DUSP2

Summary

DUSP2 (dual specificity phosphatase 2, HGNC:3068) is a protein-coding gene on chromosome 2q11.2, encoding Dual specificity protein phosphatase 2 (Q05923). Dephosphorylates both phosphorylated Thr and Tyr residues in MAPK1, and dephosphorylation of phosphotyrosine is slightly faster than that of phosphothreonine.

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 and ERK2, is predominantly expressed in hematopoietic tissues, and is localized in the nucleus.

Source: NCBI Gene 1844 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 68 total — 1 likely-pathogenic
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_004418

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3068
Approved symbol	DUSP2
Name	dual specificity phosphatase 2
Location	2q11.2
Locus type	gene with protein product
Status	Approved
Aliases	PAC-1
Ensembl gene	ENSG00000158050
Ensembl biotype	protein_coding
OMIM	603068
Entrez	1844

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 3 protein_coding, 1 retained_intron

ENST00000288943, ENST00000488952, ENST00000718436, ENST00000914868

RefSeq mRNA: 1 — MANE Select: NM_004418 NM_004418

CCDS: CCDS2016

Canonical transcript exons

ENST00000288943 — 4 exons

Exon	Start	End
ENSE00001036745	96144154	96144373
ENSE00001036747	96144967	96145440
ENSE00001036749	96144761	96144882
ENSE00004035081	96143169	96144037

Expression profiles

Bgee: expression breadth ubiquitous, 209 present calls, max score 95.37.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 75.7929 / max 7760.1174, expressed in 1141 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
29705	75.7929	1141

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
seminal vesicle	UBERON:0000998	95.37	gold quality
granulocyte	CL:0000094	93.54	gold quality
lymph node	UBERON:0000029	91.14	gold quality
mucosa of urinary bladder	UBERON:0001259	90.97	gold quality
monocyte	CL:0000576	90.72	gold quality
spleen	UBERON:0002106	90.61	gold quality
mononuclear cell	CL:0000842	90.57	gold quality
leukocyte	CL:0000738	90.17	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	89.16	gold quality
gall bladder	UBERON:0002110	87.48	gold quality
bone marrow cell	CL:0002092	86.84	gold quality
vermiform appendix	UBERON:0001154	86.82	gold quality
skin of abdomen	UBERON:0001416	86.37	gold quality
cervix squamous epithelium	UBERON:0006922	85.81	silver quality
omental fat pad	UBERON:0010414	85.69	gold quality
peritoneum	UBERON:0002358	85.64	gold quality
mucosa of paranasal sinus	UBERON:0005030	85.61	silver quality
adenohypophysis	UBERON:0002196	85.43	gold quality
cartilage tissue	UBERON:0002418	84.87	gold quality
skin of leg	UBERON:0001511	84.73	gold quality
pituitary gland	UBERON:0000007	84.57	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	84.04	gold quality
adipose tissue of abdominal region	UBERON:0007808	83.94	gold quality
caecum	UBERON:0001153	83.68	gold quality
left uterine tube	UBERON:0001303	83.61	gold quality
urinary bladder	UBERON:0001255	82.65	gold quality
zone of skin	UBERON:0000014	82.25	gold quality
upper lobe of left lung	UBERON:0008952	81.44	gold quality
blood	UBERON:0000178	81.38	gold quality
lower esophagus mucosa	UBERON:0035834	80.39	gold quality

Single-cell (SCXA)

Detected in 22 experiment(s), a significant marker in 17.

Experiment	Marker?	Max mean expression
E-HCAD-36	yes	4683.94
E-CURD-122	yes	2386.39
E-MTAB-4850	yes	2283.17
E-MTAB-10553	yes	1962.53
E-CURD-46	yes	1603.12
E-HCAD-4	yes	1357.57
E-MTAB-8884	yes	981.26
E-CURD-89	yes	865.08
E-MTAB-6701	yes	120.99
E-HCAD-1	yes	82.68
E-CURD-88	yes	53.49
E-MTAB-8410	yes	34.63
E-GEOD-135922	yes	34.03
E-MTAB-10287	yes	32.20
E-HCAD-11	yes	22.49

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

51 targeting DUSP2, 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-340-5P	100.00	72.50	4437
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-302C-3P	99.89	71.20	1778
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-302A-3P	99.89	71.23	1777
HSA-MIR-302B-3P	99.89	71.23	1777
HSA-MIR-302D-3P	99.89	71.25	1777
HSA-MIR-106B-5P	99.88	74.72	2795
HSA-MIR-20A-5P	99.88	74.76	2769
HSA-MIR-20B-5P	99.88	74.01	2621
HSA-MIR-519D-3P	99.88	73.97	2607
HSA-MIR-526B-3P	99.88	74.06	2587
HSA-MIR-93-5P	99.88	73.98	2606
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-373-3P	99.84	70.68	1668
HSA-MIR-520E-3P	99.84	70.55	1698
HSA-MIR-544A	99.84	68.66	1965
HSA-MIR-3663-3P	99.84	70.39	798
HSA-MIR-372-3P	99.83	70.58	1691
HSA-MIR-520A-3P	99.83	70.59	1687
HSA-MIR-520B-3P	99.83	70.56	1699
HSA-MIR-520C-3P	99.83	70.56	1699
HSA-MIR-520D-3P	99.83	70.78	1676
HSA-MIR-6785-5P	99.82	68.68	4428

Literature-anchored findings (GeneRIF, showing 21)

• During apoptosis, p53 activates transcription of PAC1 by binding to a palindromic site in the PAC1 promoter (PMID:12673251)
• relationships between the expression levels of CD61, CD63, and PAC-1 on the platelet surface and the incidences of acute rejection and tubular necrosis as well as the recovery of graft function after renal transplantation (PMID:12826159)
• variation in large granular lymphocyte leukemia (PMID:14680939)
• These results reveal a crucial role of PAC1 in E2F-1-directed apoptosis. (PMID:17471234)
• a novel, stimulus-specific, and phosphatase-specific mechanism of ERK2 regulation in the nucleus by DUSP1, -2, and -4. (PMID:18178562)
• Induction of hypercortisolism in healthy volunteers was not associated with changes in the platelet activation marker PAC-1 or the number of circulating platelet-leucocyte aggregates. (PMID:18600034)
• Dipyridamole reduced expression of PAC-1 and CD62p in patients with malignant lymphoma. (PMID:20723301)
• DUSP2 is a key downstream regulator of HIF-1-mediated tumor progression and chemoresistance (PMID:21490398)
• DUSP2 is an important molecule in endometrial physiology and that hypoxia-inhibited DUSP2 expression is a critical factor for the development of endometriosis. (PMID:21984126)
• Data show that hypoxia promotes lapatinib resistance in ERBB2-positive breast cancer cells through activation of the MEK-ERK pathway a HIF-1-dependent manner via regulation of dual-specificity phosphatase 2 (DUSP2). (PMID:25596742)
• identified among the key genes in circulating monocytes that were altered by exercise (PMID:26207425)
• Highly recurrent mutation of DUSP2 is associated with nodular lymphocyte predominant Hodgkin lymphoma. (PMID:26658840)
• Our data show that aberrant epigenetic inactivation of DUSP2 occurs in carcinogenesis and that CTCF is involved in the epigenetic regulation of DUSP2 expression. (PMID:26833217)
• Hypoxia inhibits DUSP2 expression in colon cancer, leading to up-regulation of IL-8, which facilitates angiogenesis and tumour metastasis. (PMID:28026024)
• Regulation of atypical MAP kinases ERK3 and ERK4 by the phosphatase DUSP2 has been reported. (PMID:28252035)
• hypoxia-induced IL-6 production in endometriotic lesions is mediated via downregulation of DUSP2, which causes aberrant activation of STAT3 signaling pathway and helps the endometriotic cells survive under the ectopic environment (PMID:28440564)
• Authors report that hypoxia-mediated downregulation of the dual specificity phosphatase 2 (DUSP2) is critical for the accumulation of CSC in colorectal cancer. (PMID:28652251)
• Taken together, our findings for the first time suggested DUSP2 as a progression and prognosis biomarker for bladder cancer. (PMID:30458195)
• Down-regulation of DUSP2 expression in serous ovarian carcinoma was an independent risk factor for patient survival. (PMID:31889045)
• PAC1 is selectively upregulated in exhausted tumor-infiltrating lymphocytes and is associated with poor prognosis of patients with cancer. PAC1(hi) effector T cells lose their proliferative and effector capacities and convert into exhausted T cells. (PMID:31932812)
• Retinoblastoma-associated protein is important for TRIM24-mediated activation of the mTOR signaling pathway through DUSP2 action in prostate cancer. (PMID:38514847)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	dusp2	ENSDARG00000098108
mus_musculus	Dusp2	ENSMUSG00000027368
rattus_norvegicus	Dusp2	ENSRNOG00000013862

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), DUSP6 (ENSG00000139318), SSH2 (ENSG00000141298), DUSP10 (ENSG00000143507), DUSP15 (ENSG00000149599), 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 2 — Q05923 (reviewed: Q05923)

Alternative names: Dual specificity protein phosphatase PAC-1

All UniProt accessions (1): Q05923

UniProt curated annotations — full annotation on UniProt →

Function. Dephosphorylates both phosphorylated Thr and Tyr residues in MAPK1, and dephosphorylation of phosphotyrosine is slightly faster than that of phosphothreonine. Can dephosphorylate MAPK1.

Subunit / interactions. Interacts with MAPK14; this interaction does not lead to catalytic activation of DUSP2 and dephosphorylation of MAPK14.

Subcellular location. Nucleus.

Tissue specificity. Expressed in hematopoietic tissues.

Induction. By mitogens.

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

RefSeq proteins (1): NP_004409* (*=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

Enzyme classification (BRENDA):

• EC 3.1.3.16 — protein-serine/threonine phosphatase (BRENDA: 92 organisms, 641 substrates, 468 inhibitors, 127 Km, 67 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
6,8-DIFLUORO-4-METHYLUMBELLIFERYL PHOSPHATE	0.023–0.862	22
4-NITROPHENYL PHOSPHATE	0.0028–12.7	13
P-NITROPHENYL PHOSPHATE	3–200	11
RRAPTVA	0.058–1.954	4
PHOSPHOCASEIN	0.0001–0.002	3
PHOSPHOHISTONE	0.0023–0.0723	3
PHOSPHORYLATED MYOSIN LIGHT CHAIN PEPTIDE	0.01–0.11	3
PHOSPHOSERINE-MYELIN BASIC PROTEIN	0.0004–0.022	3
DLDVPIPGRFDRRVSVAAE	0.0006–0.0138	2
DLDVPIPGRFDRRVY(P)VAAE	0.0025–0.023	2
PHOSPHORYLASE A	0.004–0.021	2
RRA(PT)VA	0.0536–0.308	2
80S-RIBOSOME	0.0027	1
AAAPTVA	0.206	1
AGPALSPVPPV	0.357	1

Catalyzed reactions (Rhea), 2 shown:

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

UniProt features (18 total): strand 7, helix 5, domain 2, chain 1, active site 1, mutagenesis site 1, turn 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
1M3G	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q05923-F1	90.59	0.79

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): 257 (phosphocysteine intermediate)

Mutagenesis-validated functional residues (1):

Position	Phenotype
257	loss of tyrosine phosphatase activity.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

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

MSigDB gene sets: 425 (showing top): BROWNE_HCMV_INFECTION_30MIN_DN, GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_UP, TGGTGCT_MIR29A_MIR29B_MIR29C, MODULE_416, WALLACE_PROSTATE_CANCER_RACE_UP, YAGI_AML_WITH_INV_16_TRANSLOCATION, MODULE_169, GOBP_FORMATION_OF_PRIMARY_GERM_LAYER, KEGG_MAPK_SIGNALING_PATHWAY, MODULE_64, NAGASHIMA_NRG1_SIGNALING_UP, CHANDRAN_METASTASIS_DN, GOBP_NEGATIVE_REGULATION_OF_MAPK_CASCADE, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, MODULE_173

GO Biological Process (5): endoderm formation (GO:0001706), protein dephosphorylation (GO:0006470), signal transduction (GO:0007165), negative regulation of MAPK cascade (GO:0043409), dephosphorylation (GO:0016311)

GO Molecular Function (8): phosphoprotein phosphatase activity (GO:0004721), protein serine/threonine phosphatase activity (GO:0004722), protein tyrosine phosphatase activity (GO:0004725), protein tyrosine/threonine phosphatase activity (GO:0008330), MAP kinase tyrosine/serine/threonine phosphatase activity (GO:0017017), mitogen-activated protein kinase binding (GO:0051019), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (4): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), nuclear membrane (GO:0031965)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
MAPK1/MAPK3 signaling	1
RAF/MAP kinase cascade	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
phosphoprotein phosphatase activity	3
cellular anatomical structure	2
formation of primary germ layer	1
endoderm development	1
dephosphorylation	1
protein modification process	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
MAPK cascade	1
regulation of MAPK cascade	1
negative regulation of intracellular signal transduction	1
phosphate-containing compound metabolic process	1
phosphatase activity	1
catalytic activity, acting on a protein	1
protein tyrosine/serine/threonine phosphatase activity	1
MAP kinase phosphatase activity	1
protein kinase binding	1
binding	1
catalytic activity	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
nucleus	1
nuclear envelope	1
organelle membrane	1

Protein interactions and networks

STRING

1824 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DUSP2	SNRK	Q9NRH2	762
DUSP2	DUSP12	Q9UNI6	606
DUSP2	MAPK3	P27361	563
DUSP2	CTNNBIP1	Q9NSA3	466
DUSP2	PTPN7	P35236	447
DUSP2	DUSP4	Q13115	442
DUSP2	DICER1	Q9UPY3	437
DUSP2	EGR1	P18146	416
DUSP2	JUN	P05412	411
DUSP2	ADRA2B	P18089	410
DUSP2	CD28	P10747	395
DUSP2	FOS	P01100	394
DUSP2	UBR5	O95071	388
DUSP2	RANBP2	P49792	385
DUSP2	NR4A1	P22736	375

IntAct

4 interactions, top by confidence:

A	B	Type	Score
DUSP2	MAPK3	psi-mi:“MI:0203”(dephosphorylation reaction)	0.440
DUSP2	MAPK1	psi-mi:“MI:0915”(physical association)	0.400
DUSP2	SYN3	psi-mi:“MI:0914”(association)	0.350

BioGRID (91): DUSP2 (Affinity Capture-RNA), MAPK1 (Affinity Capture-MS), DUSP2 (Affinity Capture-MS), MAPK14 (Affinity Capture-MS), DUSP3 (Affinity Capture-MS), MAPK4 (Affinity Capture-MS), PTGES3 (Affinity Capture-MS), CHCHD4 (Affinity Capture-MS), UQCRFS1P1 (Affinity Capture-MS), AP3S1 (Affinity Capture-MS), TMEM126A (Affinity Capture-MS), EIF5A (Affinity Capture-MS), PARK7 (Affinity Capture-MS), PRDX5 (Affinity Capture-MS), ACP1 (Affinity Capture-MS)

ESM2 similar proteins: A7MB73, G3MZR2, O00587, O09008, O19058, P17405, P21217, P22083, P51993, P56433, P56434, Q05923, Q0VD19, Q10979, Q11126, Q11127, Q11128, Q11130, Q11131, Q17QZ8, Q32NY4, Q5GFD5, Q5T4B2, Q62994, Q659K9, Q6IQX7, Q6UX72, Q6ZMB0, Q712G6, Q8HYJ3, Q8HYJ4, Q8HYJ5, Q8HYJ6, Q8HYJ7, Q8HZR3, Q8IZ52, Q8N3Y3, Q8NET6, Q8NI29, Q8VD52

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

5 interactions.

A	Effect	B	Mechanism
DUSP2	“down-regulates activity”	MAPK4	dephosphorylation
DUSP2	“down-regulates activity”	MAPK6	dephosphorylation
MAPK4	“up-regulates activity”	DUSP2	phosphorylation
DUSP2	down-regulates	MAPK1	dephosphorylation
DUSP2	down-regulates	MAPK14	dephosphorylation

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	60
Likely benign	1
Benign	1

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
929311	GRCh37/hg19 2q11.1-11.2(chr2:96737083-98261802)x1	Likely pathogenic

SpliceAI

317 predictions. Top by Δscore:

Variant	Effect	Δscore
2:96143908:A:C	donor_gain	1.0000
2:96144033:CCAGT:C	acceptor_gain	1.0000
2:96144034:CAGT:C	acceptor_gain	1.0000
2:96144034:CAGTC:C	acceptor_gain	1.0000
2:96144035:AGT:A	acceptor_gain	1.0000
2:96144036:GT:G	acceptor_gain	1.0000
2:96144038:C:CC	acceptor_gain	1.0000
2:96144148:CCTTA:C	donor_loss	1.0000
2:96144149:CTTAC:C	donor_loss	1.0000
2:96144150:TTA:T	donor_loss	1.0000
2:96144151:TA:T	donor_loss	1.0000
2:96144152:A:AC	donor_gain	1.0000
2:96144153:C:A	donor_loss	1.0000
2:96144153:C:CC	donor_gain	1.0000
2:96144153:CCA:C	donor_gain	1.0000
2:96144165:ATGG:A	donor_gain	1.0000
2:96144171:T:TA	donor_gain	1.0000
2:96144369:CCACC:C	acceptor_gain	1.0000
2:96144370:CACC:C	acceptor_gain	1.0000
2:96144370:CACCC:C	acceptor_gain	1.0000
2:96144372:CC:C	acceptor_gain	1.0000
2:96144373:CC:C	acceptor_gain	1.0000
2:96144373:CCTGG:C	acceptor_loss	1.0000
2:96144374:C:CC	acceptor_gain	1.0000
2:96144374:C:T	acceptor_gain	1.0000
2:96144374:CTG:C	acceptor_loss	1.0000
2:96144758:CAC:C	donor_loss	1.0000
2:96144759:A:AC	donor_gain	1.0000
2:96144759:AC:A	donor_gain	1.0000
2:96144760:C:CC	donor_gain	1.0000

AlphaMissense

2000 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:96143857:A:G	L304P	0.999
2:96143868:G:C	F300L	0.999
2:96143868:G:T	F300L	0.999
2:96143870:A:G	F300L	0.999
2:96143881:G:T	P296H	0.999
2:96143908:A:T	V287D	0.999
2:96143957:A:C	Y271D	0.999
2:96143964:A:C	C268W	0.999
2:96143997:G:C	C257W	0.999
2:96143998:C:T	C257Y	0.999
2:96143999:A:G	C257R	0.999
2:96144207:T:A	D226V	0.999
2:96144207:T:G	D226A	0.999
2:96144208:C:G	D226H	0.999
2:96144276:A:T	L203H	0.999
2:96144279:A:T	V202D	0.999
2:96143869:A:G	F300S	0.998
2:96143877:G:C	N297K	0.998
2:96143877:G:T	N297K	0.998
2:96143882:G:A	P296S	0.998
2:96143916:A:C	F284L	0.998
2:96143916:A:T	F284L	0.998
2:96143918:A:G	F284L	0.998
2:96143962:A:G	L269P	0.998
2:96143965:C:T	C268Y	0.998
2:96143966:A:G	C268R	0.998
2:96143968:A:T	I267N	0.998
2:96143974:G:T	A265D	0.998
2:96143977:G:A	S264F	0.998
2:96143981:G:C	R263G	0.998

dbSNP variants (sampled 300 via entrez): RS1000563304 (2:96143454 C>T), RS1000803475 (2:96143117 C>T), RS1001333526 (2:96142761 G>A), RS1002576159 (2:96145734 C>G,T), RS1003685871 (2:96146404 G>C,T), RS1003780845 (2:96146817 A>G), RS1003801270 (2:96145081 C>G,T), RS1003894730 (2:96143356 G>A), RS1004808530 (2:96146124 G>A,C), RS1004903341 (2:96146359 G>A), RS1005029732 (2:96144980 C>G,T), RS1005653932 (2:96144103 G>T), RS1006491581 (2:96146207 G>A), RS1007674982 (2:96146608 G>A,C), RS1007690212 (2:96144734 G>A)

Disease associations

OMIM: gene MIM:603068 | disease phenotypes: MIM:171300

GenCC curated gene-disease

Mondo (1): pheochromocytoma (MONDO:0008233)

Orphanet (1): Hereditary pheochromocytoma-paraganglioma (Orphanet:29072)

HPO phenotypes

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

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D010673	Pheochromocytoma	C04.557.465.625.650.700.725; C04.557.580.625.650.700.725

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2157858 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 207 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1933349	MK-0893	2	207

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

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
5.04	IC50	9200	nM	MK-0893

PubChem BioAssay actives

1 with measured affinity, of 1 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
3-[[4-[(1S)-1-[3-(3,5-dichlorophenyl)-5-(6-methoxynaphthalen-2-yl)pyrazol-1-yl]ethyl]benzoyl]amino]propanoic acid	696508: Antagonist activity at human PAC1 expressed in mouse HIN 3T3 cells assessed as inhibition of glucagon-induced cAMP accumulation preincubated for 30 mins prior to glucagon challenge measured after 30 mins post glucagon challenge by liquid scintillation counter	ic50	9.2000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases reaction, increases expression, decreases expression	6
Benzo(a)pyrene	affects methylation, decreases expression, decreases methylation, increases expression, increases methylation	3
Valproic Acid	increases methylation	3
(+)-JQ1 compound	decreases expression	2
Air Pollutants	increases expression, affects cotreatment, decreases expression, increases abundance	2
Estradiol	increases expression	2
Formaldehyde	increases expression	2
Tobacco Smoke Pollution	increases expression, affects expression	2
Aflatoxin B1	increases expression	2
Cadmium Chloride	increases expression	2
Raloxifene Hydrochloride	affects cotreatment, increases expression, decreases expression	2
aristolochic acid I	increases expression	1
GSK-J4	increases expression	1
Glupearl 19S	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
2-methyl-4-isothiazolin-3-one	increases expression	1
beta-lapachone	increases expression	1
potassium chromate(VI)	increases expression	1
methacrylaldehyde	affects cotreatment, decreases expression, increases abundance	1
S-(1,2-dichlorovinyl)cysteine	decreases reaction, increases expression	1
mercuric bromide	affects cotreatment, increases expression	1
di-n-butylphosphoric acid	affects expression	1
tebuconazole	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
ON 01910	decreases expression	1
dorsomorphin	increases expression, affects cotreatment	1
(4-amino-1,4-dihydro-3-(2-pyridyl)-5-thioxo-1,2,4-triazole)copper(II)	increases expression	1
licochalcone B	increases expression	1
PCI 5002	affects cotreatment, increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2160597	Functional	Antagonist activity at human PAC1 expressed in mouse HIN 3T3 cells assessed as inhibition of glucagon-induced cAMP accumulation preincubated for 30 mins prior to glucagon challenge measured after 30 mins post glucagon challenge by liquid sc	Discovery of a novel glucagon receptor antagonist N-[(4-{(1S)-1-[3-(3, 5-dichlorophenyl)-5-(6-methoxynaphthalen-2-yl)-1H-pyrazol-1-yl]ethyl}phenyl)carbonyl]-β-alanine (MK-0893) for the treatment of type II diabetes. — 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_D8KG	Ubigene HCT 116 DUSP2 KO	Cancer cell line	Male
CVCL_E0C3	Ubigene HeLa DUSP2 KO	Cancer cell line	Female
CVCL_E1VU	HAP1 DUSP2 (-) 1	Cancer cell line	Male
CVCL_E1VV	HAP1 DUSP2 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01379898	PHASE4	COMPLETED	Phenoxybenzamine Versus Doxazosin in PCC Patients
NCT01959711	PHASE4	COMPLETED	Randomized Clinical Trial of Posterior Retroperitoneoscopic Adrenalectomy Versus Lateral Laparoscopic Adrenalectomy
NCT05702944	PHASE4	RECRUITING	The Effect and Safety of Omitting Preoperative Alpha-adrenergic Blockade for Normotensive Pheochromocytoma
NCT00002641	PHASE3	COMPLETED	Surgery With or Without Chemotherapy in Treating Patients With Soft Tissue Sarcoma
NCT00002764	PHASE3	COMPLETED	Surgery With or Without Combination Chemotherapy in Treating Patients With Lung Metastases From Soft Tissue Sarcoma
NCT00126412	PHASE3	COMPLETED	Meta-Iodobenzylguanidine (123I mIBG) Scintigraphy in Patients Being Evaluated for Phaeochromocytoma or Neuroblastoma
NCT01373736	PHASE3	UNKNOWN	123I-MIBG Scintigraphy in Patients Being Evaluated for Neuroendocrine Tumors
NCT03176693	PHASE3	COMPLETED	Preoperative Alpha Blockade for Pheochromocytoma
NCT00002608	PHASE2	COMPLETED	Combination Chemotherapy and Tamoxifen in Treating Patients With Solid Tumors
NCT00028106	PHASE2	COMPLETED	131MIBG to Treat Malignant Pheochromocytoma
NCT00107289	PHASE2	RECRUITING	Iodine I 131 Metaiodobenzylguanidine in Treating Patients With Recurrent, Progressive, or Refractory Neuroblastoma or Malignant Pheochromocytoma or Paraganglioma
NCT00466856	PHASE2	TERMINATED	Internal Radiation Therapy in Treating Patients With Liver Metastases From Neuroendocrine Tumors
NCT00843037	PHASE2	COMPLETED	Study Of Sunitinib In Patients With Recurrent Paraganglioma/Pheochromocytoma
NCT00874614	PHASE2	UNKNOWN	A Study Evaluating Ultratrace Iobenguane I131 in Patients With Malignant Relapsed/Refractory Pheochromocytoma/Paraganglioma
NCT00923481	PHASE2	COMPLETED	A Broad Multi-histology Phase II Study of the Multi-Kinase Inhibitor R935788 (Fostamatinib Disodium) in Advanced Colorectal, Non-small Cell Lung, Head and Neck Hepatocellular and Renal Cell Carcinomas, and Pheochromocytoma and Thyroid Tumors (Multi-H…
NCT01152827	PHASE2	COMPLETED	RAD001 in Pheochromocytoma or Nonfunctioning Carcinoid
NCT01413503	PHASE2	COMPLETED	A Phase II Study of 131I- Metaiodobenzylguanidine (MIBG) for Treatment of Metastatic or Unresectable Pheochromocytoma and Related Tumors
NCT01635907	PHASE2	COMPLETED	Dovitinib in Neuroendocrine Tumors
NCT01967576	PHASE2	COMPLETED	Phase II Study of Axitinib (AG-013736) With Evaluation of the VEGF-pathway in Metastatic, Recurrent or Primary Unresectable Pheochromocytoma/Paraganglioma
NCT03165721	PHASE2	TERMINATED	A Phase II Trial of the DNA Methyl Transferase Inhibitor, Guadecitabine (SGI-110), in Children and Adults With Wild Type GIST,Pheochromocytoma and Paraganglioma Associated With Succinate Dehydrogenase Deficiency and HLRCC-associated Kidney Cancer
NCT03206060	PHASE2	RECRUITING	Lu-177-DOTATATE (Lutathera) in Therapy of Inoperable Pheochromocytoma/ Paraganglioma
NCT03839498	PHASE2	ACTIVE_NOT_RECRUITING	Study of Axitinib (AG-013736) With Evaluation of the VEGF-pathway in Pheochromocytoma/Paraganglioma
NCT03946527	PHASE2	ACTIVE_NOT_RECRUITING	LAnreotide in Metastatic Pheochromocytoma / PARAganglioma (LAMPARA)
NCT04276597	PHASE2	WITHDRAWN	Phase-II Study of Lu177DOTATOC in Adults With STTR(+)Pulmonary, Pheochromocytoma, Paraganglioma, Unknown Primary, Thymus NETs (PUTNET), or Any Other Non-.GEP-NET.
NCT04320589	PHASE2	COMPLETED	the Effect of Dexmedetomidine and Magnesium Sulfate in Open Resection of Pheochromocytoma
NCT04400474	PHASE2	COMPLETED	Trial of Cabozantinib Plus Atezolizumab in Advanced and Progressive Neoplasms of the Endocrine System. The CABATEN Study
NCT04711135	PHASE2	ACTIVE_NOT_RECRUITING	Study to Evaluate Safety and Dosimetry of Lutathera in Adolescent Patients With GEP-NETs and PPGLs
NCT04924075	PHASE2	RECRUITING	Belzutifan/MK-6482 for the Treatment of Advanced Pheochromocytoma/Paraganglioma (PPGL), Pancreatic Neuroendocrine Tumor (pNET), Von Hippel-Lindau (VHL) Disease-Associated Tumors, Advanced Gastrointestinal Stromal Tumor (wt GIST), or Solid Tumors With HIF-2α Related Genetic Alterations (MK-6482-015)
NCT05133349	PHASE2	UNKNOWN	A Prospective Phase II Efficacy and Safety Study of Anlotinib in Metastatic or Locally Advanced Pheochromocytoma/ Paraganglioma : Open-label Single-arm, Exploratory Trial
NCT05883085	PHASE2	UNKNOWN	A Study on the Safety and Effectiveness of Anlotinib for Neoadjuvant Treatment of PPGL
NCT05885386	PHASE2	UNKNOWN	A Study on the Safety and Effectiveness of Temozolomide for Neoadjuvant Treatment of PPGL
NCT06045260	PHASE2	RECRUITING	Receptor Radionuclide Therapy With 177Lu-DOTATOC
NCT06233903	PHASE2	WITHDRAWN	18F-mFBG Expression in Neural Crest Tumors and Organs Innervated by the Sympathetic Nervous System
NCT06429397	PHASE2	NOT_YET_RECRUITING	Anlotinib Combined With Benmelstobart for Advanced Pheochromocytoma
NCT06503146	PHASE2	RECRUITING	18F-Fibroblast Activation Protein Inhibitor ([18F]FAPI-74) PET Imaging for Cancer Detection
NCT06683846	PHASE2	RECRUITING	Ivonescimab in the Treatment of Multiple Advanced Tumors
NCT07167329	PHASE2	RECRUITING	Real-World Effectiveness and Pharmacogenetics of Belzutifan in VHL Syndrome: The BELIEVE-VHL Trial
NCT00002947	PHASE1	TERMINATED	Indium In 111 Pentetreotide in Treating Patients With Refractory Cancer
NCT00004847	PHASE1	RECRUITING	Diagnosis of Pheochromocytoma
NCT00049023	PHASE1	COMPLETED	Radiolabeled Octreotide in Treating Children With Advanced or Refractory Solid Tumors