NOTCH2

Summary

NOTCH2 (notch receptor 2, HGNC:7882) is a protein-coding gene on chromosome 1p12, encoding Neurogenic locus notch homolog protein 2 (Q04721). Functions as a receptor for membrane-bound ligands Jagged-1 (JAG1), Jagged-2 (JAG2) and Delta-1 (DLL1) to regulate cell-fate determination.

This gene encodes a member of the Notch family. Members of this Type 1 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 family members play a role in a variety of developmental processes by controlling cell fate decisions. The Notch signaling network is an evolutionarily conserved intercellular signaling pathway which regulates interactions between physically adjacent cells. In Drosophilia, notch interaction with its cell-bound ligands (delta, serrate) establishes an intercellular signaling pathway that plays a key role in development. Homologues of the notch-ligands have also been identified in human, but precise interactions between these ligands and the human notch homologues remain to be determined. This protein is cleaved in the trans-Golgi network, and presented on the cell surface as a heterodimer. This protein functions as a receptor for membrane bound ligands, and may play a role in vascular, renal and hepatic development. Two transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 4853 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Alagille syndrome (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 11
• Clinical variants (ClinVar): 2,194 total — 58 pathogenic, 38 likely-pathogenic
• Phenotypes (HPO): 132
• Druggable target: yes
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 13 cancer types
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_024408

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7882
Approved symbol	NOTCH2
Name	notch receptor 2
Location	1p12
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000134250
Ensembl biotype	protein_coding
OMIM	600275
Entrez	4853

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 6 protein_coding, 4 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay, 1 retained_intron

ENST00000256646, ENST00000478864, ENST00000479412, ENST00000489731, ENST00000493703, ENST00000640021, ENST00000650638, ENST00000651371, ENST00000652264, ENST00000652302, ENST00000652737, ENST00000924185, ENST00000924186

RefSeq mRNA: 2 — MANE Select: NM_024408 NM_001200001, NM_024408

CCDS: CCDS908

Canonical transcript exons

ENST00000256646 — 34 exons

Exon	Start	End
ENSE00000913335	119950724	119950837
ENSE00000913336	119949007	119949126
ENSE00000913339	119940555	119940756
ENSE00000913340	119937857	119938010
ENSE00000913341	119937282	119937466
ENSE00000913342	119935472	119935604
ENSE00000913344	119926499	119926611
ENSE00000913345	119925305	119925810
ENSE00000913346	119923637	119923984
ENSE00000913347	119922636	119922778
ENSE00000913348	119922236	119922446
ENSE00000913349	119921713	119921809
ENSE00000913350	119920229	119920397
ENSE00000913351	119919312	119919613
ENSE00000913352	119918406	119918553
ENSE00000913353	119917665	119917762
ENSE00000957931	119928976	119929212
ENSE00001022881	119941526	119941754
ENSE00001073396	119948414	119948566
ENSE00001123152	119911553	119916694
ENSE00003518443	120069334	120069662
ENSE00003603367	120029906	120029987
ENSE00003715919	119963574	119963807
ENSE00003716326	119967433	119967621
ENSE00003717703	119953543	119953688
ENSE00003720435	119986960	119987082
ENSE00003724994	119959392	119959502
ENSE00003725181	119996997	119997332
ENSE00003730187	119966376	119966489
ENSE00003735657	120005329	120005588
ENSE00003741888	119969511	119969744
ENSE00003744555	119968077	119968232
ENSE00003747412	119965453	119965566
ENSE00003747835	119955040	119955232

Expression profiles

Bgee: expression breadth ubiquitous, 294 present calls, max score 98.42.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 2.5068 / max 215.6569, expressed in 1339 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
14101	1.4790	987
14096	0.6063	284
14098	0.2569	119
14100	0.1454	59
14099	0.0191	7

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pigmented layer of retina	UBERON:0001782	98.42	gold quality
retina	UBERON:0000966	98.40	gold quality
skin of hip	UBERON:0001554	98.28	gold quality
upper leg skin	UBERON:0004262	98.13	gold quality
ventricular zone	UBERON:0003053	98.01	gold quality
synovial joint	UBERON:0002217	98.00	gold quality
caput epididymis	UBERON:0004358	97.80	gold quality
mammalian vulva	UBERON:0000997	97.65	gold quality
mammary duct	UBERON:0001765	97.65	gold quality
blood vessel layer	UBERON:0004797	97.56	gold quality
cauda epididymis	UBERON:0004360	97.53	gold quality
upper arm skin	UBERON:0004263	97.51	gold quality
epithelium of mammary gland	UBERON:0003244	97.47	gold quality
corpus epididymis	UBERON:0004359	97.47	gold quality
oral cavity	UBERON:0000167	97.39	gold quality
cervix squamous epithelium	UBERON:0006922	97.17	gold quality
trabecular bone tissue	UBERON:0002483	97.12	gold quality
tendon of biceps brachii	UBERON:0008188	97.12	gold quality
adult organism	UBERON:0007023	97.07	gold quality
periodontal ligament	UBERON:0008266	97.07	gold quality
cartilage tissue	UBERON:0002418	96.91	gold quality
esophagus squamous epithelium	UBERON:0006920	96.84	gold quality
visceral pleura	UBERON:0002401	96.81	gold quality
pleura	UBERON:0000977	96.80	gold quality
urethra	UBERON:0000057	96.79	gold quality
parietal pleura	UBERON:0002400	96.71	gold quality
saphenous vein	UBERON:0007318	96.69	gold quality
superficial temporal artery	UBERON:0001614	96.59	gold quality
epithelium of esophagus	UBERON:0001976	96.43	gold quality
squamous epithelium	UBERON:0006914	96.43	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-HCAD-13	yes	164.72
E-MTAB-5061	yes	26.43
E-GEOD-125970	yes	21.20
E-GEOD-93593	yes	15.48
E-ANND-3	yes	14.28
E-GEOD-83139	yes	10.97
E-GEOD-98556	no	2709.09

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

6 targets.

Target	Regulation
ASCL1	Repression
CDKN1A	Activation
CDKN1B	Activation
FCER2	Activation
HES1	Activation
SOX9	Repression

Upstream regulators (CollecTRI, top): CD46, ESR1, ESR2, FOS, FOSL1, GATA3, HES1, HEY1, IRF4, PAX6, PROP1, RBPJ

miRNA regulators (miRDB)

247 targeting NOTCH2, 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-4262	100.00	73.26	3931
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-5193	100.00	67.26	1744
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-4514	99.99	67.10	1870
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-34C-5P	99.97	70.45	1577

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• expressed in human osteoblastic cells and that the expression is differentially regulated upon stimulation with osteogenic factors (PMID:11836628)
• Notch signalling involved in differentiation of normal adult human epidermis is altered under experimental conditions and pathologies which modify this program. (PMID:11978185)
• Notch2 protein distribution in human teeth under normal and pathological conditions, and in embryo and adult. (PMID:12531696)
• identified two proteins that interacted with the Tat protein of the caprine arthritis encephalitis virus: the EGF-like repeats 1-6 of the extracellular domain of the human Notch2 receptor and the epithelin/granulin growth factor precursor (PMID:12931033)
• EGF-like repeats1-6 of human Notch2 interact with Tat protein of Hiv-1 (PMID:14609630)
• Notch receptors 1&2 and their ligand Jagged1 are highly expressed in cultured and primary MM cells, suggesting Notch signaling is involved in the tight interactions between neoplastic plasma cells and their bone marrow microenvironment (PMID:14726396)
• Notch-2 could play a tumour-suppressive role in human breast cancer. (PMID:15492845)
• c-jun, junD, junB, and c-fos and Notch2 are expressed in splenic marginal zone lymphoma (PMID:15507668)
• Loss of Notch2 activity is an early steps in PI-induced apoptosis of B-cell chronic lymphocytic leukemia lymphocytes and may be part of the full apoptotic response. (PMID:15565166)
• review of mechanisms leading to the upregulation of CD23 in the leukemic cells and review of the potential functions of CD23 as well as its regulation by Notch2 in B-CLL (PMID:15621797)
• density of Notch ligands in different organ systems may be an important determinant in regulating cell-fate outcomes (PMID:15976178)
• Alagille syndrome is a heterogeneous disorder and implicates NOTCH2 mutations in human disease (PMID:16773578)
• The X-ray structure of the human NOTCH2 negative regulatory region, which adopts an autoinhibited conformation, is presented. (PMID:17401372)
• NOTCHES N1, N2, and N3 all bound to FIH; results suggest the possibility that Notch ICDs are FIH substrates. (PMID:17573339)
• Loss of NOTCH2 positively predicts survival in subgroups of human glial brain tumors. (PMID:17593975)
• Notch family members and ligands are expressed in the human corneal epithelium and appear to play pivotal roles in corneal epithelial cell differentiation (PMID:17652726)
• Results demonstrate that Notch2 signaling is a potent inhibitory signal in human breast cancer xenografts. (PMID:17675579)
• Cytoplasmic expression of Notch 2 receptors was downregulated and Notch signaling might be involved in development of hepatocellular carcinoma. (PMID:17920003)
• support the role of Notch and Akt in breast cancer progression (PMID:18087195)
• 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)
• The absence of mutations in NOTCH2 and Hey2 its downstream target in the heart does not exclude the possibility that other genes in this pathway might be implicated in the diverse phenotypes observed in Alagille syndrome (PMID:18266235)
• activation of the Notch pathway, which is critical in glomerular patterning, contributes to the development of glomerular disease (PMID:18311147)
• analysis of potentially activating mutations of NOTCH2 in 5% of MZL cases, comprising a splenic and an extranodal MZL case (PMID:18508802)
• Wnt (Wnt2), Stat3, and Notch-1 and -2 signaling are correlated in human epidermal tumors. (PMID:18703315)
• Results suggest that the NOTCH2 gene is not physically rearranged by t(1;19) translocation of oligodendroglioma tumors, and that the t(1;19) translocation arises from complex intra and interchromosomal rearrangements. (PMID:19119320)
• In gliomas, the TNC gene is transactivated by Notch2 in an RBPJk-dependent manner mediated by an RBPJk binding element in the TNC promoter. (PMID:19147558)
• Notch-2 and its ligand, Jagged-1, are highly up-regulated in gemcitabine resistant pancreatic cancer cells, which is consistent with the role of the Notch signaling pathway in the acquisition of EMT and cancer stem-like cell phenotype. (PMID:19276344)
• Notch signaling in B cells and B-cell lymphomas is only compatible with proliferation if pathways leading to antiapototic signals are active. (PMID:19339697)
• The levels of expression of Notch2 and Notch3 were minimally detected in renal cell carcinoma tumours and non-neoplastic tissues (PMID:19404845)
• mutant Notch2 receptors show increased activity compared with wild-type Notch2 (PMID:19445024)
• Notch2 decreased statistically in immune thrombocytopenic purpura patients. (PMID:19603167)
• Notch2 expression is decreased in colorectal cancer and related to tumor differentiation status. (PMID:19653042)
• S1 cleavage has distinct effects on the surface expression of Notch1 and Notch2, but is not generally required for physiologic or pathophysiologic activation of Notch proteins (PMID:19701457)
• TNF signaling activates Notch2 that sensitizes endothelial cells to apoptosis via modulation of the key apoptosis regulator survivin. (PMID:20011512)
• 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)
• Notch2- but not Notch1-deficient CD8-positive T cells fail to expand in response to tumor inoculation; Notch2 signaling directly controls cytotoxic T lymphocyte effector molecules. (PMID:20351182)
• expression of NOTCH2 differs in subgroups of breast tumors and by genotypes of the breast cancer-associated SNP rs11249433 (PMID:20482849)
• The implication of a dysregulated Notch pathway to endothelial and vascular dysfunction. (PMID:20643108)
• Notch 2 contributes to stem cell factor-mediated delay of erythroid differentiation. (PMID:20829885)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	notch2	ENSDARG00000043130
danio_rerio	si:ch73-281k2.5	ENSDARG00000104329
mus_musculus	Notch2	ENSMUSG00000027878
rattus_norvegicus	Notch2	ENSRNOG00000018835

Paralogs (7): NOTCH3 (ENSG00000074181), NOTCH1 (ENSG00000148400), SNED1 (ENSG00000162804), NOTCH2NLA (ENSG00000264343), NOTCH2NLB (ENSG00000286019), NOTCH2NLR (ENSG00000286106), NOTCH2NLC (ENSG00000286219)

Protein

Protein identifiers

Neurogenic locus notch homolog protein 2 — Q04721 (reviewed: Q04721)

All UniProt accessions (6): Q04721, A0A1W2PQQ5, A0A494C049, A0A494C1F1, A0A494C1H8, A0A494C1U9

UniProt curated annotations — full annotation on UniProt →

Function. Functions as a receptor for membrane-bound ligands Jagged-1 (JAG1), Jagged-2 (JAG2) and Delta-1 (DLL1) 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. Involved in bone remodeling and homeostasis. In collaboration with RELA/p65 enhances NFATc1 promoter activity and positively regulates RANKL-induced osteoclast differentiation. Positively regulates self-renewal of liver cancer cells.

Subunit / interactions. Heterodimer of a C-terminal fragment N(TM) and an N-terminal fragment N(EC) which are probably linked by disulfide bonds. Interacts with MAML1, MAML2 and MAML3 which act as transcriptional coactivators for NOTCH2. Interacts with RELA/p65. Interacts with HIF1AN. Interacts (via ANK repeats) with TCIM, the interaction inhibits the nuclear translocation of NOTCH2 N2ICD. Interacts with CUL1, RBX1, SKP1 and FBXW7 that are SCF(FBXW7) E3 ubiquitin-protein ligase complex components. Interacts with MINAR1; this interaction increases MINAR1 stability and function. Interacts with NOTCH2NL (NOTCH2NLA, NOTCH2NLB and/or NOTCH2NLC); leading to enhance Notch signaling pathway in a non-cell-autonomous manner. Interacts with MDK; this interaction mediates a nuclear accumulation of NOTCH2 and therefore activation of NOTCH2 signaling leading to interaction between HES1 and STAT3. Interacts with MINAR2.

Subcellular location. Cell membrane Nucleus. Cytoplasm.

Tissue specificity. Expressed in the brain, heart, kidney, lung, skeletal muscle and liver. Ubiquitously expressed in the embryo.

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. Hydroxylated by HIF1AN. Can be either O-glucosylated or O-xylosylated at Ser-613 by POGLUT1. Phosphorylated by GSK3. GSK3-mediated phosphorylation is necessary for NOTCH2 recognition by FBXW7, ubiquitination and degradation via the ubiquitin proteasome pathway.

Disease relevance. Alagille syndrome 2 (ALGS2) [MIM:610205] A form of Alagille syndrome, an autosomal dominant multisystem disorder. It is clinically defined by hepatic bile duct paucity and cholestasis in association with cardiac, skeletal, and ophthalmologic manifestations. There are characteristic facial features and less frequent clinical involvement of the renal and vascular systems. The disease is caused by variants affecting the gene represented in this entry. Hajdu-Cheney syndrome (HJCYS) [MIM:102500] A rare, autosomal dominant skeletal disorder characterized by the association of facial anomalies, acro-osteolysis, general osteoporosis, insufficient ossification of the skull, and periodontal disease (premature loss of permanent teeth). Other features include cleft palate, congenital heart defects, polycystic kidneys, orthopedic problems and anomalies of the genitalia, intestines and eyes. The disease is caused by variants affecting the gene represented in this entry. NOTCH2 nonsense and frameshift mutations associated with Hajdu-Cheney syndrome cluster to the last coding exon of the gene. Mutant mRNA products escape nonsense-mediated decay and the resulting truncated NOTCH2 proteins act in a gain-of-function manner. The pathological mechanism at cellular level involves disruption of a high affinity degron recognized by FBXW7 at the C-terminus, loss of interaction with FBXW7, reduced ubiquitination and degradation, and increased NOTCH2 levels. Bone marrow cells derived from HJCYS patients have an enhanced capacity of osteoclastogenesis due to sustained NOTCH2 activity.

Similarity. Belongs to the NOTCH family.

RefSeq proteins (2): NP_001186930, NP_077719* (*=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
IPR022336	Notch_2	Family
IPR024600	Notch_C	Domain
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, PF00023, PF00066, PF06816, PF07645, PF07684, PF12661, PF12796

UniProt features (256 total): disulfide bond 115, domain 35, strand 17, helix 15, sequence variant 14, modified residue 11, repeat 9, sequence conflict 8, compositionally biased region 7, glycosylation site 7, turn 5, region of interest 4, chain 3, topological domain 2, signal peptide 1, mutagenesis site 1, transmembrane region 1, site 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
5MWB	X-RAY DIFFRACTION	1.86
2OO4	X-RAY DIFFRACTION	2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q04721-F1	59.51	0.04

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): 614 (essential for o-xylosylation)

Post-translational modifications (11): 1716, 1778, 1802, 1804, 1808, 1842, 1845, 2070, 2078, 2081, 2097

Disulfide bonds (115): 269–284, 286–295, 302–315, 309–324, 326–335, 342–353, 347–362, 364–373, 379–390, 384–401, 403–412, 419–433, 427–442, 444–453, 460–471, 465–480, 482–491, 498–509, 503–518, 520–529 …

Glycosylation sites (7): 46, 155, 613, 613, 733, 1102, 1465

Mutagenesis-validated functional residues (1):

Position	Phenotype
2416	loss of interaction with fbw7. results in decreased ubiquitination and degradation.

Function

Pathways and Gene Ontology

Reactome pathways

9 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-2197563	NOTCH2 intracellular domain regulates transcription
R-HSA-2979096	NOTCH2 Activation and Transmission of Signal to the Nucleus
R-HSA-350054	Notch-HLH transcription pathway
R-HSA-5083630	Defective LFNG causes SCDO3
R-HSA-9013695	NOTCH4 Intracellular Domain Regulates Transcription
R-HSA-9976102	Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)

MSigDB gene sets: 843 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_CARDIAC_CHAMBER_DEVELOPMENT, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, REACTOME_SIGNALING_BY_NOTCH, 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, YAATNRNNNYNATT_UNKNOWN, GOBP_DENDRITIC_CELL_DIFFERENTIATION, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_REGULATION_OF_OSTEOCLAST_DIFFERENTIATION, GOBP_CARDIAC_SEPTUM_DEVELOPMENT, GOBP_AXIS_SPECIFICATION, GOBP_GLAND_MORPHOGENESIS

GO Biological Process (65): negative regulation of transcription by RNA polymerase II (GO:0000122), in utero embryonic development (GO:0001701), cell fate determination (GO:0001709), heart looping (GO:0001947), morphogenesis of an epithelial sheet (GO:0002011), marginal zone B cell differentiation (GO:0002315), inflammatory response to antigenic stimulus (GO:0002437), atrioventricular node development (GO:0003162), pulmonary valve morphogenesis (GO:0003184), apoptotic process (GO:0006915), humoral immune response (GO:0006959), Notch signaling pathway (GO:0007219), nervous system development (GO:0007399), axon guidance (GO:0007411), animal organ morphogenesis (GO:0009887), negative regulation of gene expression (GO:0010629), positive regulation of keratinocyte proliferation (GO:0010838), hemopoiesis (GO:0030097), embryonic limb morphogenesis (GO:0030326), BMP signaling pathway (GO:0030509), positive regulation of BMP signaling pathway (GO:0030513), multicellular organism growth (GO:0035264), intracellular signal transduction (GO:0035556), intrahepatic bile duct development (GO:0035622), wound healing (GO:0042060), defense response to bacterium (GO:0042742), myeloid dendritic cell differentiation (GO:0043011), positive regulation of apoptotic process (GO:0043065), negative regulation of apoptotic process (GO:0043066), positive regulation of osteoclast differentiation (GO:0045672), positive regulation of transcription by RNA polymerase II (GO:0045944), positive regulation of Ras protein signal transduction (GO:0046579), bone remodeling (GO:0046849), positive regulation of smooth muscle cell differentiation (GO:0051152), atrial septum morphogenesis (GO:0060413), placenta blood vessel development (GO:0060674), ciliary body morphogenesis (GO:0061073), positive regulation of ERK1 and ERK2 cascade (GO:0070374), left/right axis specification (GO:0070986), cellular response to tumor cell (GO:0071228)

GO Molecular Function (6): transcription coactivator activity (GO:0003713), calcium ion binding (GO:0005509), enzyme binding (GO:0019899), signaling receptor activity (GO:0038023), NF-kappaB binding (GO:0051059), protein binding (GO:0005515)

GO Cellular Component (12): Golgi membrane (GO:0000139), extracellular region (GO:0005576), nucleus (GO:0005634), nucleoplasm (GO:0005654), endoplasmic reticulum membrane (GO:0005789), Golgi apparatus (GO:0005794), plasma membrane (GO:0005886), cilium (GO:0005929), cell surface (GO:0009986), membrane (GO:0016020), signaling receptor complex (GO:0043235), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Pre-NOTCH Expression and Processing	3
Signaling by NOTCH2	2
Generic Transcription Pathway	1
Diseases associated with O-glycosylation of proteins	1
Signaling by NOTCH4	1
Differentiation of T cells	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
immune response	2
intracellular membrane-bounded organelle	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
chordate embryonic development	1
cell fate commitment	1
cellular developmental process	1
embryonic heart tube morphogenesis	1
determination of heart left/right asymmetry	1
morphogenesis of an epithelium	1
mature B cell differentiation involved in immune response	1
inflammatory response	1
cardiac conduction system development	1
cardiac muscle tissue development	1
pulmonary valve development	1
heart valve morphogenesis	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
cell surface receptor signaling pathway	1
system development	1
axonogenesis	1
neuron projection guidance	1
anatomical structure morphogenesis	1
animal organ development	1
gene expression	1
regulation of gene expression	1
negative regulation of macromolecule biosynthetic process	1
regulation of keratinocyte proliferation	1
keratinocyte proliferation	1
positive regulation of epithelial cell proliferation	1
cell development	1
limb morphogenesis	1
embryonic appendage morphogenesis	1
cellular response to BMP stimulus	1
transforming growth factor beta receptor superfamily signaling pathway	1
transcription coregulator activity	1
positive regulation of DNA-templated transcription	1

Protein interactions and networks

STRING

4568 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NOTCH2	DLL4	Q9NR61	991
NOTCH2	JAG1	P78504	991
NOTCH2	DLL1	O00548	991
NOTCH2	JAG2	Q9Y219	991
NOTCH2	DLL3	Q9NYJ7	988
NOTCH2	RBPJ	Q06330	939
NOTCH2	MDK	P21741	910
NOTCH2	MAML1	Q92585	885
NOTCH2	SRRT	Q9BXP5	818
NOTCH2	HEY2	Q9UBP5	797
NOTCH2	HES5	Q5TA89	793
NOTCH2	LFNG	Q8NES3	785
NOTCH2	HEY1	Q9Y5J3	782
NOTCH2	DLK1	P15803	766
NOTCH2	GSK3B	P49841	766

IntAct

187 interactions, top by confidence:

A	B	Type	Score
RBPJ	NOTCH1	psi-mi:“MI:0914”(association)	0.910
ANKRD44	PPP6C	psi-mi:“MI:0914”(association)	0.790
RABGGTB	YKT6	psi-mi:“MI:0914”(association)	0.740
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
ANKRD44	ANKRD28	psi-mi:“MI:0914”(association)	0.710
AGRP	TK1	psi-mi:“MI:0914”(association)	0.640
SLC12A2	CLGN	psi-mi:“MI:0914”(association)	0.640
SLC39A5	FAM171A2	psi-mi:“MI:0914”(association)	0.640
PDGFRB	PIK3R2	psi-mi:“MI:0914”(association)	0.610
SMAD4	LATS1	psi-mi:“MI:0914”(association)	0.600
NOTCH2	ST14	psi-mi:“MI:0915”(physical association)	0.550
SMAD4	NOTCH2	psi-mi:“MI:2364”(proximity)	0.540
SMAD4	NOTCH2	psi-mi:“MI:0915”(physical association)	0.540
RABGGTB	PIPSL	psi-mi:“MI:0914”(association)	0.530
VASN	AP3B1	psi-mi:“MI:0914”(association)	0.530
LGALS1	PODXL	psi-mi:“MI:0914”(association)	0.530
ZFP41	LRP4	psi-mi:“MI:0914”(association)	0.530
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
DLK1	SCAMP3	psi-mi:“MI:0914”(association)	0.530
LGALS1	LAMA5	psi-mi:“MI:0914”(association)	0.530
GREM2	ZZEF1	psi-mi:“MI:0914”(association)	0.530
IGFBP4	MYCBP2	psi-mi:“MI:0914”(association)	0.530

BioGRID (511): NOTCH2 (Affinity Capture-MS), NOTCH2 (Affinity Capture-MS), NOTCH2 (Affinity Capture-MS), NOTCH2 (Affinity Capture-MS), EEF2 (Co-fractionation), MLLT4 (Co-fractionation), NOTCH2 (Co-fractionation), NOTCH2 (Co-fractionation), NOTCH2 (Co-fractionation), NOTCH2 (Co-fractionation), PDIA6 (Co-fractionation), CST6 (Two-hybrid), EPSTI1 (Two-hybrid), FAM84B (Two-hybrid), IL13RA2 (Two-hybrid)

ESM2 similar proteins: A0A096LNW5, B8JI71, D3ZHH1, G3I6Z6, O00548, O35516, O57409, P0DPK3, P0DPK4, P35442, P46531, P78504, P97677, Q01705, Q04721, Q05793, Q07008, Q08E66, Q2QI47, Q5G872, Q5ZQU0, Q61483, Q63722, Q66PY1, Q6DI48, Q6NZL8, Q70E20, Q7TQN3, Q7Z3S9, Q8IWY4, Q8IX30, Q8JZM4, Q8K3K1, Q8NFT8, Q8TER0, Q8TEU8, Q8UWJ4, Q8VHS2, Q90Y54, Q90Y57

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

23 interactions.

A	Effect	B	Mechanism
GSK3B	“down-regulates activity”	NOTCH2	phosphorylation
LFNG	up-regulates	NOTCH2	binding
LFNG	down-regulates	NOTCH2	binding
MFNG	up-regulates	NOTCH2	binding
MDK	up-regulates	NOTCH2	binding
GXYLT1	up-regulates	NOTCH2	binding
GXYLT2	up-regulates	NOTCH2	binding
JAG1	up-regulates	NOTCH2	binding
POGLUT1	up-regulates	NOTCH2	binding
DLL1	up-regulates	NOTCH2	binding
gamma-secretase	“up-regulates activity”	NOTCH2	cleavage
“MBD2/NuRD complex”	“down-regulates quantity by repression”	NOTCH2	“transcriptional regulation”
“MBD3/NuRD complex”	“down-regulates quantity by repression”	NOTCH2	“transcriptional regulation”
NOTCH2	“down-regulates activity”	TRAF6	binding
NOTCH2	down-regulates	TCF3	binding
JAG2	up-regulates	NOTCH2	binding
MAML1	up-regulates	NOTCH2	binding
MAML3	up-regulates	NOTCH2	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 213 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
Downstream signal transduction	6	15.3×	6e-04
Somitogenesis	5	7.8×	9e-03
EPH-Ephrin signaling	6	6.7×	7e-03
Post-translational protein phosphorylation	8	5.4×	4e-03
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	8	4.7×	8e-03
PIP3 activates AKT signaling	9	4.0×	9e-03

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of cell migration	14	4.6×	2e-03
positive regulation of gene expression	17	3.5×	4e-03

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 13 cancer types — ACYC, AML, BCC, BLCA, BRCA, CSCC, DLBCLNOS, ESCA, HNSC, MLYM, NHL, PRAD…(+1 more).

Clinical variants and AI predictions

ClinVar

2194 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	58
Likely pathogenic	38
Uncertain significance	1190
Likely benign	564
Benign	98

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1012187	NM_024408.4(NOTCH2):c.6125T>C (p.Met2042Thr)	Pathogenic
1028812	NM_024408.4(NOTCH2):c.5123_5132delinsAGA (p.Ser1708_Leu1711delinsTer)	Pathogenic
1068831	NM_024408.4(NOTCH2):c.1668C>A (p.Cys556Ter)	Pathogenic
1344580	NM_024408.4(NOTCH2):c.30G>A (p.Trp10Ter)	Pathogenic
1344880	NM_024408.4(NOTCH2):c.1211C>T (p.Pro404Leu)	Pathogenic
1451302	NM_024408.4(NOTCH2):c.2235_2236del (p.Cys745_Asp746delinsTer)	Pathogenic
1457269	NM_024408.4(NOTCH2):c.3415del (p.Leu1139fs)	Pathogenic
1685986	NM_024408.4(NOTCH2):c.6832dup (p.Thr2278fs)	Pathogenic
1703257	NM_024408.4(NOTCH2):c.5930-2A>G	Pathogenic
1805545	NM_024408.4(NOTCH2):c.6667C>T (p.Gln2223Ter)	Pathogenic
1805691	NM_024408.4(NOTCH2):c.4593dup (p.Leu1532fs)	Pathogenic
1992457	NM_024408.4(NOTCH2):c.7030G>T (p.Glu2344Ter)	Pathogenic
2015161	NM_024408.4(NOTCH2):c.4025_4027delinsTCT (p.Cys1342_Gln1343delinsPheTer)	Pathogenic
2029083	NM_024408.4(NOTCH2):c.901G>T (p.Glu301Ter)	Pathogenic
2127842	NM_024408.4(NOTCH2):c.7099C>T (p.Gln2367Ter)	Pathogenic
2578107	NM_024408.4(NOTCH2):c.7021C>T (p.Gln2341Ter)	Pathogenic
2769216	NM_024408.4(NOTCH2):c.6343del (p.Ser2115fs)	Pathogenic
2788908	NM_024408.4(NOTCH2):c.5356C>T (p.Arg1786Ter)	Pathogenic
280705	NM_024408.4(NOTCH2):c.6787C>T (p.Gln2263Ter)	Pathogenic
280845	NM_024408.4(NOTCH2):c.6659C>G (p.Ser2220Ter)	Pathogenic
2850278	NM_024408.4(NOTCH2):c.4810_4811del (p.Arg1604fs)	Pathogenic
30055	NM_024408.4(NOTCH2):c.6272del (p.Phe2091fs)	Pathogenic
30056	NOTCH2, 1-BP DEL, 6460T	Pathogenic
30057	NM_024408.4(NOTCH2):c.6622C>T (p.Gln2208Ter)	Pathogenic
30058	NM_024408.4(NOTCH2):c.7119T>G (p.Tyr2373Ter)	Pathogenic
30059	NM_024408.4(NOTCH2):c.6949C>T (p.Gln2317Ter)	Pathogenic
30060	NM_024408.4(NOTCH2):c.6895G>T (p.Glu2299Ter)	Pathogenic
30061	NM_024408.4(NOTCH2):c.7165C>T (p.Gln2389Ter)	Pathogenic
3010709	NM_024408.4(NOTCH2):c.5987T>A (p.Leu1996Ter)	Pathogenic
3635019	NM_024408.4(NOTCH2):c.5842del (p.Pro1947_Leu1948insTer)	Pathogenic

SpliceAI

5732 predictions. Top by Δscore:

Variant	Effect	Δscore
1:119916691:CTTC:C	acceptor_gain	1.0000
1:119916693:TCC:T	acceptor_loss	1.0000
1:119916694:CCTA:C	acceptor_loss	1.0000
1:119916695:CT:C	acceptor_loss	1.0000
1:119916696:T:A	acceptor_loss	1.0000
1:119917660:TGTAC:T	donor_loss	1.0000
1:119917661:GTA:G	donor_loss	1.0000
1:119917662:TAC:T	donor_loss	1.0000
1:119917663:ACCT:A	donor_loss	1.0000
1:119917664:C:T	donor_loss	1.0000
1:119917758:TTTTC:T	acceptor_gain	1.0000
1:119917759:TTTC:T	acceptor_gain	1.0000
1:119917760:TTC:T	acceptor_gain	1.0000
1:119917763:C:CC	acceptor_gain	1.0000
1:119917764:T:C	acceptor_loss	1.0000
1:119918401:CCTA:C	donor_loss	1.0000
1:119918403:TACC:T	donor_loss	1.0000
1:119918404:A:AC	donor_gain	1.0000
1:119918404:ACCA:A	donor_loss	1.0000
1:119918405:C:A	donor_loss	1.0000
1:119918405:C:CC	donor_gain	1.0000
1:119918429:T:TA	donor_gain	1.0000
1:119918549:AGAAT:A	acceptor_gain	1.0000
1:119918550:GAAT:G	acceptor_gain	1.0000
1:119918551:AAT:A	acceptor_gain	1.0000
1:119918552:AT:A	acceptor_gain	1.0000
1:119918553:TC:T	acceptor_loss	1.0000
1:119918554:C:CC	acceptor_gain	1.0000
1:119919308:TTA:T	donor_loss	1.0000
1:119919309:TAC:T	donor_loss	1.0000

AlphaMissense

16407 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:119916636:A:G	L2029P	1.000
1:119917745:A:G	W1983R	1.000
1:119917745:A:T	W1983R	1.000
1:119917750:A:T	L1981H	1.000
1:119918447:A:G	L1963P	1.000
1:119918543:C:G	R1931P	1.000
1:119918549:A:G	L1929P	1.000
1:119919373:T:A	D1907V	1.000
1:119919403:A:G	L1897P	1.000
1:119919406:A:G	L1896P	1.000
1:119919415:G:T	A1893D	1.000
1:119919439:G:T	A1885D	1.000
1:119925466:C:A	W1450C	1.000
1:119925466:C:G	W1450C	1.000
1:119929203:C:G	C1222S	1.000
1:119929204:A:T	C1222S	1.000
1:119950807:C:G	C799S	1.000
1:119950808:A:T	C799S	1.000
1:119950827:G:C	C792W	1.000
1:119950828:C:G	C792S	1.000
1:119950829:A:G	C792R	1.000
1:119950829:A:T	C792S	1.000
1:119953566:C:G	C781S	1.000
1:119953567:A:T	C781S	1.000
1:119953593:C:G	C772S	1.000
1:119953594:A:T	C772S	1.000
1:119953626:C:G	C761S	1.000
1:119953627:A:T	C761S	1.000
1:119953646:A:C	C754W	1.000
1:119953647:C:G	C754S	1.000

dbSNP variants (sampled 300 via entrez): RS1000139830 (1:119915234 G>A,T), RS1000175155 (1:119935750 C>A,G), RS1000209105 (1:119916680 C>G,T), RS1000225646 (1:119922032 C>T), RS1000242020 (1:119914803 G>A), RS1000320403 (1:119970813 T>A), RS1000381969 (1:119928465 T>C), RS1000417046 (1:119923117 G>T), RS1000445195 (1:119977240 C>T), RS1000508084 (1:119981885 A>G), RS1000554951 (1:119934110 C>T), RS1000578816 (1:119983327 A>G), RS1000584763 (1:119933721 G>A,C,T), RS1000593133 (1:119918281 A>G), RS1000781179 (1:119948037 T>C)

Disease associations

OMIM: gene MIM:600275 | disease phenotypes: MIM:102500, MIM:610205, MIM:142623, MIM:241550, MIM:610805, MIM:192350

GenCC curated gene-disease

Disease	Classification	Inheritance
acroosteolysis dominant type	Definitive	Autosomal dominant
Alagille syndrome due to a NOTCH2 point mutation	Strong	Autosomal dominant
Alagille syndrome	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
Alagille syndrome	Definitive	AD
acroosteolysis dominant type	Definitive	AD

Mondo (11): acroosteolysis dominant type (MONDO:0007057), Alagille syndrome due to a NOTCH2 point mutation (MONDO:0012439), keratoacanthoma (MONDO:0002527), Hirschsprung disease, susceptibility to, 1 (MONDO:0007723), hypoplastic left heart syndrome (MONDO:0004933), congenital heart disease (MONDO:0005453), congenital anomaly of kidney and urinary tract (MONDO:0019719), VACTERL/vater association (MONDO:0008642), primary ovarian failure (MONDO:0005387), hereditary breast ovarian cancer syndrome (MONDO:0003582), Alagille syndrome (MONDO:0007318)

Orphanet (9): Alagille syndrome due to a NOTCH2 point mutation (Orphanet:261629), Alagille syndrome (Orphanet:52), Hajdu-Cheney syndrome (Orphanet:955), Hirschsprung disease (Orphanet:388), Hypoplastic left heart syndrome (Orphanet:2248), Renal or urinary tract malformation (Orphanet:93545), VACTERL/VATER association (Orphanet:887), Hereditary breast and/or ovarian cancer syndrome (Orphanet:145), NON RARE IN EUROPE: Primary ovarian failure (Orphanet:619)

HPO phenotypes

132 total (30 of 132 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
HP:0000047	Hypospadias
HP:0000083	Renal insufficiency
HP:0000089	Renal hypoplasia
HP:0000093	Proteinuria
HP:0000107	Renal cyst
HP:0000113	Polycystic kidney dysplasia
HP:0000160	Narrow mouth
HP:0000164	Abnormality of the dentition
HP:0000175	Cleft palate
HP:0000218	High palate
HP:0000233	Thin vermilion border
HP:0000238	Hydrocephalus
HP:0000256	Macrocephaly
HP:0000268	Dolichocephaly
HP:0000269	Prominent occiput
HP:0000272	Malar flattening
HP:0000277	Abnormal mandible morphology
HP:0000280	Coarse facial features
HP:0000286	Epicanthus
HP:0000293	Full cheeks
HP:0000294	Low anterior hairline
HP:0000307	Pointed chin
HP:0000316	Hypertelorism
HP:0000325	Triangular face
HP:0000337	Broad forehead
HP:0000343	Long philtrum
HP:0000347	Micrognathia

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST000167_8	Type 2 diabetes	4.000000e-08
GCST005752_13	Systemic lupus erythematosus	2.000000e-07
GCST006585_862	Blood protein levels	8.000000e-06
GCST006867_4	Type 2 diabetes	1.000000e-10
GCST007400_55	Systemic lupus erythematosus	7.000000e-06
GCST009379_31	Type 2 diabetes	3.000000e-16
GCST010303_36	Nevus count or cutaneous melanoma	2.000000e-08
GCST010461_6	Hepatocyte growth factor levels	6.000000e-07
GCST90013445_14	Type 1 diabetes	2.000000e-08
GCST90013445_28	Type 1 diabetes	2.000000e-08
GCST90014023_13	Type 1 diabetes	8.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004632	nevus count

MeSH disease descriptors (9)

Descriptor	Name	Tree numbers
D016738	Alagille Syndrome	C06.130.120.135.250.125; C06.552.150.125; C14.240.400.044; C16.131.077.065; C16.131.240.400.044; C16.320.051
D006330	Heart Defects, Congenital	C14.240.400; C14.280.400; C16.131.240.400
D061325	Hereditary Breast and Ovarian Cancer Syndrome	C04.588.180.483; C04.588.322.455.431; C04.700.517; C12.050.351.500.056.630.705.431; C12.050.351.937.418.685.431; C12.100.250.056.630.705.431; C12.900.418.685.431; C16.320.700.517; C17.800.090.500.483; C19.344.410.431; C19.391.630.705.431
D018636	Hypoplastic Left Heart Syndrome	C14.240.400.625; C14.280.400.625; C16.131.240.400.625
D007636	Keratoacanthoma	C17.800.417
D016649	Primary Ovarian Insufficiency	C12.050.351.500.056.630.750; C12.100.250.056.630.750; C19.391.630.750
C535663	Acroosteolysis dominant type (supp.)
C566906	Cakut (supp.)
C537586	Serpentine fibula polycystic kidney syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3407320 (SINGLE PROTEIN), CHEMBL4524007 (PROTEIN FAMILY)

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: other protein — Notch receptors

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

Ligand	Action	Affinity	Parameter
tarextumab	Binding	10.0	pKd

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
9.00	IC50	1	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	1198938: Inhibition of Notch2 intracellular domain fragment transfected in human HeLa cells co-transfected with CBF1-PGL3 luciferase reporter vector by transactivation assay	ic50	0.0010	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Tobacco Smoke Pollution	affects expression, decreases expression, increases expression	4
bisphenol A	affects expression, affects binding, increases reaction, decreases expression	3
Resveratrol	decreases expression, increases expression	3
Air Pollutants	decreases expression, affects cotreatment, increases abundance, increases expression	3
Tretinoin	increases expression	3
Cadmium Chloride	increases abundance, increases expression	3
arsenite	affects expression, affects binding, decreases reaction	2
sodium arsenite	affects expression, affects cotreatment, decreases expression	2
methacrylaldehyde	affects cotreatment, decreases expression, increases expression, increases abundance	2
Acrolein	affects cotreatment, decreases expression, increases expression, increases abundance	2
Benzo(a)pyrene	increases expression, increases methylation	2
Cadmium	increases abundance, increases expression	2
Cisplatin	decreases expression, increases reaction, affects response to substance	2
Ozone	affects cotreatment, decreases expression, increases expression, increases abundance	2
bisphenol F	affects cotreatment, decreases expression	1
napabucasin	decreases expression	1
dicrotophos	increases expression	1
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
uranyl acetate	affects expression	1
cypermethrin	decreases reaction, decreases expression	1
ochratoxin A	decreases expression	1
coumarin	increases phosphorylation	1
phenethyl isothiocyanate	increases response to substance, increases activity, increases cleavage, increases localization, increases expression	1
di-n-butylphosphoric acid	affects expression	1
monoisoamyl-2,3-dimercaptosuccinate	increases expression, affects cotreatment, decreases expression	1
deguelin	increases expression	1
entinostat	increases expression	1
N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester	decreases activity, decreases cleavage	1
bisphenol B	increases expression	1
abrine	increases 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
CHEMBL3412055	Binding	Inhibition of Notch2 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

20 cell lines: 18 cancer cell line, 2 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B8LK	Abcam HCT 116 NOTCH2 KO	Cancer cell line	Male
CVCL_B8ZK	Abcam MCF-7 NOTCH2 KO	Cancer cell line	Female
CVCL_B9NQ	Abcam A-549 NOTCH2 KO	Cancer cell line	Male
CVCL_C5U2	Arbo	Cancer cell line	Male
CVCL_D7VZ	Ubigene A-549 NOTCH2 KO	Cancer cell line	Male
CVCL_D8RK	Ubigene HCT 116 NOTCH2 KO	Cancer cell line	Male
CVCL_D9LF	Ubigene HEK293 NOTCH2 KO	Transformed cell line	Female
CVCL_E0J9	Ubigene HeLa NOTCH2 KO	Cancer cell line	Female
CVCL_G300	SCCIC1	Cancer cell line	Male
CVCL_G301	SCCIC12	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05488067	PHASE4	COMPLETED	Atorvastatin Therapy on Xanthoma in Alagille Syndrome
NCT07290257	PHASE4	RECRUITING	Long-Term Low-Intervention SafEty and Clinical Outcomes Clinical Study of LivmArli® in Patients With Alagille Syndrome in the European Union (LEAP-EU)
NCT03630198	PHASE4	COMPLETED	Pain Outcomes Following Intralesional Corticosteroid Injections
NCT02343562	PHASE4	UNKNOWN	Probiotics for Prophylaxis of Postoperative Hirschsprungs Associated Enterocolitis
NCT07186647	PHASE4	COMPLETED	Laparoscopic-Assisted Transanal Pull-Through for Hirschsprung Disease in Pediatric:Short and Intermediate Outcomes of Two Different Techniques
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
NCT04674761	PHASE3	COMPLETED	Efficacy and Safety of Odevixibat in Patients With Alagille Syndrome
NCT05035030	PHASE3	RECRUITING	Long-term Safety and Efficacy of Odevixibat in Patients With Alagille Syndrome
NCT05543174	PHASE3	COMPLETED	A Study of TAK-625 for the Treatment of Alagille Syndrome (ALGS)
NCT04904081	PHASE3	UNKNOWN	Feasibility of Use of Indocyanine Green in Pediatric Colorectal Surgery
NCT02781922	PHASE3	RECRUITING	Cardiac Stem/Progenitor Cell Infusion in Univentricular Physiology (APOLLON Trial)
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
NCT01903460	PHASE2	COMPLETED	Safety and Efficacy Study of LUM001 in the Treatment of Cholestatic Liver Disease in Patients With Alagille Syndrome
NCT02047318	PHASE2	COMPLETED	An Extension Study to Evaluate the Long-Term Safety and Durability of Effect of LUM001 in the Treatment of Cholestatic Liver Disease in Subjects With Alagille Syndrome (ALGS)
NCT02057692	PHASE2	COMPLETED	Evaluation of LUM001 in the Reduction of Pruritus in Alagille Syndrome