
• EC 3.1.3.48 — protein-tyrosine-phosphatase (BRENDA: 59 organisms, 501 substrates, 1326 inhibitors, 270 Km, 165 kcat entries)

Substrate kinetics (BRENDA)

129 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
4-NITROPHENYL PHOSPHATE	0.0008–148	84
6,8-DIFLUORO-4-METHYLUMBELLIFERYL PHOSPHATE	0.0039–0.862	27
6,8-DIFLUORO-4-METHYLUMBELLIFERYL PHOSPHATE	0.023–0.862	22
P-NITROPHENYL PHOSPHATE	0.0024–10	20
4-NITROPHENYL PHOSPHATE	0.0028–12.7	13
DADEPYLIPQQG	0.0003–0.1	12
P-NITROPHENYL PHOSPHATE	3–200	11
PHOSPHOTYROSINE	0.012–30	11
LYSOZYME	0.0003–0.012	5
MYELIN BASIC PROTEIN	0.0001–0.022	5
RRAPTVA	0.058–1.954	4
ACETYL-DADEPY-NH2	0.0228–0.219	4
ACETYL-DADEPYL-NH2	1.1–97.5	4
PHOSPHOCASEIN	0.0001–0.002	3
PHOSPHOHISTONE	0.0023–0.0723	3

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 (41 total): strand 14, helix 12, sequence variant 7, domain 2, chain 1, turn 1, region of interest 1, compositionally biased region 1, active site 1, splice variant 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
1MKP	X-RAY DIFFRACTION	2.35
1HZM	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q16828-F1	76.13	0.38

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): 293 (phosphocysteine intermediate)

Function

Pathways and Gene Ontology

Reactome pathways

4 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
R-HSA-9652817	Signaling by MAPK mutants

MSigDB gene sets: 798 (showing top): GSE45365_NK_CELL_VS_BCELL_UP, CREL_01, TONKS_TARGETS_OF_RUNX1_RUNX1T1_FUSION_MONOCYTE_UP, GOBP_NEGATIVE_REGULATION_OF_ERK1_AND_ERK2_CASCADE, MODULE_52, LEE_NEURAL_CREST_STEM_CELL_DN, BROWNE_HCMV_INFECTION_6HR_DN, WANG_CLIM2_TARGETS_UP, REACTOME_INNATE_IMMUNE_SYSTEM, BENPORATH_ES_WITH_H3K27ME3, HNF3ALPHA_Q6, SWEET_KRAS_ONCOGENIC_SIGNATURE, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_REGULATION_OF_DEVELOPMENTAL_GROWTH, KEGG_MAPK_SIGNALING_PATHWAY

GO Biological Process (14): MAPK cascade (GO:0000165), signal transduction (GO:0007165), response to xenobiotic stimulus (GO:0009410), cell differentiation (GO:0030154), peptidyl-tyrosine dephosphorylation (GO:0035335), positive regulation of apoptotic process (GO:0043065), negative regulation of MAPK cascade (GO:0043409), response to nitrosative stress (GO:0051409), regulation of heart growth (GO:0060420), ERK1 and ERK2 cascade (GO:0070371), negative regulation of ERK1 and ERK2 cascade (GO:0070373), response to growth factor (GO:0070848), protein dephosphorylation (GO:0006470), dephosphorylation (GO:0016311)

GO Molecular Function (9): protein serine/threonine phosphatase activity (GO:0004722), protein tyrosine phosphatase activity (GO:0004725), protein tyrosine/serine/threonine phosphatase activity (GO:0008138), protein tyrosine/threonine phosphatase activity (GO:0008330), MAP kinase tyrosine/serine/threonine phosphatase activity (GO:0017017), MAP kinase tyrosine phosphatase activity (GO:0033550), phosphoprotein phosphatase activity (GO:0004721), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (3): nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-4 pathways:

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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
phosphoprotein phosphatase activity	4
cellular anatomical structure	3
MAPK cascade	2
MAP kinase phosphatase activity	2
intracellular signaling cassette	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
response to chemical	1
cellular developmental process	1
protein dephosphorylation	1
apoptotic process	1
regulation of apoptotic process	1
positive regulation of programmed cell death	1
regulation of MAPK cascade	1
negative regulation of intracellular signal transduction	1
response to stress	1
regulation of organ growth	1
heart growth	1
regulation of multicellular organismal development	1
negative regulation of MAPK cascade	1
ERK1 and ERK2 cascade	1
regulation of ERK1 and ERK2 cascade	1
response to endogenous stimulus	1
dephosphorylation	1
protein modification process	1
phosphate-containing compound metabolic process	1
protein tyrosine/serine/threonine phosphatase activity	1
protein tyrosine phosphatase activity	1
phosphatase activity	1
catalytic activity, acting on a protein	1
binding	1
catalytic activity	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1

Protein interactions and networks

STRING

2230 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DUSP6	MAPK1	P28482	928
DUSP6	SPRY2	O43597	776
DUSP6	MAPK3	P27361	746
DUSP6	SPRY4	Q9C004	725
DUSP6	FOS	P01100	660
DUSP6	JUN	P05412	644
DUSP6	EGR1	P18146	642
DUSP6	NRARP	Q7Z6K4	621
DUSP6	FGF3	P11487	612
DUSP6	TP53	P04637	605
DUSP6	NKD1	Q969G9	591
DUSP6	ETV4	P43268	589
DUSP6	MAP2K2	P36507	579
DUSP6	MAP2K1	Q02750	578
DUSP6	ETV5	P41161	575

IntAct

32 interactions, top by confidence:

A	B	Type	Score
MAPK1	DUSP6	psi-mi:“MI:0915”(physical association)	0.760
DUSP6	MAPK3	psi-mi:“MI:0914”(association)	0.740
DUSP6	MAPK3	psi-mi:“MI:0915”(physical association)	0.740
TXK	DUSP6	psi-mi:“MI:0915”(physical association)	0.560
DUSP6	PHB2	psi-mi:“MI:0915”(physical association)	0.560
APP	DUSP6	psi-mi:“MI:0915”(physical association)	0.560
FAM217B	NCK2	psi-mi:“MI:0914”(association)	0.530
DUSP6	SRPK1	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
DUSP6	NEIL1	psi-mi:“MI:0915”(physical association)	0.400
DUSP6	LMTK2	psi-mi:“MI:0915”(physical association)	0.370
DUSP6	AATK	psi-mi:“MI:0915”(physical association)	0.370
DUSP6	ERBB4	psi-mi:“MI:0915”(physical association)	0.370
DUSP6	ROR2	psi-mi:“MI:0915”(physical association)	0.370
DUSP6	LTK	psi-mi:“MI:0915”(physical association)	0.370
DUSP6	MDFI	psi-mi:“MI:0915”(physical association)	0.370
DUSP6	TEX11	psi-mi:“MI:0915”(physical association)	0.370
CAND1	GTPBP10	psi-mi:“MI:0914”(association)	0.350
DUSP6	HSPA8	psi-mi:“MI:0914”(association)	0.350
DUSP6	HSPB1	psi-mi:“MI:0914”(association)	0.350
MAPK3	HMMR	psi-mi:“MI:0914”(association)	0.350
ADIPOR2	NCK2	psi-mi:“MI:0914”(association)	0.350
MAEA	MPO	psi-mi:“MI:0914”(association)	0.350

BioGRID (159): MAPK3 (Affinity Capture-Western), MAPK1 (Affinity Capture-Western), DUSP6 (Affinity Capture-Western), DUSP6 (Affinity Capture-Western), DUSP6 (Affinity Capture-Western), TAGLN (Affinity Capture-Western), DUSP6 (Affinity Capture-MS), MDFI (Two-hybrid), TEX11 (Two-hybrid), MAPK1 (Affinity Capture-MS), MAPK3 (Affinity Capture-MS), DUSP6 (Affinity Capture-MS), WRB (Affinity Capture-MS), MAPK3 (Affinity Capture-MS), TMEM126A (Affinity Capture-MS)

ESM2 similar proteins: A4D256, A4IHU7, O14830, O35239, O35385, O95147, P0C591, P0C592, P0C593, P0C594, P0C595, P0C596, P0C597, P0C598, P0C599, P0C5A0, P0C5A1, P0C5A2, P43378, P51452, Q16828, Q17QM8, Q29RA3, Q2KJ36, Q4KL92, Q4RQD3, Q566R7, Q5RD73, Q5XHB2, Q641Z2, Q64346, Q68J44, Q6AXW7, Q6GQJ8, Q86BN8, Q8BK84, Q8K4T5, Q8WTR2, Q8WUK0, Q90W58

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

19 interactions.

A	Effect	B	Mechanism
DUSP6	down-regulates	MAPK1	dephosphorylation
DUSP6	down-regulates	MAPK3	dephosphorylation
MAPK1	“down-regulates quantity by destabilization”	DUSP6	phosphorylation
MAPK3	down-regulates	DUSP6	phosphorylation
DUSP6	up-regulates	FOXO1	dephosphorylation
INS	down-regulates	DUSP6
DUSP6	up-regulates	FOXO	dephosphorylation
F2RL1	“up-regulates quantity by expression”	DUSP6	“transcriptional regulation”
DUSP6	down-regulates	Gbeta	dephosphorylation
DUSP6	down-regulates	ERK1/2	dephosphorylation
Gbeta	down-regulates	DUSP6	phosphorylation
ERK1/2	down-regulates	DUSP6	phosphorylation
DUSP6	“up-regulates activity”	FOXO1	dephosphorylation
DUSP6	“down-regulates activity”	MAPK1	dephosphorylation
DUSP6	“down-regulates activity”	MAPK7	dephosphorylation
DUSP6	“down-regulates activity”	MAPK8	dephosphorylation
ETV3	“down-regulates quantity by repression”	DUSP6	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 25 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
protein phosphorylation	6	17.0×	4e-04
negative regulation of apoptotic process	6	8.7×	2e-03

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	50
Likely benign	21
Benign	16

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
1033462	NM_001946.4(DUSP6):c.117C>A (p.Cys39Ter)	Pathogenic

SpliceAI

333 predictions. Top by Δscore:

Variant	Effect	Δscore
12:89349558:TCAT:T	acceptor_gain	1.0000
12:89349559:CAT:C	acceptor_gain	1.0000
12:89349559:CATC:C	acceptor_gain	1.0000
12:89349561:TC:T	acceptor_loss	1.0000
12:89349562:C:A	acceptor_loss	1.0000
12:89349562:C:CC	acceptor_gain	1.0000
12:89349563:T:A	acceptor_loss	1.0000
12:89349569:C:CT	acceptor_gain	1.0000
12:89350673:T:A	donor_gain	1.0000
12:89351024:ACCTG:A	acceptor_loss	1.0000
12:89351025:CCT:C	acceptor_loss	1.0000
12:89351026:C:T	acceptor_loss	1.0000
12:89351027:T:A	acceptor_loss	1.0000
12:89351635:CGTA:C	donor_loss	1.0000
12:89351636:GTAC:G	donor_loss	1.0000
12:89351637:TAC:T	donor_loss	1.0000
12:89351638:ACCTT:A	donor_gain	1.0000
12:89351639:CCTT:C	donor_gain	1.0000
12:89351639:CCTTC:C	donor_gain	1.0000
12:89351642:T:A	donor_gain	1.0000
12:89351669:T:TA	donor_gain	1.0000
12:89349557:TTCAT:T	acceptor_gain	0.9900
12:89349560:AT:A	acceptor_gain	0.9900
12:89349571:C:CT	acceptor_gain	0.9900
12:89349572:A:T	acceptor_gain	0.9900
12:89350582:TCTCA:T	donor_loss	0.9900
12:89350583:CTCAC:C	donor_loss	0.9900
12:89350584:TCACC:T	donor_loss	0.9900
12:89350585:CA:C	donor_loss	0.9900
12:89350586:A:AG	donor_loss	0.9900

AlphaMissense

2514 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:89349369:T:A	E344V	1.000
12:89349372:A:G	F343S	1.000
12:89349378:A:G	L341P	1.000
12:89349381:A:C	L340R	1.000
12:89349381:A:G	L340P	1.000
12:89349381:A:T	L340Q	1.000
12:89349383:C:A	Q339H	1.000
12:89349383:C:G	Q339H	1.000
12:89349384:T:G	Q339P	1.000
12:89349387:C:T	G338D	1.000
12:89349388:C:G	G338R	1.000
12:89349390:A:G	M337T	1.000
12:89349392:G:C	F336L	1.000
12:89349392:G:T	F336L	1.000
12:89349393:A:C	F336C	1.000
12:89349393:A:G	F336S	1.000
12:89349394:A:C	F336V	1.000
12:89349394:A:G	F336L	1.000
12:89349394:A:T	F336I	1.000
12:89349399:A:G	F334S	1.000
12:89349401:G:C	N333K	1.000
12:89349401:G:T	N333K	1.000
12:89349403:T:C	N333D	1.000
12:89349405:G:A	P332L	1.000
12:89349405:G:C	P332R	1.000
12:89349405:G:T	P332H	1.000
12:89349406:G:A	P332S	1.000
12:89349406:G:C	P332A	1.000
12:89349406:G:T	P332T	1.000
12:89349409:A:G	S331P	1.000

dbSNP variants (sampled 300 via entrez): RS1000286467 (12:89351249 C>T), RS1000776426 (12:89346874 G>C), RS1001171054 (12:89350052 A>G), RS1001285633 (12:89349830 T>C), RS1002554967 (12:89352979 C>G,T), RS1002880407 (12:89354388 C>T), RS1002891404 (12:89347975 A>G), RS1003020884 (12:89352901 T>C), RS1003216589 (12:89349189 T>C), RS1003331551 (12:89348991 C>A,G), RS1003515788 (12:89348640 T>G), RS1004518395 (12:89347508 T>C), RS1004675428 (12:89347292 A>G), RS1005159984 (12:89346986 G>C), RS1006396621 (12:89348323 T>C)

Disease associations

OMIM: gene MIM:602748 | disease phenotypes: MIM:615269

GenCC curated gene-disease

Disease	Classification	Inheritance
hypogonadotropic hypogonadism	Supportive	Autosomal dominant
Kallmann syndrome	Supportive	Autosomal dominant
hypogonadotropic hypogonadism 19 with or without anosmia	Limited	Autosomal dominant

Mondo (3): hypogonadotropic hypogonadism 19 with or without anosmia (MONDO:0014105), hypogonadotropic hypogonadism (MONDO:0018555), Kallmann syndrome (MONDO:0018800)

Orphanet (1): Kallmann syndrome (Orphanet:478)

HPO phenotypes

79 total (30 of 79 shown, HPO-id order):

HPO	Term
HP:0000002	Abnormality of body height
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000008	Abnormal morphology of female internal genitalia
HP:0000013	Hypoplasia of the uterus
HP:0000026	Male hypogonadism
HP:0000027	Azoospermia
HP:0000028	Cryptorchidism
HP:0000044	Hypogonadotropic hypogonadism
HP:0000054	Micropenis
HP:0000104	Renal agenesis
HP:0000118	Phenotypic abnormality
HP:0000134	Female hypogonadism
HP:0000144	Decreased fertility
HP:0000164	Abnormality of the dentition
HP:0000175	Cleft palate
HP:0000316	Hypertelorism
HP:0000365	Hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000458	Anosmia
HP:0000505	Visual impairment
HP:0000508	Ptosis
HP:0000551	Color vision defect
HP:0000639	Nystagmus
HP:0000716	Depression
HP:0000739	Anxiety
HP:0000771	Gynecomastia
HP:0000786	Primary amenorrhea
HP:0000789	Infertility
HP:0000802	Impotence

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST003542_154	Night sleep phenotypes	6.000000e-06
GCST007543_9	Attention deficit hyperactivity disorder	7.000000e-09
GCST012597_10	Attention deficit hyperactivity disorder	2.000000e-06
GCST90000047_184	Age at first sexual intercourse	3.000000e-08
GCST90011899_55	Aspartate aminotransferase levels	1.000000e-08

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0009749	age at first sexual intercourse measurement
EFO:0004736	aspartate aminotransferase measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D017436	Kallmann Syndrome	C12.050.351.875.253.096.750; C12.200.706.316.096.750; C12.800.316.096.750; C16.131.939.316.096.750; C16.320.467; C19.391.119.096.750; C19.391.482.600

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1250381 (SINGLE PROTEIN)

Clinical evidence (CIViC)

Drug × variant × indication: 1 predictive associations from 1 curated evidence items.

Variant	Therapy	Indication	Effect	Level	CIViC
DUSP6 EXPRESSION	Trametinib	Cancer	Sensitivity/Response	CIViC D	EID934

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

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
6.24	IC50	582	nM	CHEMBL590572

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, increases expression	7
Benzo(a)pyrene	affects methylation, increases expression	6
Tetrachlorodibenzodioxin	affects cotreatment, decreases expression, affects expression, increases expression	6
Tretinoin	increases expression	5
Asbestos, Crocidolite	affects expression, increases expression, increases reaction, decreases reaction	5
sodium arsenite	decreases expression, increases expression	4
Estradiol	affects cotreatment, decreases expression, increases expression	4
Aflatoxin B1	affects expression, decreases methylation, increases expression	4
Cadmium Chloride	increases abundance, increases expression, decreases expression	4
Cisplatin	increases expression, decreases response to substance, increases response to substance, affects cotreatment, decreases expression (+1 more)	3
Progesterone	affects cotreatment, decreases expression, increases expression	3
Tobacco Smoke Pollution	decreases expression, increases expression	3
Tunicamycin	increases expression, decreases expression	3
Particulate Matter	increases abundance, increases expression, decreases expression	3
bisphenol A	increases expression	2
mono-(2-ethylhexyl)phthalate	increases expression	2
chromium hexavalent ion	increases expression, increases abundance	2
(+)-JQ1 compound	decreases expression, affects cotreatment	2
Decitabine	affects expression, increases expression	2
Air Pollutants	decreases expression, increases abundance, increases expression	2
Cadmium	increases abundance, increases expression	2
Doxorubicin	decreases expression, increases expression	2
Formaldehyde	increases expression	2
Indomethacin	affects cotreatment, increases expression, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Smoke	increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression, increases expression	2
Cyclosporine	decreases expression, increases expression	2
Thapsigargin	decreases expression, increases expression	2
Genistein	decreases expression, increases expression	2

ChEMBL screening assays

38 unique, capped per target: 37 binding, 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1244655	Binding	Inhibition of Dusp6 in Tg(dusp:EGFP)pt6 zebrafish assessed as increase in FGF-signaling mediated d2EGFP fluorescence at 10 uM after 2 hrs	Zebrafish chemical screening reveals an inhibitor of Dusp6 that expands cardiac cell lineages. — Nat Chem Biol
CHEMBL4626304	ADMET	Inhibition of MKP3 (unknown origin) expressed in Escherichia coli BL21 using p-nitrophenyl phosphate as substrate measured after 30 mins by UV-vis spectrophotometric method	Highly Potent and Selective N-Aryl Oxamic Acid-Based Inhibitors for Mycobacterium tuberculosis Protein Tyrosine Phosphatase B. — J Med Chem

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1C3	Abcam A-431 DUSP6 KO	Cancer cell line	Female
CVCL_C0R8	Caco-2 DUSP6 KO	Cancer cell line	Male
CVCL_D8KJ	Ubigene HCT 116 DUSP6 KO	Cancer cell line	Male
CVCL_E0C6	Ubigene HeLa DUSP6 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00328926	PHASE4	TERMINATED	Luveris® (Lutropin Alfa for Injection) in Women With Hypogonadotropic Hypogonadism (Luteinizing Hormone [LH] Less Than [<] 1.2 International Unit Per Liter [IU/L])
NCT01403532	PHASE4	COMPLETED	Sequential Therapy for Hypogonadotropic Hypogonadism
NCT01454011	PHASE4	COMPLETED	The Effect of Testosterone Replacement on the High Density Lipoprotein Cholesterol Subgroups
NCT01601327	PHASE4	COMPLETED	Effects of Medications in Patients With Hypogonadism
NCT02310074	PHASE4	UNKNOWN	Efficacy and Safety of Pulsatile Gonadotropin Releasing Hormone Pump Treatment in Patients With Idiopathic Hypogonadotropic Hypogonadism
NCT02880280	PHASE4	UNKNOWN	Human Menopausal Gonadotropin Combining With Human Chorionic Gonadotropin Treat Congenital Hypogonadotropic Hypogonadism
NCT03490513	PHASE4	COMPLETED	Aromatase Inhibitors and Weight Loss in Severely Obese Men With Hypogonadism
NCT04456296	PHASE4	COMPLETED	A Study of the Effect of Testosterone Replacement Therapy on Blood Pressure in Adult Male Participants With Hypogonadism
NCT05205837	PHASE4	TERMINATED	A Randomized, Double-blinded, Clinical, Placebo-controlled Trial on the Effects of Therapy With Letrozole and hUman Choriongonadotropin in Male Hypogonadism Induced by Illicit Use of Anabolic Androgenic Steroids- The LUCAS Trial
NCT03687606	PHASE4	UNKNOWN	Efficacy and Safety of Long Term Use of hCG or hCG Plus hMG in Males With Isolated Hypogonadotropic Hypogonadism (IHH)
NCT00467870	PHASE3	COMPLETED	Long-term Safety Study of Intramuscular Injections of 750 mg and 1000 mg Testosterone Undecanoate in Hypogonadal Men
NCT00962637	PHASE3	COMPLETED	Study to Evaluate the Safety and Efficacy of Androxal™ Treatment in Men With Secondary Hypogonadism
NCT01067365	PHASE3	COMPLETED	Study to Evaluate the Safety and Efficacy of Androxal Treatment in Men With Secondary Hypogonadism
NCT01532414	PHASE3	COMPLETED	Phase III Study to Evaluated Morning Testosterone Normalization in Men With Secondary Hypogonadism
NCT01534208	PHASE3	COMPLETED	Safety Study of Enclomiphene Citrate in the Treatment of Men With Secondary Hypogonadism
NCT01709331	PHASE3	COMPLETED	A Study of the Efficacy and Safety of Corifollitropin Alfa (MK-8962) in Combination With Human Chorionic Gonadotropin (hCG) in Adult Men With Hypogonadotropic Hypogonadism (HH) (P07937)
NCT01739582	PHASE3	COMPLETED	An Extension Study of Enclomiphene Citrate in the Treatment of Men With Secondary Hypogonadism
NCT01739595	PHASE3	COMPLETED	Phase III Study to Evaluate Morning Testosterone Normalization in Overweight Men With Secondary Hypogonadism
NCT01993212	PHASE3	COMPLETED	A Randomized, Double Blind, Placebo-Controlled, Multi-Center Phase III Study in Men With Acquired Hypogonadotropic Hypogonadism to Compare Changes in Testosterone and Sperm Concentration Following Treatment With 12.5 mg or 25 mg Androxal or AndroGel 1.62%
NCT01993225	PHASE3	COMPLETED	A Randomized, Double Blind, Placebo-Controlled, Multi-Center Phase III Study in Men With Acquired Hypogonadotropic Hypogonadism to Compare Changes in Testosterone and Sperm Concentration Following Treatment With 12.5 mg or 25 mg Androxal or AndroGel 1.62%
NCT02110368	PHASE3	COMPLETED	Bioequivalence Study of Test and Reference Testosterone Topical Gel, 1.62% Metered Pump in Testosterone Deficient Adult Male Subjects Under Fasting Conditions
NCT03019575	PHASE3	COMPLETED	Efficacy and Safety of Corifollitropin Alfa (MK-8962) in Combination With Human Chorionic Gonadotropin (hCG) in Adolescent Males With Hypogonadotropic Hypogonadism (HH) (MK-8962-043)
NCT06561594	PHASE3	NOT_YET_RECRUITING	To Evaluate Recombinant Human Follicle Stimulating Hormone-CTP Fusion Protein Injection or Placebo Combined With Chorionic Gonadotropin for Injection
NCT00193661	PHASE2	COMPLETED	Observation Study of T-Gel (1%) in Treatment of Adolescent Boys With Hypogonadism
NCT00383656	PHASE2	UNKNOWN	Pulsatile GnRH in Anovulatory Infertility
NCT00697814	PHASE2	COMPLETED	Clomiphene in Males With Prolactinomas and Persistent Hypogonadism
NCT00706719	PHASE2	COMPLETED	To Evaluate Sperm Parameters in Men With Secondary Hypogonadism Previously Treated With Topical Testosterone
NCT00911586	PHASE2	COMPLETED	Pharmacokinetic Study to Determine Time to Steady-state
NCT01155518	PHASE2	TERMINATED	Hypogonadism in Young Men With Type 2 Diabetes
NCT01191320	PHASE2	COMPLETED	Study to Evaluate the Efficacy of Androxal in Controlling Blood Glucose in Men With Type-2 Diabetes Mellitus
NCT01270841	PHASE2	COMPLETED	Normalization of Morning Testosterone Levels in Men With Secondary Hypogonadism
NCT01386606	PHASE2	COMPLETED	The Effect on Androxal Versus Androgel on Morning Testosterone in Men With Secondary Hypogonadism (Low Testosterone)
NCT01894308	PHASE2	NOT_YET_RECRUITING	A Dose Ranging Study to Examine TDS-Testosterone 5%
NCT02369796	PHASE2	TERMINATED	A Phase 2a Pharmacodynamic Study of TAK-448 in Participants With Hypogonadotropic Hypogonadism
NCT02443090	PHASE2	UNKNOWN	Safety and Efficacy Study of Oral Fispemifene for the Treatment of Sexual Dysfunction in Hypogonadal Men
NCT02651688	PHASE2	COMPLETED	A Multi-Center Study in Men With Acquired Hypogonadotropic Hypogonadism to Compare Changes in Body Composition and Metabolic Parameters With Diet and Exercise in Conjunction With Treatment With 12.5 mg or 25 mg Enclomiphene
NCT02730169	PHASE2	COMPLETED	Safety and Efficacy of BGS649 in Male Obese Subjects With Hypogonadotropic Hypogonadism
NCT02733133	PHASE2	NOT_YET_RECRUITING	Product Transference Study of Testagen™ TDS®-Testosterone
NCT02908074	PHASE2	COMPLETED	A 6 Month Safety Extension Study of MBGS205
NCT03245827	PHASE2	TERMINATED	Hypogonadotropic Hypogonadism in Obese Young Males