PROX1

Summary

PROX1 (prospero homeobox 1, HGNC:9459) is a protein-coding gene on chromosome 1q32.3, encoding Prospero homeobox protein 1 (Q92786). Transcription factor involved in developmental processes such as cell fate determination, gene transcriptional regulation and progenitor cell regulation in a number of organs.

The protein encoded by this gene is a member of the homeobox transcription factor family. Members of this family contain a homeobox domain that consists of a 60-amino acid helix-turn-helix structure that binds DNA and RNA. The protein encoded by this gene is conserved across vertebrates and may play an essential role during development. Altered levels of this protein have been reported in cancers of different organs, such as colon, brain, blood, breast, pancreas, liver and esophagus. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 5629 — RefSeq curated summary.

At a glance

• Gene–disease (curated): congenital heart disease (Disputed, ClinGen)
• GWAS associations: 42
• Clinical variants (ClinVar): 78 total
• Druggable target: yes
• Transcription factor: yes — 38 downstream targets (CollecTRI)
• MANE Select transcript: NM_001270616

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9459
Approved symbol	PROX1
Name	prospero homeobox 1
Location	1q32.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000117707
Ensembl biotype	protein_coding
OMIM	601546
Entrez	5629

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 18 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000366958, ENST00000435016, ENST00000471129, ENST00000607425, ENST00000607726, ENST00000881019, ENST00000881020, ENST00000881021, ENST00000881022, ENST00000881023, ENST00000881024, ENST00000881025, ENST00000881026, ENST00000881027, ENST00000881028, ENST00000881029, ENST00000881030, ENST00000952521, ENST00000952522

RefSeq mRNA: 2 — MANE Select: NM_001270616 NM_001270616, NM_002763

CCDS: CCDS31021

Canonical transcript exons

ENST00000366958 — 5 exons

Exon	Start	End
ENSE00001308453	214011521	214011715
ENSE00001443118	214035649	214041510
ENSE00001505910	214005165	214005272
ENSE00001816151	213996469	213998260
ENSE00001936642	213987973	213988483

Expression profiles

Bgee: expression breadth ubiquitous, 225 present calls, max score 94.02.

FANTOM5 (CAGE): breadth broad, TPM avg 12.8197 / max 928.7385, expressed in 789 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
8513	9.7431	704
8515	0.7951	284
8514	0.7689	279
8520	0.2369	118
8517	0.2332	114
8519	0.2321	109
8516	0.2124	112
8522	0.1914	51
8512	0.1662	81
201948	0.1308	61

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sural nerve	UBERON:0015488	94.02	gold quality
liver	UBERON:0002107	93.01	gold quality
right lobe of liver	UBERON:0001114	92.79	gold quality
heart right ventricle	UBERON:0002080	88.43	gold quality
adrenal tissue	UBERON:0018303	85.66	gold quality
buccal mucosa cell	CL:0002336	83.63	gold quality
corpus callosum	UBERON:0002336	82.21	gold quality
biceps brachii	UBERON:0001507	81.38	gold quality
islet of Langerhans	UBERON:0000006	81.35	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	81.25	gold quality
pancreas	UBERON:0001264	80.58	gold quality
body of pancreas	UBERON:0001150	80.34	gold quality
cardiac ventricle	UBERON:0002082	79.94	gold quality
heart left ventricle	UBERON:0002084	79.79	gold quality
lateral nuclear group of thalamus	UBERON:0002736	79.37	gold quality
adrenal gland	UBERON:0002369	79.04	gold quality
right atrium auricular region	UBERON:0006631	78.97	gold quality
left adrenal gland	UBERON:0001234	78.75	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	78.48	gold quality
cardiac atrium	UBERON:0002081	78.43	gold quality
left adrenal gland cortex	UBERON:0035825	78.03	gold quality
renal medulla	UBERON:0000362	77.54	gold quality
heart	UBERON:0000948	77.09	gold quality
spinal cord	UBERON:0002240	77.02	gold quality
adrenal cortex	UBERON:0001235	76.81	gold quality
inferior vagus X ganglion	UBERON:0005363	76.30	gold quality
right adrenal gland	UBERON:0001233	76.02	gold quality
cerebellar vermis	UBERON:0004720	75.63	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	75.59	gold quality
myocardium	UBERON:0002349	75.54	gold quality

Single-cell (SCXA)

Detected in 14 experiment(s), a significant marker in 12.

Experiment	Marker?	Max mean expression
E-MTAB-11121	yes	1132.60
E-MTAB-7316	yes	627.95
E-MTAB-8142	yes	38.90
E-HCAD-1	yes	16.89
E-CURD-46	yes	15.50
E-MTAB-6701	yes	15.26
E-GEOD-125970	yes	14.69
E-MTAB-8410	yes	12.26
E-CURD-114	yes	11.98
E-ANND-3	yes	11.45
E-GEOD-130148	yes	6.51
E-GEOD-137537	yes	6.45
E-MTAB-6678	no	822.61
E-MTAB-6386	no	3.32

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

38 targets.

Target	Regulation
AKT2
CALCRL	Activation
CCNE1	Activation
CD74
CDH17
CDKN1B	Activation
CDKN1C	Activation
CDKN2A	Unknown
CRYBB1	Activation
CYP7A1	Repression
EYA1
EYA2
FGFR3	Activation
FLT4
GHRHR
HIF1A	Activation
HOXD8	Activation
IFNG	Repression
ITGA9	Activation
KDR
MIR9-2
NES
NOTCH1
NR1I2	Repression
NR5A2	Repression
NRP1
OGG1
PAX6
PCK2	Repression
PRKCB

JASPAR motifs

Motif	Name	Family
MA0794.1	PROX1	HD-PROS factors

JASPAR matrix evidence (PMIDs): PMID:21040746

Upstream regulators (CollecTRI, top): DAB2IP, EPAS1, FOXC1, FOXN4, HEY1, HIF1A, HOXD8, MAZ, NFKB1, PAX6, RELA, SOX18, STAT5A, TP53

miRNA regulators (miRDB)

262 targeting PROX1, 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-6867-5P	100.00	82.21	3464
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-4425	100.00	67.59	1049
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-3148	99.97	75.06	6478

Literature-anchored findings (GeneRIF, showing 40)

• Prox 1 is expressed in both quiescent and proliferating lymphatic endothelial cells in the adult human and mouse liver. Unlike the putative lymphatic marker LYVE-1, Prox 1 is not expressed in liver sinusoidal endothelial cells. (PMID:11719431)
• Prox 1 is expressed in both quiescent and proliferating lymphatic endothelial cells in the liver. Unlike the putative lymphatic marker LYVE-1, Prox 1 is not expressed in liver sinusoidal endothelial cells. (PMID:11719431)
• PROX1 is a marker of lymphatic endothelial cells in the lymphatics of human fetuses. (PMID:11789987)
• Prox1 is differentially localized during lens development (PMID:11850194)
• Prox-1 acts as a cell proliferation inducer and a fate determination factor for lymphatic endothelial cells. (PMID:12198161)
• lymphatic vasculature originated from the blood vasculature by the additional expression of only a few gene products such as Prox1. (PMID:12412020)
• Prox1 activity is both necessary and sufficient for progenitor-cell proliferation and cell-fate determination in the vertebrate retina. (PMID:12692551)
• PROX1 gene corresponds to that of a candidate tumor-suppressor gene. (PMID:12874782)
• The homeodomain protein Prox1 was characterized as a co-repressor for liver receptor homologue 1 (LRH1/NR5A2). (PMID:15143342)
• The suppression by Prox1 on the transcriptional activity of liver receptor homolog-1 can be mediated through its interaction with the ligand binding domain of LRH-1. (PMID:15205472)
• Prox1 is a highly conserved transcription factor, expressed in hepatocytes from the earliest stages of development into adulthood and over-expressed in hepatoma cell lines. (PMID:15232737)
• CD 31/Prox-1 double-immunolabeling can be used as an adjunct marker to identify lymphatic vessels in routinely processed formalin-fixed, paraffin-embedded samples. (PMID:16308102)
• Prox1 is a novel co-regulator of HNF4alpha that may play a key role in the regulation of bile acid synthesis and gluconeogenesis in the liver (PMID:16488887)
• Prox1 was significantly reduced in pancreatic cancer specimens from patients with short survival rates, and loss of Prox1 function may be a driving force behind pancreatic carcinoma progression. (PMID:16525637)
• Prox1 is involved in the differentiation and progression of hepatoma, and may be a candidate for the development of novel diagnostic and therapeutic strategies. (PMID:17062673)
• mechanisms like genomic deletions and hypermethylation, which are prototypic for the inactivation of tumor suppressor genes, inactivate PROX1 in carcinomas of the bilary system (PMID:17069925)
• RNA mutation of the prox1 gene plays a pivotal role in the pathogenesis of human cancer progression. (PMID:17217617)
• we have identified PROX1 as a novel target gene that is hypermethylated and transcriptionally silenced in primary and metastatic breast cancer. (PMID:17415710)
• analysis of prox1 RNA mutations detected in human esophageal cancer cells by the shifted termination assay (PMID:17533110)
• interaction of CEACAM1 with Prox1 and VEGFR-3 plays a crucial role in tumor lymphangiogenesis and reprogramming of vascular endothelial cells to lymphatic endothelial cells (PMID:17761831)
• Altered Prox1 mRNA expression is partly regulated by MAZ, and mutation of the prospero domain in hepatocellular carcinoma indicates an involvement for Prox1 during tumor progression. (PMID:18400094)
• In intestinal tumors PROX1 is a direct and dose-dependent target of the beta-catenin/TCF signaling pathway, responsible for the neoplastic transformation. (PMID:18455124)
• Prox1 plays an important, previously unanticipated role in mediating the aggressive behavior of vascular neoplasms such as Kaposi’s sarcoma (PMID:18580962)
• venous endothelial cell fate regulator COUP-TFII is expressed in lymphatic cells throughout development and physically interacts with Prox1 to form a stable complex in various cell types (PMID:18815287)
• These findings suggest that sumoylation may serve as a novel mechanism for the regulation of Prox1’s corepressor activity. (PMID:18948102)
• These findings establish Prox1 as a new negative regulator of IFN-gamma expression in T cells . (PMID:19160541)
• The present study shows that COUP-TFII plays important roles in the regulation of the function of Prox1. (PMID:19210544)
• This study showed that that nuclear factor Prospero-related homeobox protein (Prox1) represses HBV antigen expression and genome replication in cultured hepatocytes. (PMID:19264593)
• Patients with familial combined hyperlipidaemia had lower Prox-1 expression than controls. (PMID:19339011)
• Sumoylation of Prox1 controls its ability to induce VEGFR3 expression and lymphatic phenotypes in endothelial cells. (PMID:19706680)
• Prox1 and HoxD8 play important roles in the maturation and maintenance of lymphatic vessels. (PMID:19825936)
• Prox1 synergizes with the p50 of NF-kappaB to control VEGFR-3 expression. (PMID:19901262)
• Data show that tumor spheroid cells express ABCG2, Bmi1, WNT5A, CD133, prox1 and VEGFR3. (PMID:19940551)
• This study identified and replicated a locus upstream of PROX1 that is associated with delayed progression to clinical AIDS. PROX1 is a negative regulator of interferon-gamma expression in T cells. (PMID:20064070)
• study investigated PROX1 expression patterns in 56 human astrocytic gliomas of different grades; an average of 79% of cells in World Health Organization Grade IV & 57% of cells in World Health Organization Grade III were strongly PROX1 positive (PMID:20084020)
• Data suggest a novel model that the endothelial cell fate regulators, Notch, COUP-TFII, and Prox1, are under an exquisite feedback control mechanism and dynamically regulate each other in LECs. (PMID:20351309)
• study shows that Prox1 is expressed at low levels in 24 neuroblastoma (NB) cell lines; in NB stages 1, 2, 3, and 4, we observed almost equal expression levels, but significantly higher amounts in stage 4s NB (PMID:20453716)
• Prox1 is an immunohistochemical biomarker helpful in confirming the diagnosis of Kaposiform hemangioendothelioma/tufted angioma and in distinguishing it from infantile hemangioma and pyogenic granuloma. (PMID:20975337)
• Data show that SNPs from MADD, PROX1, and SLC30A8 were associated with type 2 diabetes. (PMID:21103350)
• Loss of Prox1 is associated with esophageal cancer. (PMID:21452064)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	prox1a	ENSDARG00000055158
mus_musculus	Prox1	ENSMUSG00000010175
rattus_norvegicus	Prox1	ENSRNOG00000003694
drosophila_melanogaster	pros	FBGN0004595
caenorhabditis_elegans		WBGENE00000448

Paralogs (1): PROX2 (ENSG00000119608)

Protein

Protein identifiers

Prospero homeobox protein 1 — Q92786 (reviewed: Q92786)

Alternative names: Homeobox prospero-like protein PROX1

All UniProt accessions (3): C9JU29, Q92786, U3KPY6

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor involved in developmental processes such as cell fate determination, gene transcriptional regulation and progenitor cell regulation in a number of organs. Plays a critical role in embryonic development and functions as a key regulatory protein in neurogenesis and the development of the heart, eye lens, liver, pancreas and the lymphatic system. Involved in the regulation of the circadian rhythm. Represses: transcription of the retinoid-related orphan receptor RORG, transcriptional activator activity of RORA and RORG and the expression of RORA/G-target genes including core clock components: BMAL1, NPAS2 and CRY1 and metabolic genes: AVPR1A and ELOVL3.

Subunit / interactions. Interacts with RORA and RORG (via AF-2 motif).

Subcellular location. Nucleus.

Tissue specificity. Most actively expressed in the developing lens. Detected also in embryonic brain, lung, liver and kidney. In adult, it is more abundant in heart and liver than in brain, skeletal muscle, kidney and pancreas.

Domain organisation. The Prospero-type homeodomain and the adjacent Prospero domain act as a single structural unit, the Homeo-Prospero domain. The Prospero-type homeodomain is essential for repression of RORG transcriptional activator activity.

Similarity. Belongs to the Prospero homeodomain family.

RefSeq proteins (2): NP_001257545, NP_002754 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR009057	Homeodomain-like_sf	Homologous_superfamily
IPR023082	Homeo_prospero_dom	Domain
IPR037131	Homeo_prospero_dom_sf	Homologous_superfamily
IPR039350	Prospero_homeodomain	Family

Pfam: PF05044

UniProt features (38 total): helix 9, modified residue 8, region of interest 7, compositionally biased region 5, sequence conflict 3, domain 2, chain 1, cross-link 1, sequence variant 1, strand 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2LMD	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q92786-F1	61.63	0.29

Functional residue map

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

Post-translational modifications (9): 177, 179, 199, 291, 295, 511, 514, 557, 324

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 548 (showing top): GSE45365_NK_CELL_VS_CD11B_DC_UP, GOBP_CARDIAC_CHAMBER_DEVELOPMENT, GOBP_CIRCADIAN_RHYTHM, GOBP_SPINAL_CORD_DEVELOPMENT, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_DENTATE_GYRUS_DEVELOPMENT, GOBP_HINDBRAIN_DEVELOPMENT, GOBP_REGULATION_OF_CELL_CYCLE_CHECKPOINT, GOBP_LENS_FIBER_CELL_DIFFERENTIATION, GOBP_HEPATICOBILIARY_SYSTEM_DEVELOPMENT, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, FREAC2_01, GOBP_METENCEPHALON_DEVELOPMENT

GO Biological Process (70): negative regulation of transcription by RNA polymerase II (GO:0000122), kidney development (GO:0001822), liver development (GO:0001889), positive regulation of endothelial cell proliferation (GO:0001938), lymphangiogenesis (GO:0001946), lens development in camera-type eye (GO:0002088), hepatocyte cell migration (GO:0002194), regulation of transcription by RNA polymerase II (GO:0006357), transcription by RNA polymerase II (GO:0006366), neuroblast proliferation (GO:0007405), negative regulation of neuroblast proliferation (GO:0007406), brain development (GO:0007420), circadian rhythm (GO:0007623), positive regulation of cell population proliferation (GO:0008284), negative regulation of cell population proliferation (GO:0008285), regulation of gene expression (GO:0010468), positive regulation of endothelial cell migration (GO:0010595), epithelial cell migration (GO:0010631), dorsal spinal cord development (GO:0021516), dentate gyrus development (GO:0021542), cerebellar granule cell differentiation (GO:0021707), neural tube development (GO:0021915), skeletal muscle thin filament assembly (GO:0030240), lung development (GO:0030324), olfactory placode formation (GO:0030910), pancreas development (GO:0031016), response to nutrient levels (GO:0031667), regulation of circadian rhythm (GO:0042752), otic placode formation (GO:0043049), negative regulation of viral genome replication (GO:0045071), positive regulation of cell cycle (GO:0045787), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of transcription by RNA polymerase II (GO:0045944), lens placode formation involved in camera-type eye formation (GO:0046619), neuron fate determination (GO:0048664), venous blood vessel morphogenesis (GO:0048845), ventricular cardiac myofibril assembly (GO:0055005), atrial cardiac muscle tissue morphogenesis (GO:0055009), ventricular cardiac muscle tissue morphogenesis (GO:0055010), retina morphogenesis in camera-type eye (GO:0060042)

GO Molecular Function (12): transcription cis-regulatory region binding (GO:0000976), RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription repressor activity, RNA polymerase II-specific (GO:0001227), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), DNA binding (GO:0003677), nuclear receptor binding (GO:0016922), DNA binding domain binding (GO:0050692), LBD domain binding (GO:0050693), sequence-specific double-stranded DNA binding (GO:1990837), protein binding (GO:0005515), sequence-specific DNA binding (GO:0043565)

GO Cellular Component (5): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA polymerase II transcription regulatory region sequence-specific DNA binding	4
cellular anatomical structure	4
anatomical structure development	3
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
animal organ development	2
cell population proliferation	2
regulation of cell population proliferation	2
DNA-binding transcription factor activity, RNA polymerase II-specific	2
protein domain specific binding	2
negative regulation of DNA-templated transcription	1
renal system development	1
gland development	1
hepaticobiliary system development	1
endothelial cell proliferation	1
regulation of endothelial cell proliferation	1
positive regulation of epithelial cell proliferation	1
anatomical structure morphogenesis	1
lymph vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
camera-type eye development	1
cell migration	1
regulation of DNA-templated transcription	1
DNA-templated transcription	1
generation of neurons	1
neural precursor cell proliferation	1
neuroblast proliferation	1
negative regulation of neurogenesis	1
regulation of neuroblast proliferation	1
negative regulation of neural precursor cell proliferation	1
central nervous system development	1
head development	1
rhythmic process	1
positive regulation of cellular process	1
negative regulation of cellular process	1
gene expression	1
regulation of macromolecule biosynthetic process	1
regulation of endothelial cell migration	1
positive regulation of cell migration	1
endothelial cell migration	1

Protein interactions and networks

STRING

1602 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PROX1	PDPN	Q86YL7	913
PROX1	SOX18	P35713	864
PROX1	VEGFD	O43915	843
PROX1	LYVE1	Q9Y5Y7	825
PROX1	VEGFC	P49767	822
PROX1	FOXN4	Q96NZ1	808
PROX1	FLT4	P35916	778
PROX1	ONECUT1	Q9UBC0	753
PROX1	NR2F2	P24468	737
PROX1	NEUROD1	Q13562	670
PROX1	HNF4A	P41235	655
PROX1	HHEX	Q03014	644
PROX1	PROM1	O43490	644
PROX1	NR5A2	O00482	638
PROX1	NEUROD4	Q9HD90	629

IntAct

41 interactions, top by confidence:

A	B	Type	Score
HDAC2	KDM1A	psi-mi:“MI:0914”(association)	0.890
PROX1	NR5A2	psi-mi:“MI:0915”(physical association)	0.630
PROX1	NR5A2	psi-mi:“MI:0403”(colocalization)	0.630
NR5A2	PROX1	psi-mi:“MI:0403”(colocalization)	0.630
NR5A2	PROX1	psi-mi:“MI:0915”(physical association)	0.630
HNF4A	PROX1	psi-mi:“MI:0915”(physical association)	0.580
RBBP4	TNRC18	psi-mi:“MI:0914”(association)	0.530
HNF1A	PROX1	psi-mi:“MI:0915”(physical association)	0.520
PROX1	HNF1A	psi-mi:“MI:0915”(physical association)	0.520
PROX1	CTBP2	psi-mi:“MI:0915”(physical association)	0.510
CTBP2	PROX1	psi-mi:“MI:0915”(physical association)	0.510
PROX1	CEBPZ	psi-mi:“MI:0915”(physical association)	0.400
HDAC3	PROX1	psi-mi:“MI:0915”(physical association)	0.400
SUMO1	PROX1	psi-mi:“MI:0915”(physical association)	0.400
PROX1	NR5A2	psi-mi:“MI:0915”(physical association)	0.400
CCL26	PROX1	psi-mi:“MI:0915”(physical association)	0.370
IL18	PROX1	psi-mi:“MI:0915”(physical association)	0.370
TNFSF4	PROX1	psi-mi:“MI:0915”(physical association)	0.370
IRF4	PROX1	psi-mi:“MI:0915”(physical association)	0.370
PROX1	ZBTB3	psi-mi:“MI:0915”(physical association)	0.370
GIT2	PROX1	psi-mi:“MI:0915”(physical association)	0.370
PROX1	LBH	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (45): PROX1 (Affinity Capture-MS), EP300 (Two-hybrid), PROX1 (Affinity Capture-MS), PPARG (Affinity Capture-Western), PROX1 (Affinity Capture-Western), PROX1 (Proximity Label-MS), PROX1 (Reconstituted Complex), PROX1 (Affinity Capture-MS), PROX1 (Affinity Capture-MS), PROX1 (Affinity Capture-MS), PROX1 (Affinity Capture-RNA), PROX1 (Affinity Capture-MS), PROX1 (Affinity Capture-MS), PROX1 (Affinity Capture-MS), PROX1 (Affinity Capture-MS)

ESM2 similar proteins: A0A078BQN7, A6ZJ55, A8WW61, B3P773, F5GUE5, G5EBL3, G5EED4, O01477, O02039, O04116, O04407, O14342, O17617, O36398, O36407, P23984, P24433, P34450, P34520, P34619, P40744, P40745, P45897, P48437, P52354, P52539, Q09585, Q11103, Q11107, Q12020, Q17436, Q19802, Q19863, Q20646, Q21733, Q23238, Q23647, Q60WM1, Q6FJ36, Q707Y0

Diamond homologs: P29617, P34522, P48437, Q3B8N5, Q8BII1, Q91018, Q92786, Q9U6A1

SIGNOR signaling

8 interactions.

A	Effect	B	Mechanism
PROX1	“down-regulates quantity by repression”	IFNG	“transcriptional regulation”
DAB2IP	“down-regulates quantity by repression”	PROX1	“transcriptional regulation”
PROX1	“up-regulates quantity by stabilization”	HIF1A
PROX1	up-regulates	Epithelial-mesenchymal_transition
PRKAA2	“down-regulates quantity by destabilization”	PROX1	phosphorylation
PRKAB1	“down-regulates quantity by destabilization”	PROX1	phosphorylation
Cullin4-RBX1-DDB1	“down-regulates quantity by destabilization”	PROX1	polyubiquitination
PROX1	down-regulates	RORC

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 33 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
Negative Regulation of CDH1 Gene Transcription	5	23.1×	5e-04

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of cold-induced thermogenesis	5	24.8×	2e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	62
Likely benign	8
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

1169 predictions. Top by Δscore:

Variant	Effect	Δscore
1:213988720:GA:G	donor_gain	0.9900
1:213988722:G:GG	donor_gain	0.9900
1:213998253:G:GT	donor_gain	0.9900
1:213998253:G:T	donor_gain	0.9900
1:214011711:TTGAG:T	donor_loss	0.9900
1:214011712:TGAGG:T	donor_loss	0.9900
1:214011713:GAGG:G	donor_loss	0.9900
1:214011714:AGG:A	donor_loss	0.9900
1:214011715:GG:G	donor_loss	0.9900
1:214011716:GTA:G	donor_loss	0.9900
1:214011717:T:A	donor_loss	0.9900
1:214035778:G:GT	donor_gain	0.9900
1:214035827:A:AG	donor_gain	0.9900
1:214035827:A:G	donor_gain	0.9900
1:214035830:A:AG	donor_gain	0.9900
1:214035831:G:GG	donor_gain	0.9900
1:214035832:T:TA	donor_gain	0.9900
1:214035833:A:AA	donor_gain	0.9900
1:213995152:T:G	donor_gain	0.9800
1:214011511:A:G	acceptor_gain	0.9800
1:214011519:A:AG	acceptor_gain	0.9800
1:214011520:G:GA	acceptor_gain	0.9800
1:214012889:T:G	donor_gain	0.9800
1:214035858:T:G	donor_gain	0.9800
1:213996467:AG:A	acceptor_gain	0.9700
1:213996468:GG:G	acceptor_gain	0.9700
1:213998226:A:G	donor_gain	0.9700
1:214011520:GTTC:G	acceptor_gain	0.9700
1:214035646:CAGGT:C	acceptor_loss	0.9700
1:214035647:A:C	acceptor_loss	0.9700

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000014914 (1:213994633 T>G), RS1000046491 (1:213988445 A>G), RS1000101053 (1:213996353 T>A,C), RS1000139489 (1:214004881 C>A,G,T), RS1000186844 (1:214001683 A>T), RS1000189990 (1:214005100 G>A,C), RS1000281627 (1:214001978 C>T), RS1000318623 (1:214031925 T>A,G), RS1000356958 (1:213990777 A>G), RS1000387494 (1:214011602 G>A,T), RS1000409317 (1:213991174 T>C), RS1000467196 (1:214009088 G>A), RS1000527152 (1:214000206 T>C), RS1000552713 (1:213994907 T>C), RS1000563126 (1:214028961 C>A,T)

Disease associations

OMIM: gene MIM:601546 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
congenital heart disease	Disputed Evidence	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
congenital heart disease	Disputed	AD

Mondo (1): congenital heart disease (MONDO:0005453)

Orphanet (0):

HPO phenotypes

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

GWAS associations

42 associations (top):

Study	Trait	p-value
GCST000568_14	Fasting blood glucose	7.000000e-12
GCST000596_1	HIV-1 progression	2.000000e-06
GCST001527_28	Fasting blood glucose (BMI interaction)	4.000000e-09
GCST001732_3	Obesity	4.000000e-07
GCST002352_44	Type 2 diabetes	2.000000e-06
GCST002897_12	Triglycerides	4.000000e-10
GCST004125_14	Type 2 diabetes (age of onset)	9.000000e-06
GCST004601_11	Red blood cell count	1.000000e-16
GCST004604_17	Hematocrit	4.000000e-21
GCST004615_85	Hemoglobin concentration	6.000000e-18
GCST004774_6	Type 2 diabetes	3.000000e-07
GCST005047_33	Type 2 diabetes	8.000000e-09
GCST005047_74	Type 2 diabetes	9.000000e-06
GCST005112_2	Breast cancer in childhood cancer survivors treated with more than 10 gray radiotherapy	7.000000e-09
GCST005180_5	Homeostasis model assessment of beta-cell function	5.000000e-06
GCST005186_29	Fasting blood glucose	9.000000e-07
GCST005414_6	Type 2 diabetes	1.000000e-07
GCST005994_17	Hematocrit	4.000000e-11
GCST005995_6	Hemoglobin	6.000000e-11
GCST005996_53	Red blood cell count	1.000000e-09
GCST007824_1	Monoclonal gammopathy of undetermined significance	2.000000e-06
GCST008362_144	Birth weight	2.000000e-08
GCST008674_1	Glycemic traits (pleiotropy)	7.000000e-09
GCST009379_4	Type 2 diabetes	3.000000e-16
GCST009379_5	Type 2 diabetes	2.000000e-22
GCST009379_6	Type 2 diabetes	4.000000e-07
GCST009391_1608	Metabolite levels	6.000000e-06
GCST010002_377	Refractive error	1.000000e-10
GCST010083_128	Hemoglobin levels	2.000000e-50
GCST010083_301	Hemoglobin levels	1.000000e-50

EFO canonical traits (13, from GWAS)

EFO ID	Trait name
EFO:0000180	HIV-1 infection
EFO:0004340	body mass index
EFO:0004530	triglyceride measurement
EFO:0004305	erythrocyte count
EFO:0004348	hematocrit
EFO:0004509	hemoglobin measurement
EFO:0004469	HOMA-B
EFO:0004344	birth weight
EFO:0010377	phosphatidylcholine 34:3 measurement
EFO:0004468	glucose measurement
EFO:0004327	electrocardiography
EFO:0004533	alkaline phosphatase measurement
EFO:0004532	serum gamma-glutamyl transferase measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D006330	Heart Defects, Congenital	C14.240.400; C14.280.400; C16.131.240.400

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067110 (SINGLE PROTEIN)

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs340874	Toxicity	3	atenolol	Hypertension

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs340874	PROX1, PROX1-AS1	3	2.00	1	atenolol

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
5.18	Kd	6661	nM	CHEMBL3752910
5.18	ED50	6661	nM	CHEMBL3752910

PubChem BioAssay actives

1 with measured affinity, of 2 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
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149919: Binding affinity to human PROX1 incubated for 45 mins by Kinobead based pull down assay	kd	6.6612	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, decreases expression	5
Benzo(a)pyrene	decreases expression, increases methylation, affects methylation	4
Estradiol	affects binding, affects reaction, increases reaction, decreases expression	4
Cyclosporine	decreases expression, increases expression	4
bisphenol A	affects binding, decreases reaction, decreases methylation	2
Decitabine	decreases expression, decreases reaction, increases expression	2
Vorinostat	affects cotreatment, increases expression	2
Acetaminophen	decreases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Aflatoxin B1	affects expression, decreases expression	2
TAK-243	decreases sumoylation	1
testosterone enanthate	affects expression	1
methylmercuric chloride	increases expression	1
methyleugenol	decreases expression	1
pirinixic acid	increases activity, increases expression, affects binding	1
trichostatin A	increases expression	1
beta-lapachone	decreases expression	1
arsenite	increases methylation	1
sodium arsenite	decreases expression	1
ochratoxin A	decreases expression	1
lysophosphatidic acid	decreases reaction, increases expression, affects reaction	1
beta-methylcholine	affects expression	1
pentabromodiphenyl ether	increases expression	1
3-(4-dimethylamino-naphthalen-1-ylmethylene)-1,3-dihydro-indol-2-one	increases expression, decreases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
bisphenol S	affects binding, decreases reaction	1
jinfukang	affects cotreatment, decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652961	Binding	Binding affinity to human PROX1 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B8N8	Abcam HCT 116 PROX1 KO	Cancer cell line	Male
CVCL_B9AS	Abcam MCF-7 PROX1 KO	Cancer cell line	Female
CVCL_B9QI	Abcam A-549 PROX1 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00668824	PHASE4	UNKNOWN	Improved Diagnosis of Congenital Heart Disease by Magnetic Resonance Imaging Using Vasovist
NCT01368705	PHASE4	COMPLETED	Nitrogen Balance in Infants After Post Cardiothoracic Surgery
NCT01619982	PHASE4	COMPLETED	Pre-operative Prophylaxis With Vancomycin and Cefazolin in Pediatric Cardiovascular Surgery Patients
NCT02122679	PHASE4	WITHDRAWN	Tranexamic Acid Effect on Platelet Aggregation Following Infant Cardiopulmonary Bypass
NCT02527811	PHASE4	UNKNOWN	Ulinastatin Injection in in Pediatric Patients Undergoing Open Heart Surgery
NCT03014700	PHASE4	COMPLETED	Fibrinogen Concentrate vs Cryoprecipitate
NCT03408340	PHASE4	TERMINATED	Paravertebral Nerve Blocks in Neonates
NCT03630796	PHASE4	UNKNOWN	Effect of Sevoflurane in Postoperative Troponin I Levels in Children Undergoing Congenital Heart Defects Surgery
NCT03667703	PHASE4	COMPLETED	Stress Ulcer Prophylaxis Versus Placebo in Critically Ill Infants With Congenital Heart Disease
NCT04453761	PHASE4	UNKNOWN	Thiamine Influenced on Substrate Energy Effectiveness in Indonesian Children Undergoing Cardiopulmonary Bypass
NCT06668389	PHASE4	RECRUITING	Sodium-Glucose Cotransporter 2 Inhibitors for Repaired Tetralogy of Fallot Patients for Enhancement of Cardio-Pulmonary Status Trial
NCT07499154	PHASE4	NOT_YET_RECRUITING	Perioperative Lidocaine for Lung Protection in Infants Undergoing Cardiac Surgery
NCT00000470	PHASE3	COMPLETED	Infant Heart Surgery: Central Nervous System Sequelae of Circulatory Arrest
NCT00000494	PHASE3	COMPLETED	Management of Patent Ductus in Premature Infants
NCT01134302	PHASE3	UNKNOWN	Hybrid Versus Norwood Management Strategies in Infants Undergoing Single Ventricle Palliation
NCT01607983	PHASE3	WITHDRAWN	Effects of Pulmonary Vasodilation Upon VA Coupling in Fontan Patients
NCT01662011	PHASE3	UNKNOWN	Application of Neurally Adjusted Ventilatory Assist to Children After Congenital Cardiac Surgery
NCT02320669	PHASE3	COMPLETED	Phase 3 Triiodothyronine Supplementation for Infants After Cardiopulmonary Bypass
NCT02615262	PHASE3	COMPLETED	Intraoperative Dexamethasone in Pediatric Cardiac Surgery
NCT03153137	PHASE3	COMPLETED	Clinical Study Assessing the Efficacy and Safety of Macitentan in Fontan-palliated Subjects
NCT03154476	PHASE3	COMPLETED	Role of Sildenafil for Fontan Associated Liver Disease (SiFALD) Study
NCT04536194	PHASE3	COMPLETED	Dopamine Versus Norepinephrine Under General Anesthesia
NCT04702373	PHASE3	ACTIVE_NOT_RECRUITING	Training in Exercise Activities and Motion for Growth (TEAM 4 Growth) RCT
NCT05049590	PHASE3	COMPLETED	Acute Normovolemic Hemodilution in Complex Cardiac Surgery
NCT06406517	PHASE3	UNKNOWN	Comparative Effectiveness of Gadopiclenol for Evaluation of Adult Congenital Heart Anatomy and Hemodynamics
NCT06693674	PHASE3	RECRUITING	Effect of Sacubitril-Valsartan on Cardiac Structure and Function
NCT06955260	PHASE3	NOT_YET_RECRUITING	SGLT2 Inhibition With Empagliflozin in Fontan Circulatory Failure
NCT00115375	PHASE2	COMPLETED	Platelet Aggregation Inhibition in Children on Clopidogrel (PICOLO)
NCT00350220	PHASE2	COMPLETED	Transfusion Strategies in Pediatric Cardiothoracic Surgery
NCT00374088	PHASE2	COMPLETED	N-Acetylcysteine in Neonatal Congenital Heart Surgery (INACT Study)
NCT00538785	PHASE2	COMPLETED	A Study to Evaluate MEDI-524 In Children With Hemodynamically Significant Congenital Heart Disease
NCT00770705	PHASE2	WITHDRAWN	Parenteral Phenoxybenzamine During Congenital Heart Disease Surgery
NCT00919945	PHASE2	TERMINATED	Impact of Early Enteral Feeding on Splanchnic Blood Flow After Surgery for Critical Heart Disease in the Newborn
NCT01063712	PHASE2	COMPLETED	Safety and Effectiveness of the Device Nit-Occlud® PDA-R
NCT01069510	PHASE2	COMPLETED	Spironolactone in Adult Congenital Heart Disease
NCT01189981	PHASE2	COMPLETED	Effect of eHealth Encouragements to Intensive Exercise in Adolescents With Congenital Heart Disease
NCT01330433	PHASE2	COMPLETED	Effects of CoSeal on Bleeding & Adhesions in Pediatric Heart Surgery
NCT01662037	PHASE2	COMPLETED	Bosentan Therapy in Children With Functional Single Ventricle
NCT01668264	PHASE2	UNKNOWN	Imaging Assessment of Diastolic Function
NCT01827059	PHASE2	UNKNOWN	Bosentan In Exercise Induced Pulmonary Arterial Hypertension in CongenitaL Heart diseasE