NOTCH4

Summary

NOTCH4 (notch receptor 4, HGNC:7884) is a protein-coding gene on chromosome 6p21.32, encoding Neurogenic locus notch homolog protein 4 (Q99466). Functions as a receptor for membrane-bound ligands Jagged1, Jagged2 and Delta1 to regulate cell-fate determination.

This gene encodes a member of the NOTCH family of proteins. Members of this Type I transmembrane protein family share structural characteristics including an extracellular domain consisting of multiple epidermal growth factor-like (EGF) repeats, and an intracellular domain consisting of multiple different domain types. Notch signaling is an evolutionarily conserved intercellular signaling pathway that regulates interactions between physically adjacent cells through binding of Notch family receptors to their cognate ligands. The encoded preproprotein is proteolytically processed in the trans-Golgi network to generate two polypeptide chains that heterodimerize to form the mature cell-surface receptor. This receptor may play a role in vascular, renal and hepatic development. Mutations in this gene may be associated with schizophrenia. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed.

Source: NCBI Gene 4855 — RefSeq curated summary.

At a glance

• GWAS associations: 90
• Clinical variants (ClinVar): 352 total
• Druggable target: yes
• MANE Select transcript: NM_004557

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7884
Approved symbol	NOTCH4
Name	notch receptor 4
Location	6p21.32
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000204301
Ensembl biotype	protein_coding
OMIM	164951
Entrez	4855

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 4 protein_coding, 3 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000375023, ENST00000465528, ENST00000473562, ENST00000474612, ENST00000491215, ENST00000883244, ENST00000883245, ENST00000883246

RefSeq mRNA: 1 — MANE Select: NM_004557 NM_004557

CCDS: CCDS34420

Canonical transcript exons

ENST00000375023 — 30 exons

Exon	Start	End
ENSE00001631267	32216945	32217067
ENSE00001636446	32204137	32204389
ENSE00001658736	32223856	32224067
ENSE00001674309	32201117	32201500
ENSE00001691677	32215226	32215385
ENSE00001693952	32212824	32212911
ENSE00001706263	32203770	32203882
ENSE00001734912	32210752	32210936
ENSE00001737423	32214110	32214255
ENSE00001805050	32202076	32202599
ENSE00003459884	32200831	32201006
ENSE00003502305	32198649	32198730
ENSE00003503642	32197299	32197594
ENSE00003505947	32220129	32220284
ENSE00003513654	32196324	32196421
ENSE00003521490	32223005	32223086
ENSE00003540678	32217995	32218108
ENSE00003548825	32213135	32213252
ENSE00003563392	32222511	32222806
ENSE00003571831	32196925	32197072
ENSE00003572199	32220978	32221325
ENSE00003603212	32217153	32217266
ENSE00003612146	32220756	32220878
ENSE00003612686	32220405	32220641
ENSE00003634934	32198926	32199145
ENSE00003640910	32198421	32198559
ENSE00003645456	32194843	32196150
ENSE00003647801	32213688	32213840
ENSE00003661241	32212474	32212627
ENSE00003692576	32219592	32219786

Expression profiles

Bgee: expression breadth ubiquitous, 132 present calls, max score 95.64.

FANTOM5 (CAGE): breadth broad, TPM avg 3.0209 / max 114.1629, expressed in 623 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
72943	1.9181	302
72938	0.7197	397
72942	0.2766	143
72937	0.1064	40

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	95.64	gold quality
right lung	UBERON:0002167	94.67	gold quality
omental fat pad	UBERON:0010414	94.58	gold quality
adipose tissue	UBERON:0001013	93.92	gold quality
subcutaneous adipose tissue	UBERON:0002190	93.45	gold quality
upper lobe of left lung	UBERON:0008952	93.41	gold quality
thoracic mammary gland	UBERON:0005200	91.90	gold quality
heart left ventricle	UBERON:0002084	91.65	gold quality
lung	UBERON:0002048	91.13	gold quality
metanephros cortex	UBERON:0010533	90.96	gold quality
heart	UBERON:0000948	89.00	gold quality
right atrium auricular region	UBERON:0006631	89.00	gold quality
right lobe of thyroid gland	UBERON:0001119	88.85	gold quality
left lobe of thyroid gland	UBERON:0001120	87.78	gold quality
thyroid gland	UBERON:0002046	87.64	gold quality
myometrium	UBERON:0001296	87.58	gold quality
cortex of kidney	UBERON:0001225	87.34	gold quality
body of uterus	UBERON:0009853	87.29	gold quality
substantia nigra	UBERON:0002038	87.21	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	86.35	gold quality
hypothalamus	UBERON:0001898	85.94	gold quality
adult mammalian kidney	UBERON:0000082	85.83	gold quality
lower esophagus muscularis layer	UBERON:0035833	85.43	gold quality
lower esophagus	UBERON:0013473	85.42	gold quality
Ammon’s horn	UBERON:0001954	85.28	gold quality
endocervix	UBERON:0000458	85.19	gold quality
amygdala	UBERON:0001876	85.13	gold quality
temporal lobe	UBERON:0001871	85.04	gold quality
left uterine tube	UBERON:0001303	85.03	gold quality
mucosa of stomach	UBERON:0001199	84.97	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-CURD-119	yes	26.49
E-ANND-3	yes	11.97
E-MTAB-6678	yes	4.35
E-MTAB-10137	yes	3.57

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

5 targets.

Target	Regulation
CDH1	Repression
DLL4	Activation
HES1	Activation
HEY1	Activation
HEY2	Activation

Upstream regulators (CollecTRI, top): AP1, DLL4, ESR1, ETV4, HEY1, HEY2, JUN, MYC, NR3C1, PDCD10, PPARG, STAT6, TBXT, TNF, VEGFA, YBX1

miRNA regulators (miRDB)

32 targeting NOTCH4, 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-3162-3P	100.00	65.37	363
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-4713-3P	100.00	65.92	505
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-153-5P	99.89	73.86	6317
HSA-MIR-6844	99.82	70.69	2423
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-4261	99.59	70.30	3415
HSA-MIR-147B-5P	99.45	70.62	2432
HSA-MIR-302A-5P	99.39	68.21	1913
HSA-MIR-185-5P	99.35	68.60	2497
HSA-MIR-4644	99.35	69.12	2514
HSA-MIR-4506	99.34	67.47	526
HSA-MIR-542-3P	99.34	67.58	1270
HSA-MIR-6749-3P	99.00	65.73	1443
HSA-MIR-4763-5P	98.75	63.89	854
HSA-MIR-4691-5P	98.41	66.77	1343
HSA-MIR-6810-5P	98.29	66.21	975
HSA-MIR-1262	98.17	66.52	757
HSA-MIR-4701-3P	98.17	66.25	788
HSA-MIR-6736-5P	98.17	66.43	760
HSA-MIR-6747-3P	97.73	64.84	1596
HSA-MIR-3157-5P	97.41	67.61	998
HSA-MIR-3116	97.07	65.78	1324
HSA-MIR-6729-3P	96.91	66.79	703
HSA-MIR-4296	96.35	63.55	1233
HSA-MIR-541-3P	96.07	66.11	1271

Literature-anchored findings (GeneRIF, showing 40)

• The Notch gene family regulates embryonic cell migration, vascular morphogenesis and remodeling. The Notch 4 locus has been implicated in schizophrenia, but this study rules out a significant role for the Notch4 gene in schizophrenia in the Han Chinese. (PMID:11803454)
• expressed in human osteoblastic cells and that the expression is differentially regulated upon stimulation with osteogenic factors (PMID:11836628)
• Genetic analysis of (CTG)n polymorphism in bipolar pedigrees (PMID:11901359)
• Activated Notch4 inhibits angiogenesis: role of beta 1-integrin activation. (PMID:11909975)
• significant association of alopecia areata in the overall data set with the Notch4(T+1297C) polymorphism (P<0.001) but not with Notch4(A+3063G) (PMID:12589427)
• The investigated NOTCH4 variants do not have a major influence on susceptibility to schizophrenia or related neurobiological traits. (PMID:12605097)
• Findings may reflect the interaction of NOTCH4 with the underlying genetic and phenotypic complexity that characterizes both schizophrenia and normal cognition and brain development. (PMID:12627456)
• NOTCH4 T-25C polymorphism has an important effect on the age of onset in schizophrenia. (PMID:12782960)
• Notch4 signaling in vascular endothelial cells. (PMID:12814948)
• NOTCH4 is not a significant susceptibility gene for schizophrenia when clinical heterogeneity is ignored; however, NOTCH4 may be associated with early-onset schizophrenia or schizophrenia with many negative symptoms. (PMID:12873802)
• Notch4 activation inhibits apoptosis through multiple pathways and provides one mechanism to explain the remarkable capacity of endothelial cells to withstand apoptosis (PMID:14701863)
• The haplotype -1725G/-25T associates to schizophrenia in AA subjects (p =.0008), but not in EA subjects. Alleles -1725G and allele -25T are in positive LD both in AAs and EAs. Allele and haplotype frequencies differ significantly between AAs and EAs. (PMID:14732589)
• Transduction with deletion mutants of Int-3 defined the importance of individual domains of the protein (in particular, the ANK domain and the C-terminal domain) in the inhibition of differentiation and growth arrest of HL-60 cells. (PMID:14961038)
• The finding of the present study could not support the original findings that the NOTCH4 gene itself is associated with susceptibility to schizophrenia. (PMID:15009827)
• 4 functional SNPs (rs367398, rs915894, rs520692 & rs422951) at the NOTCH4 locus among 141 schizophrenic family trios of Chinese Han descent. Of these 4 SNPs, rs520692 was the only one associated with schizophrenia. (PMID:15091315)
• Notch4 intracellular region reduced VEGF receptor-2 (VEGFR-2) and vascular endothelial (VE)-cadherin expression. (PMID:15187023)
• no clear evidence for an association between the NOTCH4 gene and schizophrenia in the Japanese population; however, the distribution of single nucleotide polymorphism SNP2 was significantly deviated from Hardy-Weinberg equilibrium in patients (PMID:15211628)
• Notch4/Int3 ICD-induced block to mammary gland development and tumorigenesis are consequences of an increasing gradient of CBF1-dependent Notch4/Int3 signaling (PMID:15531924)
• Vascular angiogenic factors reprogrammed the endogenous NOTCH4 gene in HeLa cells from a repressed to a transcriptionally active state. (PMID:15684396)
• Notch4 intracellular domain attenuates TGF-beta signaling in several cell types. (PMID:16007227)
• NOTCH4 or neighboring gene might be a common susceptible gene for schizophrenia and mood disorders. (PMID:16378929)
• The 3 SNPs (rs367398, rs2071282, & rs422952)are not associated with the onset of schizophrenia. The linkage disequilibrium of this locus indicates that there is genetic heterogeneity in the Notch4 gene. (PMID:16538185)
• NOTCH4 gene may be associated with schizophrenia but how the gene contributes to the etiology of the illness needs a further investigation. (PMID:16894623)
• A modest association was found between schizophrenia and the distal genomic region of NOTCH4 in this Taiwanese family sample. (PMID:17054719)
• Association of the TNXB locus or its adjacent region of the NOTCH4 locus with schizophrenia. (PMID:17192952)
• SNPs studied are not associated with Alzheimer’s disease(AD). Linkage disequilibrium of this locus indicates genetic heterogeneity in Notch4 gene. Potential markers nearby the 5’ untranslated region polymorphism might affect risk for AD. (PMID:17452726)
• NOTCH4 decreases are associated with vascular function decline during pulmonary fibrosis. (PMID:17496152)
• Suggest an aberrant expression of Notch3 and Notch4 in HCC and allow the hypothesis of an activation of Notch signalling by Notch3. (PMID:17696940)
• Overexpression of notch4 is associated with breast cancer (PMID:17822320)
• Expression of Notch 4 receptors was upregulated and Notch signaling might be involved in development of hepatocellular carcinoma. (PMID:17920003)
• NOTCH2, NOTCH3 and NOTCH4 genes are rarely mutated in common human cancers. (PMID:18184405)
• Present a novel mechanism by which a balance between Notch-1/-2/-4 signaling, via CBF-1, and HRT-1/-2 activity determines the expression of smooth muscle differentiation markers including actin. (PMID:18239137)
• Combinations of antiestrogens and Notch inhibitors may be effective in ERalpha(+) breast cancers; Notch signaling is a potential therapeutic target in ERalpha(-) breast cancers. (PMID:18593923)
• The expression levels of Notch1 and Notch4 were absent or significantly decreased in renal cell carcinoma tissues (PMID:19404845)
• Notch4 signaling activity was 8-fold higher in breast cancer stem cell-enriched cell populations compared with differentiated cells, whereas Notch1 signaling activity was 4-fold lower in the stem cell-enriched cell populations. (PMID:20068161)
• The pattern of Notch gene expression mirrors the progression from immature cells to endothelial-lined vascular channels (i.e., endothelial differentiation) that characterizes the growth and involution of infantile hemangioma. (PMID:20069356)
• Notch-1, Notch-4, and Jagged-1 are highly expressed in different subcellular locations in the breast cancer cell (PMID:20444726)
• Notch 4 receptors and their ligands play differential roles in the cytodifferentiation of squamous odontogenic tumors of the mandible. (PMID:20554499)
• Notch-4 may play an important role in salivary adenoid cystic carcinoma. (PMID:20596622)
• The implication of a dysregulated Notch pathway to endothelial and vascular dysfunction. (PMID:20643108)

Cross-species orthologs

16 orthologs

Organism	Symbol	Gene ID
danio_rerio	jag1b	ENSDARG00000013168
danio_rerio	jag2a	ENSDARG00000014246
danio_rerio	jag2b	ENSDARG00000021389
danio_rerio	jag1a	ENSDARG00000030289
danio_rerio		ENSDARG00000068104
danio_rerio	dll4	ENSDARG00000070425
danio_rerio	si:ch73-105b23.1	ENSDARG00000087558
danio_rerio		ENSDARG00000114226
rattus_norvegicus	Notch4	ENSRNOG00000000442
drosophila_melanogaster	Delta	FBGN0000463
drosophila_melanogaster	Ser	FBGN0004197
caenorhabditis_elegans		WBGENE00001106
caenorhabditis_elegans	paml-2	WBGENE00009114
caenorhabditis_elegans	F55H12.3	WBGENE00010134
caenorhabditis_elegans		WBGENE00013498
caenorhabditis_elegans		WBGENE00022816

Paralogs (5): JAG1 (ENSG00000101384), DLL4 (ENSG00000128917), JAG2 (ENSG00000184916), DNER (ENSG00000187957), DLL1 (ENSG00000198719)

Protein

Protein identifiers

Neurogenic locus notch homolog protein 4 — Q99466 (reviewed: Q99466)

All UniProt accessions (2): A0A1U9X983, Q99466

UniProt curated annotations — full annotation on UniProt →

Function. Functions as a receptor for membrane-bound ligands Jagged1, Jagged2 and Delta1 to regulate cell-fate determination. Upon ligand activation through the released notch intracellular domain (NICD) it forms a transcriptional activator complex with RBPJ/RBPSUH and activates genes of the enhancer of split locus. Affects the implementation of differentiation, proliferation and apoptotic programs. May regulate branching morphogenesis in the developing vascular system.

Subunit / interactions. Heterodimer of a C-terminal fragment N(TM) and a N-terminal fragment N(EC) which are probably linked by disulfide bonds. Interacts with MAML1, MAML2 and MAML3 which act as transcriptional coactivators for NOTCH4. (Microbial infection) Interacts with Epstein-Barr virus (EBV) RK-BARF0.

Subcellular location. Cell membrane Nucleus.

Tissue specificity. Highly expressed in the heart, moderately in the lung and placenta and at low levels in the liver, skeletal muscle, kidney, pancreas, spleen, lymph node, thymus, bone marrow and fetal liver. No expression was seen in adult brain or peripheral blood leukocytes.

Post-translational modifications. Synthesized in the endoplasmic reticulum as an inactive form which is proteolytically cleaved by a furin-like convertase in the trans-Golgi network before it reaches the plasma membrane to yield an active, ligand-accessible form. Cleavage results in a C-terminal fragment N(TM) and a N-terminal fragment N(EC). Following ligand binding, it is cleaved by TNF converting enzyme (TACE) to yield a membrane-associated intermediate fragment called notch extracellular truncation (NEXT). This fragment is then cleaved by presenilin dependent gamma-secretase to release a notch-derived peptide containing the intracellular domain (NICD) from the membrane. Phosphorylated.

Polymorphism. The poly-Leu region of NOTCH4 (in the signal peptide) is polymorphic and the number of Leu varies in the population (from 6 to 12).

Similarity. Belongs to the NOTCH family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q99466-1	1	yes
Q99466-2	2
Q99466-3	3

RefSeq proteins (1): NP_004548* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000152	EGF-type_Asp/Asn_hydroxyl_site	PTM
IPR000742	EGF	Domain
IPR000800	Notch_dom	Domain
IPR001881	EGF-like_Ca-bd_dom	Domain
IPR002110	Ankyrin_rpt	Repeat
IPR008297	Notch	Family
IPR009030	Growth_fac_rcpt_cys_sf	Homologous_superfamily
IPR010660	Notch_NOD_dom	Domain
IPR011656	Notch_NODP_dom	Domain
IPR013032	EGF-like_CS	Conserved_site
IPR018097	EGF_Ca-bd_CS	Conserved_site
IPR022355	Notch_4	Family
IPR035993	Notch-like_dom_sf	Homologous_superfamily
IPR036770	Ankyrin_rpt-contain_sf	Homologous_superfamily
IPR049883	NOTCH1_EGF-like	Domain
IPR051355	Notch/Slit_guidance	Family

Pfam: PF00008, PF00066, PF06816, PF07645, PF07684, PF12661, PF12796

UniProt features (169 total): disulfide bond 95, domain 29, sequence variant 13, repeat 8, sequence conflict 5, region of interest 4, glycosylation site 4, chain 3, splice variant 2, topological domain 2, signal peptide 1, helix 1, compositionally biased region 1, transmembrane region 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
7OR3	X-RAY DIFFRACTION	1.8
7OR5	X-RAY DIFFRACTION	1.8
7OR7	X-RAY DIFFRACTION	1.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q99466-F1	62.04	0.06

Functional residue map

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

Disulfide bonds (95): 651–658, 665–672, 667–677, 679–688, 695–706, 700–715, 717–726, 733–744, 738–753, 755–764, 771–782, 776–791, 793–802, 810–821, 815–830, 832–841, 848–859, 853–868, 870–879, 886–907 …

Glycosylation sites (4): 664, 714, 964, 1143

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-1912399	Pre-NOTCH Processing in the Endoplasmic Reticulum
R-HSA-1912408	Pre-NOTCH Transcription and Translation
R-HSA-1912420	Pre-NOTCH Processing in Golgi
R-HSA-350054	Notch-HLH transcription pathway
R-HSA-5083630	Defective LFNG causes SCDO3
R-HSA-9013695	NOTCH4 Intracellular Domain Regulates Transcription
R-HSA-9013700	NOTCH4 Activation and Transmission of Signal to the Nucleus
R-HSA-9604323	Negative regulation of NOTCH4 signaling

MSigDB gene sets: 275 (showing top): GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_ENDOTHELIAL_CELL_DEVELOPMENT, REACTOME_SIGNALING_BY_NOTCH, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_EPITHELIAL_CELL_DEVELOPMENT, GOBP_REGULATION_OF_CELL_CELL_ADHESION_MEDIATED_BY_CADHERIN, GOBP_REGULATION_OF_SMOOTH_MUSCLE_CELL_DIFFERENTIATION, GOBP_POSITIVE_REGULATION_OF_MUSCLE_CELL_DIFFERENTIATION, GOBP_SMOOTH_MUSCLE_CELL_DIFFERENTIATION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_REGULATION_OF_ENDOTHELIAL_CELL_DIFFERENTIATION, GOCC_CELL_SURFACE, KEGG_DORSO_VENTRAL_AXIS_FORMATION, GOBP_NEGATIVE_REGULATION_OF_CELL_CELL_ADHESION

GO Biological Process (28): negative regulation of transcription by RNA polymerase II (GO:0000122), luteolysis (GO:0001554), branching involved in blood vessel morphogenesis (GO:0001569), cell fate determination (GO:0001709), morphogenesis of a branching structure (GO:0001763), epithelial to mesenchymal transition (GO:0001837), endothelial cell morphogenesis (GO:0001886), vasculature development (GO:0001944), positive regulation of transcription of Notch receptor target (GO:0007221), hemopoiesis (GO:0030097), cell differentiation (GO:0030154), mammary gland development (GO:0030879), negative regulation of cell differentiation (GO:0045596), negative regulation of endothelial cell differentiation (GO:0045602), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), positive regulation of smooth muscle cell differentiation (GO:0051152), negative regulation of cell adhesion molecule production (GO:0060354), negative regulation of cell-cell adhesion mediated by cadherin (GO:2000048), regulation of DNA-templated transcription (GO:0006355), Notch signaling pathway (GO:0007219), multicellular organism development (GO:0007275), tissue development (GO:0009888), endothelial cell differentiation (GO:0045446), regulation of cell differentiation (GO:0045595), cell development (GO:0048468), regulation of developmental process (GO:0050793), positive regulation of developmental process (GO:0051094)

GO Molecular Function (6): transcription coactivator activity (GO:0003713), Notch binding (GO:0005112), calcium ion binding (GO:0005509), signaling receptor activity (GO:0038023), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (9): Golgi membrane (GO:0000139), extracellular region (GO:0005576), nucleus (GO:0005634), nucleoplasm (GO:0005654), endoplasmic reticulum membrane (GO:0005789), cytosol (GO:0005829), plasma membrane (GO:0005886), cell surface (GO:0009986), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Pre-NOTCH Expression and Processing	3
Signaling by NOTCH4	3
Generic Transcription Pathway	1
Diseases associated with O-glycosylation of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
cellular developmental process	2
negative regulation of cellular process	2
DNA-templated transcription	2
positive regulation of DNA-templated transcription	2
negative regulation of DNA-templated transcription	1
female gonad development	1
ovulation cycle process	1
angiogenesis	1
blood vessel morphogenesis	1
branching morphogenesis of an epithelial tube	1
cell fate commitment	1
anatomical structure morphogenesis	1
multicellular organismal process	1
mesenchymal cell differentiation	1
endothelial cell development	1
epithelial cell morphogenesis	1
system development	1
circulatory system development	1
Notch signaling pathway	1
positive regulation of transcription by RNA polymerase II	1
cell development	1
gland development	1
cell differentiation	1
regulation of cell differentiation	1
negative regulation of developmental process	1
negative regulation of epithelial cell differentiation	1
endothelial cell differentiation	1
regulation of endothelial cell differentiation	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
smooth muscle cell differentiation	1
positive regulation of muscle cell differentiation	1
regulation of smooth muscle cell differentiation	1
cell adhesion molecule production	1
regulation of cell adhesion molecule production	1
negative regulation of cell-cell adhesion	1
cell-cell adhesion mediated by cadherin	1

Protein interactions and networks

STRING

2648 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NOTCH4	JAG1	P78504	991
NOTCH4	JAG2	Q9Y219	991
NOTCH4	DLL3	Q9NYJ7	988
NOTCH4	DLL4	Q9NR61	988
NOTCH4	DLL1	O00548	987
NOTCH4	MAML3	Q96JK9	909
NOTCH4	MAML1	Q92585	896
NOTCH4	RBPJ	Q06330	876
NOTCH4	MAML2	Q8IZL2	859
NOTCH4	HEY1	Q9Y5J3	841
NOTCH4	HEY2	Q9UBP5	819
NOTCH4	SRRT	Q9BXP5	785
NOTCH4	EGFL7	Q9UHF1	770
NOTCH4	PBX2	P40425	738
NOTCH4	NOTCH1	P46531	690

IntAct

6 interactions, top by confidence:

A	B	Type	Score
APP	NOTCH4	psi-mi:“MI:0915”(physical association)	0.560
AP2B1	NOTCH4	psi-mi:“MI:0407”(direct interaction)	0.440
NOTCH4	Dlg4	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (16): NOTCH4 (Reconstituted Complex), NOTCH4 (Protein-peptide), NOTCH4 (Reconstituted Complex), NOTCH4 (Affinity Capture-MS), NOTCH4 (Cross-Linking-MS (XL-MS)), USP10 (Affinity Capture-Western), NOTCH4 (Cross-Linking-MS (XL-MS)), NOTCH4 (Affinity Capture-Western), NOTCH4 (Affinity Capture-Western), TCEB1 (Co-purification), TCEB1 (FRET), NOTCH4 (Affinity Capture-Western), NOTCH4 (Affinity Capture-Western), NOTCH4 (Affinity Capture-Western), SMAD3 (Affinity Capture-Western)

ESM2 similar proteins: A0JM12, A1A5Y0, A4FV93, A5PKD8, A6BM72, B2LW77, D3ZUK3, E9QJQ6, O00468, O75095, O76076, O88281, O95407, P15800, P23142, P31695, P55268, P97607, Q5VY43, Q5W7P8, Q61292, Q61982, Q6DIB5, Q6UXH1, Q6UY11, Q6ZWJ8, Q75N90, Q80T14, Q80T91, Q80V70, Q80W15, Q86XX4, Q8C088, Q8K1E3, Q8MJJ9, Q8N2S1, Q8VIK5, Q96I82, Q96KG7, Q99466

Diamond homologs: A0A096LNW5, A2RUV0, B4DH59, B8JI71, G3I6Z6, O35516, O75882, P07207, P0DPK3, P0DPK4, P10040, P21783, P46530, P46531, P98160, Q01705, Q04721, Q04756, Q07008, Q20911, Q7Z3S9, Q99466, Q99J86, Q9QW30, Q9UM47, Q9WU60, O35474, O75095, O89019, P13508, P20749, P31695, P82279, Q499M5, Q502K3, Q5RBP1, Q61982, Q6UXI9, Q6UY11, Q810B6

SIGNOR signaling

10 interactions.

A	Effect	B	Mechanism
FBXW7	down-regulates	NOTCH4	ubiquitination
MDM2	down-regulates	NOTCH4	ubiquitination
ELOC	down-regulates	NOTCH4	ubiquitination
gamma-secretase	“up-regulates activity”	NOTCH4	cleavage
TNF	“up-regulates quantity by expression”	NOTCH4	“transcriptional regulation”
MAML1	up-regulates	NOTCH4	binding
MAML3	up-regulates	NOTCH4	binding
NOTCH4	up-regulates	MAML3	binding
NOTCH4	up-regulates	MAML2	binding
NOTCH4	“up-regulates quantity by expression”	HEY2	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	219
Likely benign	21
Benign	82

Top pathogenic / likely-pathogenic (0)

SpliceAI

4412 predictions. Top by Δscore:

Variant	Effect	Δscore
6:32196923:AC:A	donor_gain	1.0000
6:32196923:ACC:A	donor_gain	1.0000
6:32196924:CC:C	donor_gain	1.0000
6:32196924:CCC:C	donor_gain	1.0000
6:32196972:TCA:T	donor_gain	1.0000
6:32197068:AGAAG:A	acceptor_gain	1.0000
6:32197073:C:CC	acceptor_gain	1.0000
6:32198659:T:TA	donor_gain	1.0000
6:32198665:C:CA	donor_gain	1.0000
6:32198668:T:TA	donor_gain	1.0000
6:32198673:AGGG:A	donor_gain	1.0000
6:32198927:TGAG:T	donor_gain	1.0000
6:32204388:CA:C	acceptor_gain	1.0000
6:32217276:C:CT	acceptor_gain	1.0000
6:32217277:G:T	acceptor_gain	1.0000
6:32217994:CCAGG:C	donor_gain	1.0000
6:32219641:T:TA	donor_gain	1.0000
6:32220751:CTCA:C	donor_loss	1.0000
6:32220752:TCAC:T	donor_loss	1.0000
6:32220753:CACC:C	donor_loss	1.0000
6:32220754:ACC:A	donor_loss	1.0000
6:32196271:T:A	donor_gain	0.9900
6:32196321:AAC:A	donor_gain	0.9900
6:32196322:AC:A	donor_gain	0.9900
6:32196323:CC:C	donor_gain	0.9900
6:32196331:T:TA	donor_gain	0.9900
6:32196921:ATAC:A	donor_loss	0.9900
6:32196922:TACCC:T	donor_loss	0.9900
6:32196923:A:AC	donor_gain	0.9900
6:32196924:C:CC	donor_gain	0.9900

AlphaMissense

12924 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:32202198:C:A	W1211C	0.996
6:32202198:C:G	W1211C	0.996
6:32201419:C:A	W1279C	0.995
6:32201419:C:G	W1279C	0.995
6:32202237:C:A	W1198C	0.991
6:32202237:C:G	W1198C	0.991
6:32204247:C:G	C1003S	0.991
6:32204248:A:T	C1003S	0.991
6:32219687:C:G	C472S	0.991
6:32219688:A:T	C472S	0.991
6:32202168:C:A	W1221C	0.989
6:32202168:C:G	W1221C	0.989
6:32202160:A:C	F1224C	0.988
6:32220158:C:G	C429S	0.988
6:32220159:A:T	C429S	0.988
6:32220224:C:G	C407S	0.988
6:32220225:A:T	C407S	0.988
6:32220157:G:C	C429W	0.987
6:32220158:C:T	C429Y	0.987
6:32196999:G:T	A1709D	0.986
6:32201426:C:G	C1277S	0.986
6:32201427:A:T	C1277S	0.986
6:32201480:C:G	C1259S	0.986
6:32201481:A:T	C1259S	0.986
6:32204261:A:C	F998L	0.986
6:32204261:A:T	F998L	0.986
6:32204263:A:G	F998L	0.986
6:32213168:C:G	C802S	0.986
6:32213169:A:T	C802S	0.986
6:32219747:C:G	C452S	0.986

dbSNP variants (sampled 300 via entrez): RS1000189312 (6:32220197 G>A), RS1000276522 (6:32198843 T>C), RS1000844181 (6:32216420 G>A), RS1000877981 (6:32212392 T>C), RS1000931193 (6:32194571 C>A), RS1001030047 (6:32216921 C>A), RS1001085827 (6:32204565 C>A), RS1001415278 (6:32224976 T>G), RS1001455374 (6:32204910 T>G), RS1001541591 (6:32204881 C>T), RS1001734207 (6:32198369 A>G), RS1001782003 (6:32205236 G>C), RS1001845749 (6:32196452 A>C,G), RS1001988182 (6:32205835 C>G), RS1002177101 (6:32219135 CTTG>C)

Disease associations

OMIM: gene MIM:164951 | disease phenotypes: MIM:108010, MIM:610805, MIM:142623

GenCC curated gene-disease

Mondo (4): arteriovenous malformations of the brain (MONDO:0007154), congenital heart disease (MONDO:0005453), congenital anomaly of kidney and urinary tract (MONDO:0019719), Hirschsprung disease (MONDO:0018309)

Orphanet (4): Brain arteriovenous malformation (Orphanet:46724), Microphthalmia-anophthalmia-coloboma (Orphanet:98555), Renal or urinary tract malformation (Orphanet:93545), Hirschsprung disease (Orphanet:388)

HPO phenotypes

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

GWAS associations

90 associations (top):

Study	Trait	p-value
GCST000435_1	Schizophrenia	2.000000e-10
GCST000549_21	HIV-1 control	2.000000e-06
GCST000996_22	Systemic lupus erythematosus	3.000000e-06
GCST001156_3	Systemic sclerosis	1.000000e-08
GCST001156_6	Systemic sclerosis	9.000000e-21
GCST001183_5	Asthma	4.000000e-23
GCST001571_4	Age-related macular degeneration	2.000000e-11
GCST001762_173	Obesity-related traits	1.000000e-06
GCST001785_8	Crohn’s disease	3.000000e-07
GCST001812_2	Epstein-Barr virus immune response (EBNA-1)	2.000000e-10
GCST001851_2	Schizophrenia	5.000000e-07
GCST001851_8	Schizophrenia	3.000000e-07
GCST001942_21	Prostate cancer	5.000000e-09
GCST001979_2	Circulating myeloperoxidase levels (serum)	1.000000e-08
GCST002453_2	Ulcerative colitis	8.000000e-10
GCST002479_16	Lupus nephritis in systemic lupus erythematosus	2.000000e-06
GCST002518_1	Food antigen IgG levels	9.000000e-08
GCST002534_1	Mixed cryoglobulinemia vasculitis in chronic hepatitis C infection	2.000000e-08
GCST002876_5	Type 1 diabetes and autoimmune thyroid diseases	5.000000e-25
GCST002879_2	Chronic hepatitis B infection	5.000000e-16
GCST002977_1	Soluble receptor for advanced glycation end-product levels	2.000000e-08
GCST002977_2	Soluble receptor for advanced glycation end-product levels	3.000000e-16
GCST003161_1	Objective response to lithium treatment in bipolar disorder	2.000000e-06
GCST003450_2	Clozapine-induced agranulocytosis/granulocytopenia in treatment-resistant schizophrenia	3.000000e-09
GCST003720_13	Migraine	4.000000e-08
GCST003998_3	Joint mobility (Beighton score)	2.000000e-12
GCST004131_25	Inflammatory bowel disease	2.000000e-31
GCST004133_79	Ulcerative colitis	5.000000e-65
GCST004521_10	Autism spectrum disorder or schizophrenia	2.000000e-13
GCST004521_114	Autism spectrum disorder or schizophrenia	3.000000e-17

EFO canonical traits (17, from GWAS)

EFO ID	Trait name
EFO:0000180	HIV-1 infection
EFO:0004626	IGFBP-3 measurement
EFO:0005243	myeloperoxidase measurement
EFO:0005844	response to dietary antigen
EFO:0007622	sRAGE measurement
EFO:0007905	joint hypermobility measurement
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008002	physical activity measurement
EFO:0007986	reticulocyte count
EFO:0004736	aspartate aminotransferase measurement
EFO:0008173	interleukin 16 measurement
EFO:0004918	age at diagnosis
EFO:0008039	BMI-adjusted hip circumference
EFO:0004531	urate measurement
EFO:0004348	hematocrit
EFO:0004509	hemoglobin measurement
EFO:0007789	BMI-adjusted waist circumference

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D006330	Heart Defects, Congenital	C14.240.400; C14.280.400; C16.131.240.400
D006627	Hirschsprung Disease	C06.198.439; C06.405.469.158.701.439; C16.131.314.439
D002538	Intracranial Arteriovenous Malformations	C10.228.140.300.520; C10.500.190.500; C14.240.850.750.295; C14.240.850.875.500; C14.907.150.295; C14.907.253.560.400; C16.131.240.850.750.295; C16.131.240.850.875.500; C16.131.666.190.500
C566906	Cakut (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3407321 (SINGLE PROTEIN), CHEMBL4524007 (PROTEIN FAMILY)

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs367398	Toxicity	3	allopurinol	Severe Cutaneous Adverse Reactions

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs367398	NOTCH4	3	2.50	1	allopurinol

GtoPdb / IUPHAR curated pharmacology

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

Target class: other protein — Notch receptors

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
8.52	IC50	3	nM	CHEMBL3410161

PubChem BioAssay actives

1 with measured affinity, of 1 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(2R,3R)-N’-[(3S)-1-methyl-2-oxo-5-phenyl-3H-1,4-benzodiazepin-3-yl]-2-phenyl-3-(3,3,3-trifluoropropyl)butanediamide	1198939: Inhibition of Notch4 intracellular domain fragment transfected in human HeLa cells co-transfected with CBF1-PGL3 luciferase reporter vector by transactivation assay	ic50	0.0030	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Cadmium Chloride	increases cleavage, increases abundance, increases expression	3
Benzo(a)pyrene	affects methylation, increases methylation	2
sotorasib	affects cotreatment, decreases expression	1
bisphenol A	affects methylation	1
mono-(2-ethylhexyl)phthalate	increases expression	1
butyraldehyde	decreases expression	1
manganese chloride	decreases expression	1
perfluorooctane sulfonic acid	increases expression	1
licochalcone B	increases expression	1
bisphenol S	decreases methylation	1
trametinib	affects cotreatment, decreases expression	1
NVP-BKM120	affects cotreatment, decreases expression	1
Acetaminophen	decreases expression	1
Arsenic	affects methylation	1
Atrazine	decreases expression	1
Atropine	decreases reaction, increases expression	1
Cadmium	increases abundance, increases expression	1
Cisplatin	affects expression, affects reaction	1
Doxorubicin	decreases expression	1
Estradiol	affects cotreatment, increases expression	1
Folic Acid	affects expression, affects reaction	1
Formaldehyde	decreases expression	1
Manganese	decreases expression	1
Nickel	decreases expression	1
Parathion	decreases reaction, increases expression	1
Tetracycline	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Urethane	decreases expression	1
Asbestos, Crocidolite	affects expression	1
Acrylamide	decreases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3412056	Binding	Inhibition of Notch4 intracellular domain fragment transfected in human HeLa cells co-transfected with CBF1-PGL3 luciferase reporter vector by transactivation assay	BMS-871: a novel orally active pan-Notch inhibitor as an anticancer agent. — Bioorg Med Chem Lett

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B7YK	Abcam Raji NOTCH4 KO	Cancer cell line	Male
CVCL_B9Z9	Abcam THP-1 NOTCH4 KO	Cancer cell line	Male
CVCL_C7AY	Abcam PC-3 NOTCH4 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
NCT01758211	PHASE3	UNKNOWN	Functional Magnetic Resonance Imagine(fMRI)Navigation in Intracranial Arteriovenous Malformation 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
NCT04297033	PHASE2	UNKNOWN	Lovastatin for Treatment of Brain Arteriovenous Malformations
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