PTPN14

Summary

PTPN14 (protein tyrosine phosphatase non-receptor type 14, HGNC:9647) is a protein-coding gene on chromosome 1q32.3-q41, encoding Tyrosine-protein phosphatase non-receptor type 14 (Q15678). Protein tyrosine phosphatase which may play a role in the regulation of lymphangiogenesis, cell-cell adhesion, cell-matrix adhesion, cell migration, cell growth and also regulates TGF-beta gene expression, thereby modulating epithelial-mesenchymal transition.

The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. This PTP contains an N-terminal noncatalytic domain similar to that of band 4.1 superfamily cytoskeleton-associated proteins, which suggested the membrane or cytoskeleton localization of this protein. It appears to regulate lymphatic development in mammals, and a loss of function mutation has been found in a kindred with a lymphedema-choanal atresia.

Source: NCBI Gene 5784 — RefSeq curated summary.

At a glance

• Gene–disease (curated): lymphedema-posterior choanal atresia syndrome (Strong, GenCC)
• GWAS associations: 14
• Clinical variants (ClinVar): 277 total — 3 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 5
• Druggable target: yes
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 1 cancer types
• MANE Select transcript: NM_005401

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9647
Approved symbol	PTPN14
Name	protein tyrosine phosphatase non-receptor type 14
Location	1q32.3-q41
Locus type	gene with protein product
Status	Approved
Aliases	PEZ, PTPD2
Ensembl gene	ENSG00000152104
Ensembl biotype	protein_coding
OMIM	603155
Entrez	5784

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 3 protein_coding_CDS_not_defined, 2 protein_coding

ENST00000366956, ENST00000473261, ENST00000486173, ENST00000491277, ENST00000543945

RefSeq mRNA: 1 — MANE Select: NM_005401 NM_005401

CCDS: CCDS1514

Canonical transcript exons

ENST00000366956 — 19 exons

Exon	Start	End
ENSE00001068826	214414629	214414726
ENSE00001068827	214451805	214451974
ENSE00001068834	214401685	214401772
ENSE00001068835	214402883	214402953
ENSE00001068836	214411684	214411751
ENSE00001443111	214348700	214358050
ENSE00001443112	214464630	214464957
ENSE00001443113	214551183	214551602
ENSE00003465460	214376219	214376437
ENSE00003481112	214393695	214393777
ENSE00003493290	214383311	214384788
ENSE00003591428	214377959	214378102
ENSE00003598077	214390988	214391045
ENSE00003607890	214364512	214364675
ENSE00003628646	214394899	214394986
ENSE00003631628	214386844	214386922
ENSE00003645268	214397913	214398001
ENSE00003647659	214372711	214372839
ENSE00003691681	214369457	214369691

Expression profiles

Bgee: expression breadth ubiquitous, 257 present calls, max score 98.12.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 16.9662 / max 226.5559, expressed in 1436 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
17448	8.9268	1366
17450	3.9596	1300
17449	1.8250	989
17452	1.5059	907
17451	0.4505	291
17453	0.2984	137

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	98.12	gold quality
parietal pleura	UBERON:0002400	97.42	gold quality
tibia	UBERON:0000979	97.14	gold quality
upper leg skin	UBERON:0004262	97.07	gold quality
skin of hip	UBERON:0001554	96.34	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	96.12	gold quality
visceral pleura	UBERON:0002401	96.03	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	95.73	gold quality
nipple	UBERON:0002030	95.65	gold quality
germinal epithelium of ovary	UBERON:0001304	95.54	gold quality
biceps brachii	UBERON:0001507	95.53	gold quality
pleura	UBERON:0000977	95.18	gold quality
mammalian vulva	UBERON:0000997	94.90	gold quality
cartilage tissue	UBERON:0002418	94.59	gold quality
mammary duct	UBERON:0001765	94.37	gold quality
renal medulla	UBERON:0000362	94.31	gold quality
mucosa of paranasal sinus	UBERON:0005030	93.84	gold quality
synovial joint	UBERON:0002217	93.70	gold quality
adult organism	UBERON:0007023	93.27	gold quality
seminal vesicle	UBERON:0000998	93.22	gold quality
gingival epithelium	UBERON:0001949	93.07	gold quality
gingiva	UBERON:0001828	93.00	gold quality
cauda epididymis	UBERON:0004360	92.96	gold quality
saphenous vein	UBERON:0007318	92.78	gold quality
superficial temporal artery	UBERON:0001614	92.19	gold quality
lower lobe of lung	UBERON:0008949	91.82	gold quality
stromal cell of endometrium	CL:0002255	91.62	gold quality
penis	UBERON:0000989	91.12	gold quality
urethra	UBERON:0000057	90.75	gold quality
trigeminal ganglion	UBERON:0001675	90.56	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	12.19
E-CURD-112	no	2.41

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

317 targeting PTPN14, 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-3163	100.00	77.23	8605
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-6798-5P	100.00	65.77	699
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3662	99.99	73.82	5684
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-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-548N	99.98	71.94	4170

Literature-anchored findings (GeneRIF, showing 37)

• results provide a high-resolution crystal structure of the phosphatase PTPN14, thereby providing insight into its distinct substrate specificity and identifying unique structural features (PMID:16534812)
• Dysregulation of TGFbeta signaling as a possible link between Pez mutation and cancer progression. (PMID:18677119)
• These results suggest a unique and conserved role for PTPN14 in the regulation of lymphatic development in mammals and a nonconserved role in choanal development in humans. (PMID:20826270)
• PTPN14 has a role in angiogenesis and/or arteriovenous fate, acting via EphrinB2 and ACVRL1/activin receptor-like kinase 1 (PMID:22233626)
• YAP is a direct substrate of PTPN14. Results indicate a potential regulatory role of PTPN14 on YAP and demonstrate a novel mechanism in YAP regulation. (PMID:22525271)
• YAP forms a protein complex with PTPN14 through the WW domains of YAP and the PPXY motifs of PTPN14. (PMID:22689061)
• Data show that p130 Crk-associated substrate is a direct substrate of PTPN14 and that PTPN14 specifically regulates p130Cas phosphorylation at tyrosine residue 128 in colorectal cancer cells. (PMID:22710723)
• that PTPN14 acts to suppress cell proliferation by promoting cell density-dependent cytoplasmic translocation of YAP1 (PMID:22948661)
• Data demonstrate that PTPN14 downregulation can phenocopy YAP activation in mammary epithelial cells and synergize with YAP to induce oncogenic transformation. (PMID:23613971)
• results indicate a potential regulatory role of PTPN14 in the Hippo pathway and demonstrate another layer of regulation in the YAP oncogenic function (PMID:25023289)
• Findings indicate a pathway involving protein-tyrosine phosphatase D2 PTPD2 (PTPN14) and the lipid second messenger phosphatidic acid that promotes ERBB2 receptor function. (PMID:25681440)
• PTPN14 and PTEN were identified as direct and functional targets of miR-21. (PMID:25803229)
• PTPN14, a Pez mammalian homolog, is degraded by overexpressed Su(dx) or Su(dx) homologue WWP1 in mammalian cells. (PMID:25814387)
• The Hippo signaling pathway was significantly associated with ER-negative breast cancer (pathway level P = 0.02). Gene-based analyses revealed that CDH1 was responsible for the pathway association (P < 0.01),corrected P = 0.02). rs142697907 in PTPN14 was associated with ER-positive breast cancer and rs2456773 in CDK1 with ER-negativity in case-only analysis after gene-level correction (PMID:27485598)
• study determined that high-risk E7 proteins target the proteolysis of the cellular protein tyrosine phosphatase PTPN14 and find that this activity is correlated with the retinoblastoma-independent transforming activity of E7 (PMID:27651363)
• PTPN14 is classified as a potential tumor suppressor protein, and is very susceptible to HPV E7-induced proteasome-mediated degradation. (PMID:28100625)
• p53 deficiency promotes Yap signaling and that PTPN14 and TP53 mutations are mutually exclusive in human cancers. (PMID:29017057)
• Overexpression of PTPN14 promotes Roquin2 degradation in a KLHL6-dependant manner by promoting interaction with KLHL6. PTPN14 negatively regulates the protein stability of Roquin2. (PMID:30209976)
• MiR-4516 represents an independent negative prognostic factor in GBM patients and acts as a novel oncogene in GBM, which regulates the PTPN14/Hippo pathway. (PMID:30559405)
• PTPN14 degradation impairs keratinocyte differentiation and propose that this contributes to high-risk HPV E7-mediated oncogenic activity independent of RB1 inactivation. (PMID:30894485)
• Nonreceptor tyrosine phosphatase 14 promotes proliferation and migration through regulating phosphorylation of YAP of Hippo signaling pathway in gastric cancer cells. (PMID:31168824)
• Results indicate the significance and therapeutic potential of the intermolecular interaction between HPV18 E7 and host protein tyrosine phosphatase non-receptor type 14 (PTPN14) in HPV-mediated cell transformation and tumorigenesis. (PMID:31323018)
• microRNA-217 suppressed epithelial-to-mesenchymal transition through targeting PTPN14 in gastric cancer. (PMID:31793993)
• Stathmin levels alter PTPN14 expression and impact neuroblastoma cell migration. (PMID:31806880)
• PTPN14, a target gene of miR-4295, restricts the growth and invasion of osteosarcoma cells through inactivation of YAP1 signalling. (PMID:32141101)
• Phospholipase D2 restores endothelial barrier function by promoting PTPN14-mediated VE-cadherin dephosphorylation. (PMID:32327488)
• A Conserved Amino Acid in the C Terminus of Human Papillomavirus E7 Mediates Binding to PTPN14 and Repression of Epithelial Differentiation. (PMID:32581101)
• PTPN14 acts as a candidate tumor suppressor in prostate cancer and inhibits cell proliferation and invasion through modulating LATS1/YAP signaling. (PMID:32645410)
• Exosomal CircPRRX1 Enhances Doxorubicin Resistance in Gastric Cancer by Regulating MiR-3064-5p/PTPN14 Signaling. (PMID:32882759)
• Association of mutation in PTPN14 gene and gingival fibromatosis with distinctive facies: a novel finding in whole exome sequencing. (PMID:33491997)
• Loss-of-Function Variants in the Tumor-Suppressor Gene PTPN14 Confer Increased Cancer Risk. (PMID:33602785)
• PTPN14 deficiency alleviates podocyte injury through suppressing inflammation and fibrosis by targeting TRIP6 in diabetic nephropathy. (PMID:33684622)
• Recurrent PTPN14 Mutations in Trichilemmoma: Evidence for Distinct Pathways of Molecular Pathogenesis. (PMID:35830698)
• PTPN14 promotes gastric cancer progression by PI3KA/AKT/mTOR pathway. (PMID:36898991)
• circPTPN14 promotes renal fibrosis through its interaction with FUBP1 to enhance MYC transcription. (PMID:37014433)
• PTPN14 aggravates neointimal hyperplasia via boosting PDGFRbeta signaling in smooth muscle cells. (PMID:39191789)
• HPV18 E7 inhibits LATS1 kinase and activates YAP1 by degrading PTPN14. (PMID:39248565)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Ptpn14	ENSMUSG00000026604
rattus_norvegicus	Ptpn14	ENSRNOG00000003407

Paralogs (35): PTPRN (ENSG00000054356), PTPRU (ENSG00000060656), PTPN3 (ENSG00000070159), PTPN21 (ENSG00000070778), PTPN18 (ENSG00000072135), PTPN23 (ENSG00000076201), PTPRH (ENSG00000080031), PTPRC (ENSG00000081237), PTPN4 (ENSG00000088179), PTPRS (ENSG00000105426), PTPRZ1 (ENSG00000106278), PTPN5 (ENSG00000110786), PTPN6 (ENSG00000111679), PTPRB (ENSG00000127329), PTPN12 (ENSG00000127947), PTPRE (ENSG00000132334), PTPRA (ENSG00000132670), PTPN22 (ENSG00000134242), PTPRF (ENSG00000142949), PTPN7 (ENSG00000143851), PTPRG (ENSG00000144724), PTPRJ (ENSG00000149177), PTPRO (ENSG00000151490), PTPRK (ENSG00000152894), PTPRR (ENSG00000153233), PTPRD (ENSG00000153707), PTPRN2 (ENSG00000155093), PTPN13 (ENSG00000163629), PTPN9 (ENSG00000169410), PTPRM (ENSG00000173482), PTPN2 (ENSG00000175354), PTPN11 (ENSG00000179295), PTPRT (ENSG00000196090), PTPN1 (ENSG00000196396), PTPN20 (ENSG00000204179)

Protein

Protein identifiers

Tyrosine-protein phosphatase non-receptor type 14 — Q15678 (reviewed: Q15678)

Alternative names: Protein-tyrosine phosphatase pez

All UniProt accessions (2): Q15678, E2J9M0

UniProt curated annotations — full annotation on UniProt →

Function. Protein tyrosine phosphatase which may play a role in the regulation of lymphangiogenesis, cell-cell adhesion, cell-matrix adhesion, cell migration, cell growth and also regulates TGF-beta gene expression, thereby modulating epithelial-mesenchymal transition. Mediates beta-catenin dephosphorylation at adhesion junctions. Acts as a negative regulator of the oncogenic property of YAP, a downstream target of the hippo pathway, in a cell density-dependent manner. May function as a tumor suppressor.

Subunit / interactions. Interacts with FLT4; the interaction is enhanced by stimulation with VEGFC. Interacts (via PPxY motifs) with YAP1 (via WW domains); this interaction leads to the cytoplasmic sequestration of YAP1 and inhibits its transcriptional co-activator activity.

Subcellular location. Cytoplasm. Cytoskeleton. Nucleus.

Tissue specificity. Ubiquitous.

Post-translational modifications. Ubiquitinated by the ECS (Elongin BC-CUL2/5-SOCS-box protein)/LRR1 E3 ligase complex and subsequently targeted to proteasomal degradation.

Disease relevance. Choanal atresia and lymphedema (CATLPH) [MIM:613611] A disease characterized by posterior choanal atresia and lymphedema. Additional features are a high-arched palate, hypoplastic nipples, and mild pectus excavatum. The disease is caused by variants affecting the gene represented in this entry. A homozygous deletion in PTPN14 predicted to result in frameshift and premature truncation, has been shown to be the cause of choanal atresia and lymphedema in one family. Influence clinical severity of hereditary haemorragic telagiectasia (HHT).

Induction. Up-regulated at protein level by cell density. However, at the mRNA level remains the same regardless of the status of cell density.

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

RefSeq proteins (1): NP_005392* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000242	PTP_cat	Domain
IPR000299	FERM_domain	Domain
IPR000387	Tyr_Pase_dom	Domain
IPR003595	Tyr_Pase_cat	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR014352	FERM/acyl-CoA-bd_prot_sf	Homologous_superfamily
IPR014392	PTP_non-rcpt_14/21	Family
IPR016130	Tyr_Pase_AS	Active_site
IPR018979	FERM_N	Domain
IPR018980	FERM_PH-like_C	Domain
IPR019747	FERM_CS	Conserved_site
IPR019748	FERM_central	Domain
IPR019749	Band_41_domain	Domain
IPR029021	Prot-tyrosine_phosphatase-like	Homologous_superfamily
IPR029071	Ubiquitin-like_domsf	Homologous_superfamily
IPR035963	FERM_2	Homologous_superfamily
IPR041782	PTPN14/21_FERM_C	Domain

Pfam: PF00102, PF00373, PF09379, PF09380

Enzyme classification (BRENDA):

• EC 3.1.3.48 — protein-tyrosine-phosphatase (BRENDA: 59 organisms, 501 substrates, 1326 inhibitors, 270 Km, 165 kcat entries)

Substrate kinetics (BRENDA)

70 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
P-NITROPHENYL PHOSPHATE	0.0024–10	20
DADEPYLIPQQG	0.0003–0.1	12
PHOSPHOTYROSINE	0.012–30	11
LYSOZYME	0.0003–0.012	5
MYELIN BASIC PROTEIN	0.0001–0.022	5
ACETYL-DADEPY-NH2	0.0228–0.219	4
ACETYL-DADEPYL-NH2	1.1–97.5	4
4,6,8-TRIMETHYL-2-OXO-2H-CHROMEN-7-YL DIHYDROGEN	0.02–0.156	3
SASASPYSASA	0.53–2.3	3
1-NAPHTHYL PHOSPHATE	1.19–1.88	2
3,6-FLUORESCEIN DIPHOSPHATE	15–19	2
4-METHYLUMBELLIFERYL PHOSPHATE	0.953–2.41	2
BOVINE SERUM ALBUMIN	0.0001–0.0003	2

Catalyzed reactions (Rhea), 1 shown:

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

UniProt features (51 total): strand 12, helix 11, modified residue 8, turn 4, binding site 3, sequence variant 3, region of interest 3, domain 2, compositionally biased region 2, chain 1, sequence conflict 1, active site 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
2BZL	X-RAY DIFFRACTION	1.65
6IWD	X-RAY DIFFRACTION	1.8
6JJW	X-RAY DIFFRACTION	2.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q15678-F1	64.06	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): 1121 (phosphocysteine intermediate)

Ligand- & substrate-binding residues (3): 1121–1127; 1165; 1079

Post-translational modifications (8): 314, 461, 486, 591, 593, 594, 642, 831

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9008059	Interleukin-37 signaling

MSigDB gene sets: 260 (showing top): RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, BERTUCCI_MEDULLARY_VS_DUCTAL_BREAST_CANCER_DN, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GOBP_REGULATION_OF_PROTEIN_EXPORT_FROM_NUCLEUS, MCBRYAN_PUBERTAL_TGFB1_TARGETS_UP, GOBP_HIPPO_SIGNALING, PATIL_LIVER_CANCER, GOBP_NUCLEAR_TRANSPORT, MARTINEZ_RB1_TARGETS_UP, MCBRYAN_PUBERTAL_BREAST_4_5WK_DN, MODULE_205, GOBP_REGULATION_OF_NUCLEOCYTOPLASMIC_TRANSPORT, DOANE_RESPONSE_TO_ANDROGEN_DN

GO Biological Process (5): lymphangiogenesis (GO:0001946), protein dephosphorylation (GO:0006470), negative regulation of cell population proliferation (GO:0008285), regulation of protein export from nucleus (GO:0046825), dephosphorylation (GO:0016311)

GO Molecular Function (6): transcription coregulator activity (GO:0003712), protein tyrosine phosphatase activity (GO:0004725), receptor tyrosine kinase binding (GO:0030971), phosphoprotein phosphatase activity (GO:0004721), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (4): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytoskeleton (GO:0005856)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Interleukin-1 family signaling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
anatomical structure morphogenesis	1
lymph vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
dephosphorylation	1
protein modification process	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
protein export from nucleus	1
regulation of intracellular protein transport	1
regulation of nucleocytoplasmic transport	1
phosphate-containing compound metabolic process	1
transcription regulator activity	1
phosphoprotein phosphatase activity	1
signaling receptor binding	1
protein tyrosine kinase binding	1
phosphatase activity	1
catalytic activity, acting on a protein	1
binding	1
catalytic activity	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

1180 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PTPN14	CTNNB1	P35222	856
PTPN14	YAP1	P46937	850
PTPN14	PTS	Q03393	758
PTPN14	AMOT	Q4VCS5	739
PTPN14	WWC1	Q8IX03	728
PTPN14	FLT4	P35916	700
PTPN14	LATS1	O95835	616
PTPN14	BCAR1	P56945	566
PTPN14	PTPRA	P18433	548
PTPN14	RASSF8	Q8NHQ8	537
PTPN14	UBR4	Q5T4S7	533
PTPN14	WBP2	Q969T9	517
PTPN14	AMOTL2	Q9Y2J4	517
PTPN14	PTPRT	O14522	509
PTPN14	CDH17	Q12864	505

IntAct

135 interactions, top by confidence:

A	B	Type	Score
PTPN14	YAP1	psi-mi:“MI:0914”(association)	0.810
YAP1	PTPN14	psi-mi:“MI:0407”(direct interaction)	0.810
PTPN14	YAP1	psi-mi:“MI:0407”(direct interaction)	0.810
YWHAH	ABLIM1	psi-mi:“MI:0914”(association)	0.800
PDLIM7	BAG3	psi-mi:“MI:0914”(association)	0.800
YWHAB	PIK3C2A	psi-mi:“MI:0914”(association)	0.800
YAP1	MPDZ	psi-mi:“MI:0914”(association)	0.780
RHPN1	PODXL	psi-mi:“MI:0914”(association)	0.690
YWHAG	BLTP3B	psi-mi:“MI:0914”(association)	0.640
YWHAG	BLTP3B	psi-mi:“MI:2364”(proximity)	0.640
INAVA	CYTH3	psi-mi:“MI:0914”(association)	0.640
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
YWHAB	BLTP3B	psi-mi:“MI:2364”(proximity)	0.610
YWHAB	BLTP3B	psi-mi:“MI:0914”(association)	0.610
YWHAE	PIK3C2A	psi-mi:“MI:0914”(association)	0.570
YWHAH	BLTP3B	psi-mi:“MI:0914”(association)	0.570
YWHAZ	PIK3C2A	psi-mi:“MI:0914”(association)	0.570
YWHAH	BLTP3B	psi-mi:“MI:2364”(proximity)	0.570
SAV1	SEC16A	psi-mi:“MI:2364”(proximity)	0.570
TRIP6	PTPN14	psi-mi:“MI:0915”(physical association)	0.560
AMOT	PTPN14	psi-mi:“MI:0915”(physical association)	0.560
YWHAG	SHTN1	psi-mi:“MI:0914”(association)	0.560
YAP1	CCDC85C	psi-mi:“MI:0914”(association)	0.530
PARD6B	ZZEF1	psi-mi:“MI:0914”(association)	0.530
PHF20	PTPN14	psi-mi:“MI:0914”(association)	0.530
PDLIM7	ACTN4	psi-mi:“MI:0914”(association)	0.530

BioGRID (308): PTPN14 (Affinity Capture-MS), WWC1 (Affinity Capture-Western), PTPN14 (Affinity Capture-Western), PTPN14 (Affinity Capture-Western), LATS1 (Affinity Capture-Western), PTPN14 (Affinity Capture-MS), PTPN14 (Affinity Capture-MS), PTPN14 (Reconstituted Complex), PTPN14 (Affinity Capture-MS), PTPN14 (Affinity Capture-MS), CRLF3 (Affinity Capture-MS), PDLIM7 (Affinity Capture-MS), PTPN14 (Proximity Label-MS), PTPN14 (Reconstituted Complex), MAGI1 (Affinity Capture-MS)

ESM2 similar proteins: A0A8I3NFE2, A0FI79, B1AVH7, B5DFA1, D2H0G5, D7PF45, O00750, O15357, O70143, P29353, P97573, P98083, Q00IB7, Q0IIE2, Q15678, Q16825, Q17R13, Q2I6J0, Q2I6J1, Q2V2M9, Q5JV73, Q5M824, Q5R7W7, Q5U2X5, Q61120, Q62130, Q62136, Q62728, Q62925, Q69Z98, Q6P4S2, Q6P549, Q80TI1, Q8AY68, Q8BMC3, Q8BYW1, Q8IWQ3, Q8K245, Q92529, Q92835

Diamond homologs: A0A6I8TCE0, A1L1L3, A2ALK8, A4IFW2, B0V2N1, B0X4T2, B1AUH1, B2GV87, B2RU80, B3DK56, B9EKR1, E9Q0N2, E9Q612, F1NWE3, G5EC24, G5EGJ9, H2KZM6, O02695, O08617, O13016, O35239, O55082, P06800, P16620, P17706, P18031, P18052, P18433, P20417, P23467, P23468, P23469, P23470, P23471, P26045, P28191, P29074, P29350, P29351, P29352

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
PTPN14	down-regulates	BCAR1	dephosphorylation
PTPN14	“down-regulates activity”	CAV1	dephosphorylation
PTPN14	“down-regulates activity”	STAT3	dephosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 118 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.

Reactome pathways:

Pathway	Partners	Fold	FDR
Activation of BAD and translocation to mitochondria	7	60.6×	1e-09
Signaling by Hippo	9	55.6×	8e-12
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	7	53.4×	2e-09
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	7	53.4×	2e-09
Activation of BH3-only proteins	7	39.5×	2e-08
RHO GTPases activate PKNs	7	25.2×	5e-07
Intrinsic Pathway for Apoptosis	7	23.3×	8e-07
FOXO-mediated transcription	5	19.1×	1e-04

GO biological processes:

GO term	Partners	Fold	FDR
hippo signaling	8	53.8×	9e-10
protein targeting	7	23.5×	5e-06
cellular response to insulin stimulus	7	10.9×	8e-04
intracellular protein localization	11	10.6×	3e-06
actin cytoskeleton organization	9	6.5×	2e-03

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 1 cancer types — BCC.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	1
Uncertain significance	150
Likely benign	25
Benign	62

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
2085963	NM_005401.5(PTPN14):c.3046C>T (p.Arg1016Ter)	Pathogenic
599260	NM_005401.5(PTPN14):c.401_402insTT (p.Leu135fs)	Pathogenic
6620	NM_005401.5(PTPN14):c.581+60_669+877del	Pathogenic
916569	NM_005401.5(PTPN14):c.1919G>A (p.Arg640His)	Likely pathogenic

SpliceAI

4694 predictions. Top by Δscore:

Variant	Effect	Δscore
1:214357870:T:A	donor_gain	1.0000
1:214364508:TCA:T	donor_loss	1.0000
1:214364509:CA:C	donor_loss	1.0000
1:214364510:A:AC	donor_gain	1.0000
1:214364510:A:T	donor_loss	1.0000
1:214364511:C:CT	donor_gain	1.0000
1:214364511:CTT:C	donor_gain	1.0000
1:214364513:T:TA	donor_gain	1.0000
1:214364676:C:CC	acceptor_gain	1.0000
1:214372705:CCTTA:C	donor_loss	1.0000
1:214372706:CTTA:C	donor_loss	1.0000
1:214372707:TTA:T	donor_loss	1.0000
1:214372708:TACC:T	donor_loss	1.0000
1:214372709:A:AG	donor_loss	1.0000
1:214372709:ACCT:A	donor_gain	1.0000
1:214372710:CCTC:C	donor_gain	1.0000
1:214372745:C:CA	donor_gain	1.0000
1:214372836:CCAC:C	acceptor_gain	1.0000
1:214372837:CACC:C	acceptor_gain	1.0000
1:214372838:ACC:A	acceptor_loss	1.0000
1:214372839:CCTA:C	acceptor_loss	1.0000
1:214372841:T:A	acceptor_loss	1.0000
1:214376214:CTTA:C	donor_loss	1.0000
1:214376217:A:AC	donor_gain	1.0000
1:214376218:C:CC	donor_gain	1.0000
1:214376218:C:CT	donor_loss	1.0000
1:214376433:CTGAA:C	acceptor_gain	1.0000
1:214376434:TGAA:T	acceptor_gain	1.0000
1:214376435:GAA:G	acceptor_gain	1.0000
1:214376436:AA:A	acceptor_gain	1.0000

AlphaMissense

7863 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:214372767:A:G	W994R	0.999
1:214372767:A:T	W994R	0.999
1:214384241:G:C	S538R	0.999
1:214384241:G:T	S538R	0.999
1:214384243:T:G	S538R	0.999
1:214451926:A:G	W75R	0.999
1:214451926:A:T	W75R	0.999
1:214464637:A:G	L56P	0.999
1:214369499:A:G	W1077R	0.998
1:214369499:A:T	W1077R	0.998
1:214369520:A:G	W1070R	0.998
1:214369520:A:T	W1070R	0.998
1:214369596:A:C	F1044L	0.998
1:214369596:A:T	F1044L	0.998
1:214369598:A:G	F1044L	0.998
1:214369609:A:T	V1040D	0.998
1:214394985:A:G	W254R	0.998
1:214394985:A:T	W254R	0.998
1:214401741:A:C	Y205D	0.998
1:214414712:A:G	L120P	0.998
1:214451892:A:G	L86P	0.998
1:214364651:A:T	V1099D	0.997
1:214369661:A:G	W1023R	0.997
1:214369661:A:T	W1023R	0.997
1:214376230:A:G	S966P	0.997
1:214376232:G:T	A965D	0.997
1:214384121:G:C	S578R	0.997
1:214384121:G:T	S578R	0.997
1:214384123:T:G	S578R	0.997
1:214414629:C:G	A148P	0.997

dbSNP variants (sampled 300 via entrez): RS1000007993 (1:214398005 G>A,C,T), RS1000022112 (1:214463083 C>T), RS1000026612 (1:214380925 A>G), RS1000043791 (1:214434107 G>A), RS1000070604 (1:214420617 G>A), RS1000070845 (1:214380662 A>G), RS1000098001 (1:214506674 T>C), RS1000121660 (1:214511343 A>G), RS1000139525 (1:214552605 G>A), RS1000151335 (1:214471718 T>C), RS1000155931 (1:214428756 A>T), RS1000163587 (1:214356171 C>A,T), RS1000164693 (1:214395557 T>C), RS1000200340 (1:214404368 G>A,T), RS1000205959 (1:214444636 A>G)

Disease associations

OMIM: gene MIM:603155 | disease phenotypes: MIM:613611, MIM:189960

GenCC curated gene-disease

Disease	Classification	Inheritance
lymphedema-posterior choanal atresia syndrome	Strong	Autosomal recessive

Mondo (2): lymphedema-posterior choanal atresia syndrome (MONDO:0013324), esophageal atresia/tracheoesophageal fistula (MONDO:0008586)

Orphanet (2): Lymphedema-posterior choanal atresia syndrome (Orphanet:99141), Esophageal atresia (Orphanet:1199)

HPO phenotypes

5 total (5 of 5 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000218	High palate
HP:0000453	Choanal atresia
HP:0001004	Lymphedema
HP:0001698	Pericardial effusion

GWAS associations

14 associations (top):

Study	Trait	p-value
GCST002321_5	Lipid traits	2.000000e-06
GCST002417_2	Plasma thyroid-stimulating hormone levels	4.000000e-06
GCST002702_3	Height	1.000000e-09
GCST006444_17	Bone mineral density (hip)	7.000000e-06
GCST008058_136	Estimated glomerular filtration rate	2.000000e-15
GCST008059_50	Estimated glomerular filtration rate	2.000000e-13
GCST008163_365	Height	2.000000e-09
GCST008362_96	Birth weight	3.000000e-11
GCST008745_90	Estimated glomerular filtration rate in non-diabetics	2.000000e-09
GCST008747_113	Estimated glomerular filtration rate	1.000000e-06
GCST008839_423	Height	8.000000e-18
GCST009441_15	Age-related cognitive decline (memory) (slope of z-scores)	9.000000e-06
GCST90000025_849	Appendicular lean mass	2.000000e-38
GCST90020026_719	Hip index	3.000000e-08

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004530	triglyceride measurement
EFO:0007702	hip bone mineral density
EFO:0004344	birth weight
EFO:0007710	cognitive decline measurement
EFO:0004980	appendicular lean mass
EFO:0008039	BMI-adjusted hip circumference

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C531835	Esophageal atresia with or without tracheoesophageal fistula (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3317332 (SINGLE PROTEIN)

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

Binding affinities (BindingDB)

1 measured of 1 human assays (1 total across all organisms); most potent 1 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
6-hydroxy-3-iodo-1-methyl-2-[3-[[2-oxo-2-(4-thiophen-3-ylanilino)acetyl]amino]phenyl]indole-5-carboxylic acid	IC50	2900 nM	US-9522881: Hydroxyindole carboxylic acid based inhibitors for oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2)

ChEMBL bioactivities

3 potent at pChembl≥5 of 3 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.28	IC50	5300	nM	CHEMBL3319356
5.08	IC50	8300	nM	CHEMBL3426913

PubChem BioAssay actives

2 with measured affinity, of 2 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
6-hydroxy-3-iodo-1-methyl-2-[3-[[2-oxo-2-(4-thiophen-3-ylanilino)acetyl]amino]phenyl]indole-5-carboxylic acid	1182554: Inhibition of PEZ (unknown origin)	ic50	5.3000	uM
4-[1-(cyclohexylamino)-1-oxohexan-2-yl]oxy-2-hydroxy-5-[2-[2-(trifluoromethoxy)phenyl]ethynyl]benzoic acid	1206777: Inhibition of PEZ (unknown origin) using pNPP as substrate at pH 7 at 25 degC by spectrophotometric analysis	ic50	8.3000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression	3
bisphenol F	decreases expression, affects cotreatment, increases methylation	2
bisphenol A	affects methylation, affects cotreatment, decreases expression	2
sodium arsenite	decreases expression, increases abundance	2
Cisplatin	affects cotreatment, decreases expression	2
Valproic Acid	affects expression, increases expression	2
Cadmium Chloride	decreases expression, increases expression	2
FR900359	decreases phosphorylation	1
methylmercuric chloride	increases expression	1
beta-lapachone	decreases expression	1
arsenite	affects binding, decreases reaction	1
cobaltous chloride	decreases expression	1
manganese chloride	decreases expression, increases abundance	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment, decreases expression	1
seocalcitol	increases expression	1
cylindrospermopsin	increases expression	1
CGP 52608	increases reaction, affects binding	1
torcetrapib	increases expression	1
abrine	increases expression	1
bisphenol S	affects cotreatment, decreases expression	1
jinfukang	affects cotreatment, decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Acetaminophen	increases expression	1
Arsenic	increases abundance, decreases expression	1
Caffeine	increases phosphorylation	1
Carbamazepine	affects expression	1
Dexamethasone	affects cotreatment, decreases expression	1
Doxorubicin	decreases expression	1
Folic Acid	decreases expression	1
Indomethacin	affects cotreatment, decreases expression	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3369527	Binding	Inhibition of PEZ (unknown origin)	Therapeutic potential of targeting the oncogenic SHP2 phosphatase. — J Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03792360	PHASE1	WITHDRAWN	Adipose Derived SVF for Aero-digestive & Enterocutaneous Fistulae
NCT02033772	Not specified	COMPLETED	Prospective Data Collection of Patients < 6 Months of Age Undergoing Thoracoscopic Surgery
NCT02364843	Not specified	TERMINATED	A Physiological Study to Determine the Enteral Threonine Requirements in Infants Aged 1 to 6 Months
NCT03455881	Not specified	UNKNOWN	Phenotypic and Genetic Assessment of Tracheal and Esophageal Birth Defects in Patients
NCT03730454	Not specified	ACTIVE_NOT_RECRUITING	Transanastomotic Tube for Proximal Esophageal Atresia With Distal Tracheoesophageal Fistula Repair