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FLASH GENE

Symbol

NOTCH2

contributors: mct/shn - updated : 11/09/2011

HGNC name	notch 2
HGNC id	7882

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	ALGS2 Alagille syndrome 2 HJCYS Hajdu-Cheney syndrome
Location	1p11.2      Physical location : 120.454.177 - 120.612.276
Synonym name	Notch (Drosophila) homolog 2
	Notch homolog 2 (Drosophila)
	Notch homolog 2
	neurogenic locus notch homolog protein 2
Synonym symbol(s)	hN2, AGS2, HJCYS

DNA

TYPE	functioning gene
STRUCTURE	158.10 kb     34 Exon(s)

Genomic sequence alignment details
10 Kb 5' upstream gene genomic sequence study

MAPPING

cloned

Y

linked

status

confirmed

Map	pter - D1S185 - D1S514 - NOTCH2 - cen

Physical map

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_024408 34 splicing 11474 NP_077719 - 2471 - 1994 7698746 NM_001200001 22 splicing 4326 NP_001186930 - 1235 - -

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 heart       highly Digestive choledoque           pancreas exocrine       lowly Endocrine pancreas       highly   thyroid       highly Hearing/Equilibrium ear inner cochlea   highly Reproductive female system breast mammary gland   highly   male system testis     highly Urinary kidney       highly Visual eye anterior segment cornea   highly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Connective adipose     highly Epithelial secretory glandular endocrine   Epithelial secretory glandular exocrine   Muscular striatum skeletal

cells

System Cell Pubmed Species Stage Rna symbol Digestive acinar Skeleton osteoblast Visual epithelial cell

cell lineage
cell lines
fluid/secretion	blood

at STAGE

physiological period

embryo

Text	atrioventricular cord

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
	C terminus of the intracellular domain contains a PEST sequence known to mediate proteosomal destruction of the protein

mono polymer

heteromer , dimer

isoforms

Precursor

HOMOLOGY

interspecies	ortholog to NOTCH2, Pan troglodytes
	ortholog to notch2, danio rerio
	homolog to Notch2, Rattus norvegicus
	ortholog to Notch2, Mus musculus

Homologene

FAMILY

NOTCH family

CATEGORY

regulatory , protooncogene , receptor

SUBCELLULAR LOCALIZATION	plasma membrane
	intracellular
	intracellular,nucleus

basic FUNCTION	receptor for membrane-bound ligands Jagged1, Jagged2, Delta-like1, Delta-like3 and Delta-like4
	an important element in dental physiological and pathogenic conditions (
	mediating cell-cell interactions that specify cell fate during development
	as other Notch family members and ligands, expressed in the human corneal epithelium and appear to play pivotal roles in corneal epithelial cell differentiation
	central regulator of pancreatic intraepithelial neoplasia progression and malignant transformation
	essential role of NOTCH2 and MYC in the initiation of a neoplastic transformation program in pancreatic cells
	play a role in the regulation of red cell differentiation (
	important role for NOTCH2 signaling in bone homeostasis
	importance of NOTCH2 in the development and maintenance of the skeleton, and modulate RANKL-induced osteoclastogenesis
	NOTCH2 and NOTCH3 act together to govern vascular development and smooth muscle differentiation

CELLULAR PROCESS	cell cycle
	cell life, differentiation
	cell life, proliferation/growth
	cell life, cell death/apoptosis
	nucleotide, transcription, regulation
	cell communication

PHYSIOLOGICAL PROCESS

development

PATHWAY

metabolism

signaling

signal transduction

Notch2 signaling is required for potent antitumor immunity

a component

protein constituent of plasma membrane

INTERACTION

DNA

RNA

small molecule

protein	CBF1 (
	Delta1, Jagged1, and Jagged2 as ligands for Notch2
	mastermind-like 1 (Drosophila), MAML1
	glycogen synthase kinase-3 beta, GSK-3 beta
	TAT

cell & other

REGULATION

activated by	delta (DLK1) jagged (JAG*)
	in response to TNF (TNF signaling activates NOTCH2 that sensitizes endothelial cells to apoptosis via modulation of the key apoptosis regulator survivin

induced by

MAML1, MAML2 and MAML3 which act as transcriptional coactivators for NOTCH2

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)

ALGS2 , HJCYS

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral     --over   with FCER2 in B-cell chronic lymphocytic leukemia tumoral   translocation     in neoplasia constitutional somatic mutation       AGS is a disorder caused by mutations in JAG1 or NOTCH2 the vast majority of patients with AGS have mutations in JAG1, with only a small subset showing NOTCH2 mutations tumoral     --over   correlated closely with colorectal cancer and may play a role in tumor inhibition in colon carcinogenesis constitutional     --low   in immune thrombocytopenic purpura tumoral germinal mutation     gain of function in the pathogenesis of a subset of B-cell lymphoma

Susceptibility

Variant & Polymorphism

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed cancer digestive pancreas ablation of NOTCH2 but not NOTCH1 leads to an abrogation of pancreatic intraepithelial neoplasia progression, and increased survival osteoarticular bone ostéoporosis Notch pathway is a potential target for therapeutic intervention in osteoporosis

ANIMAL & CELL MODELS

	Mice homozygous for the Notch2(del1) mutation died perinatally from defects in glomerular development in the kidney while mice heterozygous for both the Notch2(del1) and Jag1(dDSL) mutations exhibit a less severe glomerular defect (
	mice double mutant for the Notch1 and Notch2 receptors exhibit multiple defects in left-right asymmetry (
	when Notch2 and Notch3 genes are simultaneously disrupted, mice die in utero at mid-gestation due to severe vascular abnormalities