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FLASH GENE

Symbol

NOTCH3

contributors: mct - updated : 28-05-2016

HGNC name	Notch homolog 3 (Drosophila)
HGNC id	7883

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	CADASIL cerebral arteriopathy with subcortical infarcts and leukoencephalopathy HMID hereditary multi-infarct dementia IMF2 infantile myofibromatosis-2
Location	19p13.12      Physical location : 15.270.444 - 15.311.792
Synonym name	Notch (Drosophila) homolog 3
	neurogenic locus notch homolog protein 3
Synonym symbol(s)	CASIL

DNA

TYPE	functioning gene
STRUCTURE	41.35 kb     33 Exon(s)

10 Kb 5' upstream gene genomic sequence study

MAPPING

cloned

Y

linked

status

confirmed

Map	pter - D19S226 - D19S179 - D19S415 - D19S2252 - D19S929 - D19S841 - NOTCH3 - (D19S1153 - D19S923 ) - D19S432 - D19S253 - D19S588 - D19S244 - D19S411 - D19S885 - D19S199 - cen

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_000435 33 - 8089 NP_000426 - 2321 - 2006 16574107

EXPRESSION

Type	ubiquitous

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Cardiovascular vessel       lowly Homo sapiens Hearing/Equilibrium ear inner cochlea   highly Nervous nerve       highly Reproductive female system ovary     highly Visual eye anterior segment cornea   highly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Connective adipose     moderately Epithelial barrier lining neuroepithelium     Muscular smooth vessel   predominantly Homo sapiens

cells

System Cell Pubmed Species Stage Rna symbol Visual epithelial cell

cell lineage

cell lines

fluid/secretion

at STAGE

physiological period

embryo

Text	developing aorta, embryonic tissue

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	a signal peptide
	36 extracellular EGF repeats
	three notch/lin-12 (LNR) repeats
	two PEST sequences
	six cdc10/ankyrin (ANK) repeats
	a RAM23 domain

conjugated

GlycoP , PhosphoP

mono polymer

heteromer , dimer

isoforms

Precursor

HOMOLOGY

interspecies	homolog to rattus Notch3 (91.5 pc)
	homolog to murine Notch3 (91.0 pc)

Homologene

FAMILY

NOTCH family

CATEGORY

regulatory , receptor membrane

SUBCELLULAR LOCALIZATION	extracellular
	plasma membrane
	intracellular
	intracellular,cytoplasm,organelle,membrane
	intracellular,cytoplasm,organelle,endoplasmic reticulum
	intracellular,cytoplasm,organelle,Golgi
	intracellular,cytoplasm,cytosolic
	intracellular,nucleus,nucleoplasm
text	following proteolytical processing NOTCH3 intracellular domain is translocated to the nucleus

basic FUNCTION	receptor for membrane-bound ligands Jagged1, Jagged2, Delta-like1, Delta-like3 and Delta-like4
	involved in the decision between the endocrine and exocrine fates in the developing pancreas
	mediating cell-cell interactions that specify binary cell fate decisions during development
	can function as an oncogene in the developing brain, and link the Notch pathway to choroid plexus tumors pathogenesis
	upon ligand activation, forms a transcriptional activator complex with RBP-J kappa and activates gene
	as other Notch family members and ligands, expressed in the human corneal epithelium and appear to play pivotal roles in corneal epithelial cell differentiation
	implicated in controlling vascular smooth muscle cells proliferation and differentiation
	cooperates with EGFR pathway to modulate apoptosis through the innduction of BCL2L11
	contributes to the downregulation of APOD and by itself is sufficient to attenuate APOD transcript expression
	key factor limiting the expansion of ZEB-expressing cells, providing novel mechanistic insights into the role of Notch signaling in the cell fate regulation and disease progression of esophageal squamous cancers
	NOTCH2 and NOTCH3 act together to govern vascular development and smooth muscle differentiation
	may be involved in the pathogenesis of bronchogenic carcinoma, in particular in the promotion of the lung cancer oncogene
	NOTCH3 and JAG1 may play an important role in the initiation and proliferation of non-functioning adenomas, and there may be an interaction between NOTCH3 and JAG1 in this process
	NOTCH3 is the Notch receptor that limits Neuronal stem cells activation towards amplifying divisions, thereby acting as a major checkpoint for adult germinal zones homeostasis
	NOTCH3, but not NOTCH2 protects vascular smooth muscle cell (VSMC) from apoptosis and apoptosis mediators degrade NOTCH3 protein
	discrete roles for NOTCH2 and NOTCH3 in VSMCs and these roles are linked to specific upstream regulators that control their expression
	NOTCH2 and NOTCH3 have overlapping roles in promoting development of vascular smooth muscle cells, and together contribute to functional closure of the ductus arteriosus
	NOTCH2 and NOTCH3 inhibited both cell proliferation and cell apoptosis trophoblast cell lines
	JAG1/NOTCH3 signaling pathway plays a key role in angiogenesis of breast cancer

CELLULAR PROCESS	cell life, differentiation
	nucleotide, transcription, regulation
	cell communication

PHYSIOLOGICAL PROCESS

development

PATHWAY

metabolism

signaling

signal transduction

NOTCH3–HES5 signaling pathway is crucial for the development of pulmonary arterial hypertension

a component	protein constituent of transmembrane
	heterodimer of a C-terminal fragment and a N-terminal fragment linked by disulfide bonds

INTERACTION

DNA

RNA

small molecule	other,
	Ca2+

protein	interacting with Fringe (MFNG, LFNG, RFNG), for Fringe-mediated elongation of O-fucose
	interacting with MAML1, MAML2, MAML3 acting as coactivators for NOTCH3
	interacting with PSMA1
	SDC2 regulates Notch signaling and physically interacts with NOTCH3
	both NOTCH2 and NOTCH3 can promote SDC2 expression in smooth muscle cells
	PDGFRB expression was upregulated by NOTCH3 ligand induction or by activated forms of the NOTCH3 receptor
	in cancer cells, key role for CTCFL as the main mediator of transcriptional deregulation of NOTCH3
	suppression of TP53 by NOTCH3 is mediated by CCNG1 and sustained by MDM2 in hepatocellular carcinoma

cell & other

REGULATION

activated by	delta (DLK1) jagged (JAG*)
	MSX1 (strongly up-regulated the Delta-Notch pathway genes DLK1, NOTCH3, and HEY1)

induced by

MAML1, MAML2 and MAML3 which act as transcriptional coactivators for NOTCH3

Other	undergoing a first proteolytic cleavage by furin (PACE1) in the Golgi during trafficking of Notch to the cell surface, undergoing further cleavage by gamma secretase (see PSEN1) releasing an intracellular domain (NICD) which translocates to the nucleus and modulates transcription of target genes
	modulated by FRINGE (LFNG,MFNG,RFNG) through elongation of linked fucose residues on side chains on some EGF repeats

ASSOCIATED DISORDERS

corresponding disease(s)

CADASIL , HMID , IMF2

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral   translocation     in acute lymphoblastic/myeloblastic leukemia tumoral     --over   in lung cancer constitutional     --over   in small pulmonary artery smooth muscle cells associated with pulmonary hypertension constitutional     --over   in immune thrombocytopenic purpura constitutional     --over   in fibrotic liver tissues of patients with chronic active hepatitis, but not detected in normal liver tissues

Susceptibility

Variant & Polymorphism

Candidate gene	NOTCH3-HES5 signaling pathway is crucial for the development of pulmonary arterial hypertension
Marker
Therapy target
	System Type Disorder Pubmed miscelleaneous hypertension   inhibition of the expression or effect of NOTCH3 signaling in the adult pulmonary vasculature may be a useful strategy to prevent and treat pulmonary arterial hypertension cancer reproductive ovary expression may be related to chemoresistance and that the Notch3 pathway may represent a novel therapeutic target for advanced stage chemoresistant ovarian cancer digestive liver   selective interruption of NOTCH3 may provide an anti-fibrotic strategy in hepatic fibrosis cancer angiogenesis   JAG1/NOTCH3 is expected to be a potential target for TNBC neovascularization therapy

ANIMAL & CELL MODELS

when Notch2 and Notch3 genes are simultaneously disrupted, mice die in utero at mid-gestation due to severe vascular abnormalities