PTP4A3

Summary

PTP4A3 (protein tyrosine phosphatase 4A3, HGNC:9636) is a protein-coding gene on chromosome 8q24.3, encoding Protein tyrosine phosphatase type IVA 3 (O75365). Protein tyrosine phosphatase which stimulates progression from G1 into S phase during mitosis. In precision oncology, PTP4A3 OVEREXPRESSION confers sensitivity to Cetuximab in Colorectal Cancer (CIViC Level D).

This gene encodes a member of the protein-tyrosine phosphatase family. Protein tyrosine phosphatases are cell signaling molecules that play regulatory roles in a variety of cellular processes. Studies of this class of protein tyrosine phosphatase in mice demonstrates that they are prenylated in vivo, suggesting their association with cell plasma membrane. The encoded protein may enhance cell proliferation, and overexpression of this gene has been implicated in tumor metastasis. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 11156 — RefSeq curated summary.

At a glance

• GWAS associations: 7
• Clinical variants (ClinVar): 43 total
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Precision-oncology evidence (CIViC): 1 curated variant–drug association
• MANE Select transcript: NM_032611

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9636
Approved symbol	PTP4A3
Name	protein tyrosine phosphatase 4A3
Location	8q24.3
Locus type	gene with protein product
Status	Approved
Aliases	PRL-3, PRL-R, PRL3
Ensembl gene	ENSG00000184489
Ensembl biotype	protein_coding
OMIM	606449
Entrez	11156

Gene structure

Transcript identifiers

Ensembl transcripts: 105 — 105 protein_coding

ENST00000329397, ENST00000349124, ENST00000520105, ENST00000521578, ENST00000523147, ENST00000524028, ENST00000680615, ENST00000681443, ENST00000903073, ENST00000903074, ENST00000903075, ENST00000903076, ENST00000903077, ENST00000903078, ENST00000903079, ENST00000903080, ENST00000903081, ENST00000903082, ENST00000903083, ENST00000903084, ENST00000903085, ENST00000903086, ENST00000903087, ENST00000903088, ENST00000903089, ENST00000903090, ENST00000903091, ENST00000903092, ENST00000903093, ENST00000903094, ENST00000903095, ENST00000903096, ENST00000903097, ENST00000903098, ENST00000903099, ENST00000903100, ENST00000903101, ENST00000903102, ENST00000903103, ENST00000903104, ENST00000903105, ENST00000916192, ENST00000916193, ENST00000916194, ENST00000916195, ENST00000916196, ENST00000916197, ENST00000916198, ENST00000916199, ENST00000916200, ENST00000955507, ENST00000955508, ENST00000955509, ENST00000955510, ENST00000955511, ENST00000955512, ENST00000955513, ENST00000955514, ENST00000955515, ENST00000955516, ENST00000955517, ENST00000955518, ENST00000955519, ENST00000955520, ENST00000955521, ENST00000955522, ENST00000955523, ENST00000955524, ENST00000955525, ENST00000955526, ENST00000955527, ENST00000955528, ENST00000955529, ENST00000955530, ENST00000955531, ENST00000955532, ENST00000955533, ENST00000955534, ENST00000955535, ENST00000955536, ENST00000955537, ENST00000955538, ENST00000955539, ENST00000955540, ENST00000955541, ENST00000955542, ENST00000955543, ENST00000955544, ENST00000955545, ENST00000955546, ENST00000955547, ENST00000955548, ENST00000955549, ENST00000955550, ENST00000955551, ENST00000955552, ENST00000955553, ENST00000955554, ENST00000955555, ENST00000955556, ENST00000955557, ENST00000955558, ENST00000955559, ENST00000955560, ENST00000955561

RefSeq mRNA: 2 — MANE Select: NM_032611 NM_007079, NM_032611

CCDS: CCDS6382, CCDS6383

Canonical transcript exons

ENST00000521578 — 6 exons

Exon	Start	End
ENSE00001308276	141426939	141427069
ENSE00001320798	141427750	141427824
ENSE00001328115	141425048	141425140
ENSE00002118848	141421388	141422345
ENSE00002120910	141392021	141392084
ENSE00003728124	141430927	141432454

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 99.53.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 13.0852 / max 520.2879, expressed in 1417 samples.

FANTOM5 promoters (12 alternative TSS)

Promoter ID	TPM avg	Samples expressed
91304	6.7327	1373
91312	5.8878	595
91309	0.1217	54
91314	0.0652	28
91311	0.0620	30
91308	0.0400	17
205377	0.0380	17
91313	0.0333	18
91315	0.0318	11
91310	0.0262	17

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	99.53	gold quality
mucosa of stomach	UBERON:0001199	99.30	gold quality
hindlimb stylopod muscle	UBERON:0004252	99.15	gold quality
heart left ventricle	UBERON:0002084	99.13	gold quality
gastrocnemius	UBERON:0001388	98.84	gold quality
right atrium auricular region	UBERON:0006631	98.77	gold quality
skeletal muscle tissue	UBERON:0001134	98.56	gold quality
heart	UBERON:0000948	98.20	gold quality
adenohypophysis	UBERON:0002196	97.98	gold quality
muscle of leg	UBERON:0001383	97.92	gold quality
pituitary gland	UBERON:0000007	97.91	gold quality
tibial artery	UBERON:0007610	97.12	gold quality
popliteal artery	UBERON:0002250	97.11	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	96.72	gold quality
right coronary artery	UBERON:0001625	96.68	gold quality
lower esophagus muscularis layer	UBERON:0035833	95.77	gold quality
lower esophagus	UBERON:0013473	95.68	gold quality
left coronary artery	UBERON:0001626	95.31	gold quality
body of stomach	UBERON:0001161	94.79	gold quality
fundus of stomach	UBERON:0001160	94.65	gold quality
left uterine tube	UBERON:0001303	94.56	gold quality
ascending aorta	UBERON:0001496	94.37	gold quality
thoracic aorta	UBERON:0001515	94.32	gold quality
muscle tissue	UBERON:0002385	93.84	gold quality
descending thoracic aorta	UBERON:0002345	93.72	gold quality
body of uterus	UBERON:0009853	93.58	gold quality
stomach	UBERON:0000945	92.56	gold quality
body of pancreas	UBERON:0001150	92.19	gold quality
muscle layer of sigmoid colon	UBERON:0035805	92.15	gold quality
upper lobe of left lung	UBERON:0008952	91.91	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-MTAB-8271	yes	261.37
E-MTAB-10287	yes	54.72
E-GEOD-135922	yes	27.04
E-HCAD-11	yes	19.71
E-CURD-114	yes	11.55
E-GEOD-83139	yes	3.91
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MEF2C, PGR, SNAI1

miRNA regulators (miRDB)

37 targeting PTP4A3, 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-6721-5P	99.93	68.92	2981
HSA-MIR-22-3P	99.93	68.13	917
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-6132	99.60	65.83	1554
HSA-MIR-6836-5P	99.60	65.62	1538
HSA-MIR-762	99.58	66.61	1994
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-3915	99.45	68.49	1905
HSA-MIR-185-5P	99.35	68.60	2497
HSA-MIR-4644	99.35	69.12	2514
HSA-MIR-128-1-5P	99.33	60.46	332
HSA-MIR-128-2-5P	99.33	60.83	311
HSA-MIR-18A-5P	99.29	71.05	806
HSA-MIR-18B-5P	99.29	71.05	806
HSA-MIR-4505	99.27	67.81	2678
HSA-MIR-5787	99.22	67.86	2628
HSA-MIR-4735-3P	99.14	69.85	777
HSA-MIR-5001-5P	99.05	66.76	1972
HSA-MIR-6829-5P	98.86	65.12	1480
HSA-MIR-5000-3P	98.79	65.63	1251
HSA-MIR-4297	98.77	66.95	2013
HSA-MIR-6840-3P	98.68	65.95	1923
HSA-MIR-1227-5P	98.65	65.32	1549
HSA-MIR-2467-3P	98.65	67.18	1969
HSA-MIR-4290	98.51	65.17	907
HSA-MIR-1233-5P	98.19	66.71	1201
HSA-MIR-4436A	98.05	64.83	1140

Literature-anchored findings (GeneRIF, showing 40)

• Data suggest that the PRL-3 gene is important for colorectal cancer metastasis and provide a new therapeutic target for these intractable lesions. (PMID:11598267)
• PRL-3 is expressed in tumor metastasis and vasculature, regardless of the tumor source. (PMID:14654542)
• presentation of the solution structure of PRL-3, the first structure of a PRL phosphatase. The structure places PRL phosphatases in the class of dual specificity phosphatases with closest structural homology to the VHR phosphatase (PMID:14704153)
• human PRL-3 structure by NMR (PMID:15135076)
• PRL-3 expression was up-regulated in human liver carcinoma compared with normal liver (PMID:15161639)
• PRL-3 expression in colorectal cancers may contribute to the establishment of liver metastasis (PMID:15534108)
• Elevated PRL-3 protein expression is associated with colorectal cancer metastasis (PMID:15788667)
• PRL-3 phosphatase has a role in ovarian cancer growth (PMID:16203771)
• identified integrin alpha1 as a PRL-3-interacting protein for the first time, and verified this physical association with pull-down and co-immunoprecipitation assays (PMID:16472776)
• In tumor cells, PRL-3 mRNA levels varied markedly with high expression in SKNAS neuroblastoma, MCF-7 and BT474 breast carcinoma, Hep3B hepatocellular carcinoma, and HCT116 colon carcinoma. (PMID:16505094)
• PRL-3 mRNA expression was significantly higher in malignant compared to benign breast tissue. The results suggest that PRL-3 might serve as a novel prognostic factor in breast cancer, which may help to predict an adverse disease outcome. (PMID:16832410)
• results suggest that PRL-3 may serve as an unfavorable prognostic marker in breast cancer, especially for patients with node-negative diseases (PMID:16873432)
• Injection of PRL-3-expressing CHO cells into nude mice to form local tumors resulted in the recruitment of host endothelial cells into the tumors and initiation of angiogenesis. PRL-3-expressing cells reduced IL-4 expression levels. (PMID:17018620)
• PRL-3 expression may participate in the progression and metastasis of gastric carcinoma and might be a novel molecular marker for aggressive gastric cancer. (PMID:17235563)
• Colonic adenocarcinoma cells have the ability to produce PTP4A1, PTP4a2, and PTP4A3, which may relate to the lymph node metastasis of colonic adenocarcinoma. (PMID:17440740)
• Snail regulates the activity of PRL-3 gene by binding to the promoter of PRL-3 gene in SW480 cells. (PMID:17545014)
• Data show that the entire coding region of PRL-3 gene was cloned, and the recombinant vector was successfully constructed and expressed, which may provide the basis for further study of the relationship between colorectal carcinoma and PRL-3 gene. (PMID:17545077)
• down-regulation of the PRL-3 gene is important in lung cancer metastasis and provide a new hypothesis of lung cancer metastases (PMID:17717498)
• PRL-3 is a gene product specifically expressed in malignant plasma cells and may have a role in migration of these cells. (PMID:17934070)
• This is the first report of detecting PRL-3 expression in gliomas, especially in grades III and IV. (PMID:18021371)
• The identification of Ezrin as a specific and direct cellular substrate of PRL-3, is reported. (PMID:18078820)
• PRL3 has a role in the gene-specific translational control of Csk expression (PMID:18268019)
• high expression of PRL-3 in the lymph node metastasis (LNM) of gastric cancer had a negative impact on the prognosis of the patients, and plays important roles in LNM of gastric cancer and the tumor growth (PMID:18561324)
• Data show that PRL-3 is up-regulated in tumor tissue compared with corresponding noncancerous liver tissue, and suggest that PRL-3 plays a key role in the angiogenesis and invasion of hepatocellular carcinoma. (PMID:18636172)
• PRL-1 and PRL-3 mRNAs may be involved in and used to predict the metastasis of esophageal squamous cell carcinoma. Possibility of using PRL-1 and PRL-3 as therapeutical target. (PMID:18684031)
• PRL-3 expression was closely associated with colorectal carcinoma tumor stage and lymph node metastasis, but no relationship with age, sex, tumor size, degree of differentiation. (PMID:18803057)
• liver metastasis by PRL-3 is putatively mediated through lymph node metastasis and elevated tumor markers in the serum and the PRL-3 expression may not represent a direct causative mechanism of liver metastasis. (PMID:18813812)
• PRL-3 overexpression is a common event in stage III colorectal primary tumours that is further selected during liver dissemination. PRL-3 expression correlates with tumour aggressiveness and is a promising predictor of distant metastases. (PMID:19002188)
• High expression of PRL-3 can promote growth of gastric cancer. (PMID:19009246)
• analysis of the molecular determinants of PRL-3 (PMID:19040419)
• High PRL-3 expression is associated with gastric cancer progression. (PMID:19087692)
• phosphatase of regenerating liver-3 has a role in tumor progression in nasopharyngeal carcinoma (PMID:19101992)
• PRL-3 may play an important role for the promotion of CRC cell migration and metastatic potential through direct KRT8 dephosphorylation (PMID:19115206)
• PRL-3 expression is associated with gastric cancer progression (PMID:19132388)
• PRL-3 induces microvascular and lymphatic vessel formation by facilitating VEGF and VEGF-C expression in lung cancer tissues and up-regulates pERK and Rho expression and activity (PMID:19152186)
• Knockdown of PRL-3 significantly suppressed the proliferation of SGC7901 cells in vitro and tumor growth in vivo. PRL-3 plays a key role in the growth of gastric cancer. (PMID:19187591)
• These results suggest that cellular localization of PRL-3 is highly correlated with its function in tumor metastasis. (PMID:19214221)
• PRL-3 overexpression in early stages of colonic cancer (PMID:19236507)
• PRL-3 expression is a new independent prognostic indicator to predict the potential of recurrence and survival in patients with gastric cancer at the time of tumor resection (PMID:19322925)
• Propose that PRL-3 expression can have a clinical potential as a prognostic biomarker that may facilitate the development of adjuvant chemotherapy for advanced gastric cancer with stage I disease. (PMID:19424625)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ptp4a3a	ENSDARG00000039997
danio_rerio	ptp4a3b	ENSDARG00000054814
mus_musculus	Ptp4a3	ENSMUSG00000059895
rattus_norvegicus	Ptp4a3	ENSRNOG00000007628

Paralogs (8): CDC14A (ENSG00000079335), CDC14B (ENSG00000081377), CDKN3 (ENSG00000100526), PALD1 (ENSG00000107719), PTP4A1 (ENSG00000112245), PTPDC1 (ENSG00000158079), PTP4A2 (ENSG00000184007), CDC14C (ENSG00000218305)

Protein

Protein identifiers

Protein tyrosine phosphatase type IVA 3 — O75365 (reviewed: O75365)

Alternative names: PRL-R, Protein-tyrosine phosphatase 4a3, Protein-tyrosine phosphatase of regenerating liver 3

All UniProt accessions (3): O75365, E5RFQ4, E5RGR3

UniProt curated annotations — full annotation on UniProt →

Function. Protein tyrosine phosphatase which stimulates progression from G1 into S phase during mitosis. Enhances cell proliferation, cell motility and invasive activity, and promotes cancer metastasis. May be involved in the progression of cardiac hypertrophy by inhibiting intracellular calcium mobilization in response to angiotensin II.

Subunit / interactions. Interacts with tubulin.

Subcellular location. Cell membrane. Early endosome.

Tissue specificity. Mainly expressed in cardiomyocytes and skeletal muscle; also found in pancreas. Consistently overexpressed in colon cancer metastasis.

Post-translational modifications. Farnesylated. Farnesylation is required for membrane targeting.

Activity regulation. Inhibited by sodium orthovanadate and peroxovanadium compounds, and by pentamidine.

Miscellaneous. Unstructured and inactive.

Similarity. Belongs to the protein-tyrosine phosphatase family.

Isoforms (3)

UniProt ID	Names	Canonical?
O75365-1	1	yes
O75365-2	2
O75365-3	3, short

RefSeq proteins (2): NP_009010, NP_116000* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000387	Tyr_Pase_dom	Domain
IPR003595	Tyr_Pase_cat	Domain
IPR020422	TYR_PHOSPHATASE_DUAL_dom	Domain
IPR029021	Prot-tyrosine_phosphatase-like	Homologous_superfamily
IPR050561	PTP	Family

Pfam: PF22785

Catalyzed reactions (Rhea), 1 shown:

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

UniProt features (35 total): strand 9, mutagenesis site 6, helix 6, splice variant 2, active site 2, turn 2, chain 1, propeptide 1, sequence conflict 1, domain 1, binding site 1, modified residue 1, lipid moiety-binding region 1, disulfide bond 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
5TSR	X-RAY DIFFRACTION	3.19
1R6H	SOLUTION NMR
1V3A	SOLUTION NMR
2MBC	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75365-F1	86.91	0.57

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 (2): 72 (proton donor); 104 (phosphocysteine intermediate)

Ligand- & substrate-binding residues (1): 110

Post-translational modifications (2): 170, 170

Disulfide bonds (1): 49–104

Mutagenesis-validated functional residues (6):

Position	Phenotype
49	no effect on enzymatic activity.
71	no effect on enzymatic activity.
72	abolishes enzymatic activity.
104	95% loss of enzymatic activity.
104	reduces migration-promoting activity.
111	enhances catalytic activity.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 196 (showing top): MODULE_52, SHEPARD_BMYB_MORPHOLINO_UP, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_VASCULAR_ENDOTHELIAL_GROWTH_FACTOR_SIGNALING_PATHWAY, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_RESPONSE_TO_PEPTIDE, CROONQUIST_NRAS_SIGNALING_DN, SHEPARD_CRASH_AND_BURN_MUTANT_UP, MODULE_45, PID_PRL_SIGNALING_EVENTS_PATHWAY, FOXO4_01, MODULE_16, ADDYA_ERYTHROID_DIFFERENTIATION_BY_HEMIN, CAGCTG_AP4_Q5, GNF2_MYL3

GO Biological Process (11): Notch signaling pathway (GO:0007219), positive regulation of vascular permeability (GO:0043117), endothelial cell migration (GO:0043542), regulation of vascular endothelial growth factor signaling pathway (GO:1900746), cellular response to leukemia inhibitory factor (GO:1990830), regulation of DNA-templated transcription (GO:0006355), protein dephosphorylation (GO:0006470), regulation of signal transduction (GO:0009966), dephosphorylation (GO:0016311), positive regulation of non-canonical NF-kappaB signal transduction (GO:1901224), positive regulation of establishment of protein localization (GO:1904951)

GO Molecular Function (4): protein tyrosine phosphatase activity (GO:0004725), phosphoprotein phosphatase activity (GO:0004721), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (6): nucleus (GO:0005634), cytoplasm (GO:0005737), early endosome (GO:0005769), plasma membrane (GO:0005886), endosome (GO:0005768), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
cell surface receptor signaling pathway	1
regulation of vascular permeability	1
cell migration	1
regulation of signal transduction	1
vascular endothelial growth factor signaling pathway	1
regulation of cellular response to vascular endothelial growth factor stimulus	1
cellular response to cytokine stimulus	1
response to leukemia inhibitory factor	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
dephosphorylation	1
protein modification process	1
signal transduction	1
regulation of cell communication	1
regulation of signaling	1
regulation of response to stimulus	1
phosphate-containing compound metabolic process	1
non-canonical NF-kappaB signal transduction	1
regulation of non-canonical NF-kappaB signal transduction	1
positive regulation of intracellular signal transduction	1
establishment of protein localization	1
positive regulation of biological process	1
regulation of establishment of protein localization	1
phosphoprotein phosphatase activity	1
phosphatase activity	1
catalytic activity, acting on a protein	1
binding	1
catalytic activity	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
endosome	1
membrane	1
cell periphery	1
endomembrane system	1
cytoplasmic vesicle	1

Protein interactions and networks

STRING

816 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PTP4A3	BCAR1	P56945	715
PTP4A3	CNNM4	Q6P4Q7	539
PTP4A3	PTS	Q03393	519
PTP4A3	ESR1	P03372	457
PTP4A3	CSNK2A1	P19138	451
PTP4A3	MYOZ3	Q8TDC0	449
PTP4A3	TUBA1B	P04687	443
PTP4A3	CSNK2A2	P19784	442
PTP4A3	C11orf96	Q7Z7L8	435
PTP4A3	AGT	P01019	424
PTP4A3	PIK3CG	P48736	424
PTP4A3	JAM2	P57087	399
PTP4A3	GADD45G	O95257	398
PTP4A3	ESR2	Q92731	398
PTP4A3	EPHX2	P34913	381

IntAct

122 interactions, top by confidence:

A	B	Type	Score
PTP4A2	PTP4A3	psi-mi:“MI:0914”(association)	0.640
CDKN2A	PTP4A3	psi-mi:“MI:0915”(physical association)	0.370
PTP4A3	POTEF	psi-mi:“MI:0914”(association)	0.350
PTP4A3	MLF2	psi-mi:“MI:2364”(proximity)	0.270
PTP4A3	FANCI	psi-mi:“MI:0915”(physical association)	0.000
NUP93	PTP4A3	psi-mi:“MI:0915”(physical association)	0.000
PTP4A3	MMS19	psi-mi:“MI:0915”(physical association)	0.000
PTP4A3	DNAAF5	psi-mi:“MI:0915”(physical association)	0.000
PTP4A3	XPO5	psi-mi:“MI:0915”(physical association)	0.000
PTP4A3	TNPO3	psi-mi:“MI:0915”(physical association)	0.000
PTP4A3	EPPK1	psi-mi:“MI:0915”(physical association)	0.000
PTP4A3	MDN1	psi-mi:“MI:0915”(physical association)	0.000
PTP4A3	MAD2L1	psi-mi:“MI:0915”(physical association)	0.000
PTP4A3	IPO4	psi-mi:“MI:0915”(physical association)	0.000
PTP4A3	MYO1B	psi-mi:“MI:0915”(physical association)	0.000
PTP4A3	ATXN10	psi-mi:“MI:0915”(physical association)	0.000
PTP4A3	SURF4	psi-mi:“MI:0915”(physical association)	0.000
PTP4A3	LRPPRC	psi-mi:“MI:0915”(physical association)	0.000
PTP4A3	UNC45A	psi-mi:“MI:0915”(physical association)	0.000
PTP4A3		psi-mi:“MI:0915”(physical association)	0.000
PTP4A3	HACD3	psi-mi:“MI:0915”(physical association)	0.000
PTP4A3	SLC3A2	psi-mi:“MI:0915”(physical association)	0.000
PTP4A3	IPO11	psi-mi:“MI:0915”(physical association)	0.000
GCN1	PTP4A3	psi-mi:“MI:0915”(physical association)	0.000
PTP4A3	AIFM1	psi-mi:“MI:0915”(physical association)	0.000
PTP4A3	OPA1	psi-mi:“MI:0915”(physical association)	0.000
PTP4A3	MCM7	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (165): PTP4A3 (Affinity Capture-Western), USP4 (Affinity Capture-Western), HUWE1 (Affinity Capture-MS), PIK3R3 (Proximity Label-MS), MLF2 (Proximity Label-MS), PTP4A3 (Affinity Capture-MS), PTP4A3 (Affinity Capture-MS), PTP4A3 (Two-hybrid), GCN1L1 (Affinity Capture-MS), IPO4 (Affinity Capture-MS), XPO5 (Affinity Capture-MS), LRPPRC (Affinity Capture-MS), KIAA0368 (Affinity Capture-MS), ABCD3 (Affinity Capture-MS), CNNM3 (Affinity Capture-MS)

ESM2 similar proteins: A0A7H0DN78, A2VDT1, B0UXL7, O13632, O35239, O61722, O70274, O75365, P05165, P07239, P0DOQ5, P0DOQ6, P14882, P20495, P24656, P25044, P35235, P41499, P41888, P43378, P49982, P80994, P87241, Q02256, Q06124, Q06490, Q12974, Q13557, Q22707, Q3EBD3, Q4CUJ8, Q4QEZ7, Q54DU9, Q5R7J8, Q5XHB2, Q63739, Q641Z2, Q6GQJ8, Q6P9X4, Q78EG7

Diamond homologs: A0A0R4IVA4, A1L1R5, A2VDT1, A4D256, A6N3Q4, O60729, O61722, O70274, O75365, P81299, Q00684, Q12974, Q1LWL2, Q59NH8, Q5B323, Q5R7J8, Q63739, Q6GQT0, Q6NZK8, Q6P9X4, Q6PFY9, Q78EG7, Q86BN8, Q93096, Q9D658, Q9JLY7, Q9P7H1, Q9TSM6, Q9UNH5, Q9ZQP1, Q4CUJ8, Q4QEZ7, Q54DU9, Q86IL4, Q9FLZ5, Q6NKR2, Q0IID7, Q54Y32, Q9ESS0, Q9Y6W6

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
PTP4A3	“down-regulates activity”	KRT8	dephosphorylation
PTP4A3	“down-regulates activity”	EZR	dephosphorylation
PTP4A3	“down-regulates quantity by destabilization”	PTEN	dephosphorylation
PTP4A3	“down-regulates activity”	ITGB1	dephosphorylation
SRC	“down-regulates activity”	PTP4A3	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 109 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 import into nucleus	7	9.9×	4e-03

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	33
Likely benign	2
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

2317 predictions. Top by Δscore:

Variant	Effect	Δscore
8:141425040:A:AG	acceptor_gain	1.0000
8:141425041:C:G	acceptor_gain	1.0000
8:141425123:G:GT	donor_gain	1.0000
8:141426934:CGTAG:C	acceptor_loss	1.0000
8:141426935:GTAG:G	acceptor_loss	1.0000
8:141426936:TA:T	acceptor_loss	1.0000
8:141426937:A:AG	acceptor_gain	1.0000
8:141426937:AG:A	acceptor_gain	1.0000
8:141426938:G:GG	acceptor_gain	1.0000
8:141426938:GG:G	acceptor_gain	1.0000
8:141426938:GGACT:G	acceptor_gain	1.0000
8:141427065:GGCCG:G	donor_gain	1.0000
8:141427066:GCCG:G	donor_gain	1.0000
8:141427066:GCCGG:G	donor_gain	1.0000
8:141427069:GGTG:G	donor_loss	1.0000
8:141427070:G:C	donor_loss	1.0000
8:141427070:G:GG	donor_gain	1.0000
8:141427071:TGAG:T	donor_loss	1.0000
8:141427072:GAGT:G	donor_loss	1.0000
8:141427821:GCCA:G	donor_gain	1.0000
8:141427822:CCAG:C	donor_loss	1.0000
8:141427824:AG:A	donor_loss	1.0000
8:141427825:G:GG	donor_gain	1.0000
8:141392082:CAGGT:C	donor_loss	0.9900
8:141392083:AGGTC:A	donor_loss	0.9900
8:141392085:G:GA	donor_loss	0.9900
8:141392086:T:A	donor_loss	0.9900
8:141422344:AGG:A	donor_loss	0.9900
8:141422346:G:C	donor_loss	0.9900
8:141425043:CCCA:C	acceptor_loss	0.9900

AlphaMissense

1134 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:141426954:G:C	D72H	1.000
8:141426955:A:T	D72V	1.000
8:141426958:G:A	G73E	1.000
8:141427050:T:C	C104R	1.000
8:141427051:G:A	C104Y	1.000
8:141427052:C:G	C104W	1.000
8:141427060:G:A	G107D	1.000
8:141427065:G:C	G109R	1.000
8:141427065:G:T	G109C	1.000
8:141427066:G:A	G109D	1.000
8:141427066:G:T	G109V	1.000
8:141427820:C:A	R134S	1.000
8:141422296:T:C	F19S	0.999
8:141422314:C:A	P25H	0.999
8:141425088:G:A	C49Y	0.999
8:141426948:T:C	F70L	0.999
8:141426950:T:A	F70L	0.999
8:141426950:T:G	F70L	0.999
8:141426954:G:T	D72Y	0.999
8:141426955:A:C	D72A	0.999
8:141426955:A:G	D72G	0.999
8:141426956:T:A	D72E	0.999
8:141426956:T:G	D72E	0.999
8:141426957:G:T	G73W	0.999
8:141426958:G:T	G73V	0.999
8:141426990:T:A	W84R	0.999
8:141426990:T:C	W84R	0.999
8:141427042:C:A	A101D	0.999
8:141427051:G:T	C104F	0.999
8:141427059:G:C	G107R	0.999

dbSNP variants (sampled 300 via entrez): RS1000017268 (8:141411391 G>A), RS1000137641 (8:141396772 G>C), RS1000202971 (8:141428990 G>C), RS1000300764 (8:141406315 T>C), RS1000338825 (8:141401432 C>T), RS1000434477 (8:141401882 G>A,T), RS1000488967 (8:141397929 CTG>C), RS1000523186 (8:141412000 T>A), RS1000537845 (8:141417486 C>T), RS1000542105 (8:141430533 G>A,C), RS1000641416 (8:141393295 T>A,G), RS1000658126 (8:141430358 G>A,C), RS1000704811 (8:141392173 C>T), RS1000739050 (8:141402782 A>G,T), RS1000808723 (8:141401674 T>TC)

Disease associations

OMIM: gene MIM:606449 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST006218_99	Erosive tooth wear (severe vs non-severe)	1.000000e-06
GCST006226_1	Erosive tooth wear (severe vs none or mild)	5.000000e-06
GCST007059_16	Response to antidepressants (symptom improvement)	3.000000e-06
GCST007094_114	Diastolic blood pressure	1.000000e-07
GCST007099_8	Systolic blood pressure	4.000000e-08
GCST007930_54	Medication use (agents acting on the renin-angiotensin system)	1.000000e-08
GCST008839_518	Height	9.000000e-10

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0006336	diastolic blood pressure
EFO:0006335	systolic blood pressure
EFO:0009931	Agents acting on the renin-angiotensin system use measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4162 (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: 27,049 (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
CHEMBL55	PENTAMIDINE	4	27,049

Clinical evidence (CIViC)

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

Variant	Therapy	Indication	Effect	Level	CIViC
PTP4A3 OVEREXPRESSION	Cetuximab	Colorectal Cancer	Sensitivity/Response	CIViC D	EID902

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — Dual specificity phosphatases

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
JMS-053	Inhibition	7.7	pIC50

Binding affinities (BindingDB)

8 measured of 9 human assays (9 total across all organisms); most potent 8 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
7-imino-2-phenylthieno[3,2-c]pyridine-4,6-dione	IC50	18 nM	US-10308663: Inhibitors of PTP4A3 for the treatment of cancer
2-(1-adamantyl)-N-[2-[2-[2-[[2-[4-(7-imino-4,6-dioxothieno[3,2-c]pyridin-2-yl)phenoxy]acetyl]amino]ethoxy]ethoxy]ethyl]acetamide	IC50	107 nM	US-12202839: In-flow photooxygenation of aminothienopyridinones generates PTP4A3 phosphatase inhibitors
7-amino-2-phenyl-5H-thieno[3,2-c]pyridin-4-one	IC50	132 nM	US-10308663: Inhibitors of PTP4A3 for the treatment of cancer
2-(1-adamantyl)-N-[3-[[2-[4-(7-imino-4,6-dioxothieno[3,2-c]pyridin-2-yl)phenoxy]acetyl]amino]propyl]acetamide	IC50	206 nM	US-12202839: In-flow photooxygenation of aminothienopyridinones generates PTP4A3 phosphatase inhibitors
2-(1-adamantyl)-N-[4-[4-(7-imino-4,6-dioxothieno[3,2-c]pyridin-2-yl)phenoxy]butyl]acetamide	IC50	643 nM	US-12202839: In-flow photooxygenation of aminothienopyridinones generates PTP4A3 phosphatase inhibitors
CHEMBL4864481	IC50	1920 nM
4-[4-(7-imino-4,6-dioxothieno[3,2-c]pyridin-2-yl)phenoxy]butyl 2-(1-adamantyl)acetate	IC50	4980 nM	US-12202839: In-flow photooxygenation of aminothienopyridinones generates PTP4A3 phosphatase inhibitors
CHEMBL4856668	IC50	6590 nM

ChEMBL bioactivities

36 potent at pChembl≥5 of 72 total, top 35 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.75	IC50	18	nM	CHEMBL4445621
7.70	IC50	20	nM	CHEMBL4445621
7.52	IC50	30	nM	CHEMBL4471843
7.46	IC50	35	nM	CHEMBL4445621
7.08	IC50	84	nM	CHEMBL4445621
6.97	IC50	107	nM	CHEMBL4862721
6.89	IC50	128	nM	CHEMBL3393171
6.89	IC50	130	nM	CHEMBL3393171
6.88	IC50	132	nM	CHEMBL3393171
6.69	IC50	206	nM	CHEMBL4862502
6.62	IC50	240	nM	CHEMBL3393171
6.52	IC50	300	nM	PENTAMIDINE
6.34	IC50	460	nM	CHEMBL3393171
6.10	IC50	800	nM	CHEMBL2397162
6.05	IC50	900	nM	CHEMBL207428
6.05	IC50	900	nM	CHEMBL207958
5.96	IC50	1100	nM	CHEMBL207958
5.94	IC50	1160	nM	CHEMBL4852178
5.92	IC50	1200	nM	CHEMBL379654
5.80	IC50	1600	nM	CHEMBL209088
5.77	IC50	1700	nM	CHEMBL206365
5.77	IC50	1700	nM	CHEMBL183838
5.72	IC50	1900	nM	CHEMBL378022
5.72	IC50	1920	nM	CHEMBL4864481
5.70	IC50	2000	nM	CHEMBL206973
5.62	IC50	2400	nM	CHEMBL379422
5.52	IC50	3000	nM	CHEMBL186892
5.51	IC50	3100	nM	CHEMBL210772
5.46	IC50	3500	nM	EMODIN
5.43	IC50	3700	nM	CHEMBL207365
5.40	IC50	4000	nM	CHEMBL206414
5.31	IC50	4930	nM	CHEMBL1088572
5.30	IC50	4980	nM	CHEMBL4854258
5.18	IC50	6590	nM	CHEMBL4856668
5.02	IC50	9500	nM	CHEMBL210039

PubChem BioAssay actives

34 with measured affinity, of 173 total; 27 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
7-imino-2-phenylthieno[3,2-c]pyridine-4,6-dione	1759027: Inhibition of recombinant human His6-tagged PRL-3 expressed in Escherichia coli using DiFMUP as substrate incubated for 30 mins by fluorescence based assay	ic50	0.0200	uM
2-phenylthieno[3,2-c]pyridine-4,6,7-trione	1634315: Inhibition of recombinant human His-6-tagged PTP4A3 expressed in Escherichia coli assessed as reduction in hydrolysis using DIFMUP as substrate incubated for 30 mins in presence of DTT by Fluorescence based method	ic50	0.0300	uM
2-(1-adamantyl)-N-[2-[2-[2-[[2-[4-(7-imino-4,6-dioxothieno[3,2-c]pyridin-2-yl)phenoxy]acetyl]amino]ethoxy]ethoxy]ethyl]acetamide	1764017: Inhibition of recombinant human PTP4A3	ic50	0.1070	uM
7-amino-2-phenyl-5H-thieno[3,2-c]pyridin-4-one	1189243: Inhibition of full length human fusion His6 tagged PRL3 expressed in Escherichia coli using TAMRA-Thr-Ala-Asp-Ile-Tyr(PO3H2)-Glu-NH2 substrate by immobilized metal ion affinity-based fluorescence polarization assay	ic50	0.1280	uM
2-(1-adamantyl)-N-[3-[[2-[4-(7-imino-4,6-dioxothieno[3,2-c]pyridin-2-yl)phenoxy]acetyl]amino]propyl]acetamide	1764017: Inhibition of recombinant human PTP4A3	ic50	0.2060	uM
Pentamidine	1634310: Inhibition of PTP4A3 (unknown origin)	ic50	0.3000	uM
(5Z)-5-[(E)-3-[2-[(2-methoxyphenyl)methoxy]phenyl]prop-2-enylidene]-2-sulfanylidene-1,3-thiazolidin-4-one	756164: Inhibition of human His6-tagged full length PRL3 assessed as inhibition of DiFMUP dephosphorylation	ic50	0.8000	uM
(5Z)-5-[[5-bromo-2-[(2-bromophenyl)methoxy]phenyl]methylidene]-2-sulfanylidene-1,3-thiazolidin-4-one	266442: Inhibition of human recombinant PRL-3	ic50	0.9000	uM
(5Z)-5-[[5-(1-benzothiophen-3-yl)-2-phenylmethoxyphenyl]methylidene]-2-sulfanylidene-1,3-thiazolidin-4-one	266442: Inhibition of human recombinant PRL-3	ic50	0.9000	uM
2-(1-adamantyl)-N-[4-[4-(7-imino-4,6-dioxothieno[3,2-c]pyridin-2-yl)phenoxy]butyl]acetamide	1764017: Inhibition of recombinant human PTP4A3	ic50	1.1600	uM
(5Z)-5-[[5-(1-benzofuran-3-yl)-2-phenylmethoxyphenyl]methylidene]-2-sulfanylidene-1,3-thiazolidin-4-one	266442: Inhibition of human recombinant PRL-3	ic50	1.2000	uM
(5Z)-5-[[2-[(4-bromophenyl)methoxy]phenyl]methylidene]-2-sulfanylidene-1,3-thiazolidin-4-one	266442: Inhibition of human recombinant PRL-3	ic50	1.6000	uM
(5Z)-5-[(5-phenyl-2-phenylmethoxyphenyl)methylidene]-2-sulfanylidene-1,3-thiazolidin-4-one	266442: Inhibition of human recombinant PRL-3	ic50	1.7000	uM
(5Z)-5-[[3-[(2-chloro-6-fluorophenyl)methoxy]naphthalen-2-yl]methylidene]-2-sulfanylidene-1,3-thiazolidin-4-one	266442: Inhibition of human recombinant PRL-3	ic50	1.7000	uM
(5Z)-5-[[3-[(4-phenylphenyl)methoxy]naphthalen-2-yl]methylidene]-2-sulfanylidene-1,3-thiazolidin-4-one	266442: Inhibition of human recombinant PRL-3	ic50	1.9000	uM
2-(1-adamantyl)-N-[4-(7-imino-4,6-dioxo-2-phenylthieno[3,2-c]pyridin-5-yl)butyl]acetamide	1764017: Inhibition of recombinant human PTP4A3	ic50	1.9200	uM
(5Z)-5-[(3-phenylmethoxynaphthalen-2-yl)methylidene]-2-sulfanylidene-1,3-thiazolidin-4-one	266442: Inhibition of human recombinant PRL-3	ic50	2.0000	uM
(5Z)-5-[[5-bromo-2-[(2-chlorophenyl)methoxy]phenyl]methylidene]-2-sulfanylidene-1,3-thiazolidin-4-one	266442: Inhibition of human recombinant PRL-3	ic50	2.4000	uM
(5Z)-5-[(5-bromo-2-phenylmethoxyphenyl)methylidene]-2-sulfanylidene-1,3-thiazolidin-4-one	266442: Inhibition of human recombinant PRL-3	ic50	3.0000	uM
(5Z)-5-[[3-[(3,5-dimethoxyphenyl)methoxy]naphthalen-2-yl]methylidene]-2-sulfanylidene-1,3-thiazolidin-4-one	266442: Inhibition of human recombinant PRL-3	ic50	3.1000	uM
1,3,8-trihydroxy-6-methylanthracene-9,10-dione	637923: Inhibition of PRL3 after 1 hr by DiFMUP assay	ic50	3.5000	uM
(5Z)-5-[[5-[4-(dimethylamino)phenyl]-2-phenylmethoxyphenyl]methylidene]-2-sulfanylidene-1,3-thiazolidin-4-one	266442: Inhibition of human recombinant PRL-3	ic50	3.7000	uM
5-[(5-bromo-2-phenylmethoxyphenyl)methyl]-2-sulfanylidene-1,3-thiazolidin-4-one	266442: Inhibition of human recombinant PRL-3	ic50	4.0000	uM
sodium [6-(2-fluorophenyl)-5,8-dihydro-[1,3]dioxolo[4,5-g]quinolin-8-yl] hydrogen phosphate	463846: Inhibition of human PTP4A3 by enzyme assay	ic50	4.9300	uM
4-[4-(7-imino-4,6-dioxothieno[3,2-c]pyridin-2-yl)phenoxy]butyl 2-(1-adamantyl)acetate	1764017: Inhibition of recombinant human PTP4A3	ic50	4.9800	uM
2-(1-adamantyl)-N-[4-[4-(4,6,7-trioxothieno[3,2-c]pyridin-2-yl)phenoxy]butyl]acetamide	1764017: Inhibition of recombinant human PTP4A3	ic50	6.5900	uM
(5Z)-5-[(5-bromo-2-hydroxyphenyl)methylidene]-2-sulfanylidene-1,3-thiazolidin-4-one	266442: Inhibition of human recombinant PRL-3	ic50	9.5000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression, increases methylation	5
Endosulfan	increases expression, affects reaction, decreases reaction	3
mercuric bromide	decreases expression, affects cotreatment	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
triphenyl phosphate	affects expression	1
beta-lapachone	increases expression	1
mono-(2-ethylhexyl)phthalate	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, decreases expression	1
arsenic disulfide	decreases expression	1
polyhexamethyleneguanidine	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
belinostat	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	increases expression	1
NSC 689534	increases expression	1
2-methyl-1,3,6-trihydroxy-9,10-anthraquinone-3-O-(6’-O-acetyl)-alpha-rhamnosyl(1-2)-beta-glucoside	decreases activity	1
(+)-JQ1 compound	decreases expression	1
Bortezomib	decreases expression	1
Sunitinib	decreases expression	1
Glyphosate	decreases expression	1
Air Pollutants	increases abundance, increases expression	1
Benzo(a)pyrene	decreases methylation, increases methylation	1
Cadmium	increases expression	1
Camptothecin	increases expression	1
Cycloheximide	affects cotreatment, increases expression	1
Doxorubicin	increases expression	1
Estradiol	affects expression	1
Lipopolysaccharides	affects cotreatment, decreases expression	1

ChEMBL screening assays

58 unique, capped per target: 58 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1113385	Binding	Inhibition of human PTP4A3 at 10 uM by enzyme assay	Synthesis and preclinical evaluations of 2-(2-fluorophenyl)-6,7-methylenedioxyquinolin-4-one monosodium phosphate (CHM-1-P-Na) as a potent antitumor agent. — J Med Chem

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B7Z1	Abcam Raji PTP4A3 KO	Cancer cell line	Male
CVCL_B9ZS	Abcam THP-1 PTP4A3 KO	Cancer cell line	Male
CVCL_C7BG	Abcam PC-3 PTP4A3 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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