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FLASH GENE

Symbol

NOTCH4

contributors: mct - updated : 28-05-2020

HGNC name	Notch homolog 4 (Drosophila)
HGNC id	7884

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Location	6p21.32      Physical location : 3.423.638 - 32.191.844
Synonym name	Notch (Drosophila) homolog 4
	murine mammary tumor virus integration site 3
	neurogenic locus notch homolog protein 4
Synonym symbol(s)	INT3, NOTCH3, MGC74442, FLJ16302

DNA

TYPE	functioning gene
STRUCTURE	29.22 kb     30 Exon(s)

10 Kb 5' upstream gene genomic sequence study

text structure

containing a (CTG)n repeats polymorphism

MAPPING

cloned

Y

linked

status

confirmed

Map	pter - C2 C2 - CYP21A2 CYP21A2 - TNXB - AGER - PBX2 - NOTCH4 - cen
Authors	Sugaya (94)

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_004557 30 splicing 6762 NP_004548 209.6 2003 widely 1998 9693032 also called NOTCH4S variant 3 - splicing 9300 isoform 3 - 377 - 1998 9693032 including intron 11 and 2U also called NOTCH4L2 variant 2 - splicing initiation site 9300 isoform 2 - 589 regulation of cell differentiation 1998 9693032 also called NOTCH4L1

EXPRESSION

Type

widely

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 Lymphoid/Immune thymus       lowly Nervous nerve cranial nerve     highly Reproductive female system placenta     highly Respiratory lung       highly   respiratory tract larynx     moderately Urinary bladder       moderately Visual eye anterior segment cornea   highly

cells

System Cell Pubmed Species Stage Rna symbol Cardiovascular endothelial cell Visual epithelial cell

cell lineage
cell lines	activated in certain tumor lines
fluid/secretion

at STAGE

physiological period

embryo, pregnancy

Text

placenta

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	a putative signal peptide
	29 EGF-like repeats
	a transmembrane segment (1TM)
	three notch/lin-12 (LNR) repeats
	a RAM23 domain
	six cdc10/ankyrin (ANK) repeats
	the C terminal PEST conserved region

mono polymer

heteromer , dimer

isoforms

Precursor

HOMOLOGY

interspecies	homolog to rattus Notch4 (81.24 pc)
	homolog to murine Notch4 (82.04 pc)

intraspecies

homolog to MMTV integration site int-3

Homologene

FAMILY

NOTCH family

CATEGORY

regulatory , structural protein , receptor membrane

SUBCELLULAR LOCALIZATION	extracellular
	plasma membrane
	intracellular
	intracellular,cytoplasm,organelle,membrane
	intracellular,cytoplasm,organelle,Golgi
	intracellular,cytoplasm,cytosolic
	intracellular,nucleus,nucleoplasm

basic FUNCTION	receptor for membrane-bound ligands Jagged1, Jagged2, Delta-like1, Delta-like3 and Delta-like4
	mediating cell-cell interactions that specify cell fate during development, and the changes of the endometrium during menstrual cycle and development of endometrial cancers
	involved in endothelial-pericyte interactions
	possible contribution of Notch4 signalling to the development of brain arteriovenous malformations (AVMs)
	role of NOTCH4 in the vasculature, and in fine-tuning the forming vascular plexus
	negative regulatory role for the PI3K-AKT pathway in NOTCH4 nuclear signaling
	NOTCH1 and NOTCH4 signaling pathways regulate endothelial cell homeostasis
	role of NOTCH4 signaling in promoting human megakaryopoiesis

CELLULAR PROCESS	cell life, differentiation
	nucleotide, transcription, regulation

PHYSIOLOGICAL PROCESS

development

PATHWAY

metabolism

signaling

signal transduction

AP-1-Notch4 pathway, may be crucial for transducing angiogenic signals and deregulated upon aberrant signal transduction in cancer

a component

protein constituent of transmembrane

INTERACTION

DNA

RNA

small molecule	other,
	Ca

protein	ligands
	interacting with TACC3
	antagonistic relationship between NOTCH4 and TP53, which is controlled by the MDM2-dependent ubiquitylation and degradation of the NOTCH receptor
	functional interaction of NOTCH4(ICD) and ELOC provides novel insight into regulation of NOTCH1 signaling in epithelial cell biology and disease
	IL1B regulates NOTCH1 and NOTCH4 activity in opposite directions, consistent with a selective targeting of NOTCH1 in inflamed endothelium
	NOTCH4, not NOTCH1, is the specific receptor for the DLL4/NOTCH-EFNB2 cascade
	NOTCH4 signaling controls EFNB2-induced endothelial progenitor cell dysfunction in preeclampsia
	NOTCH4 expression was negatively controlled by RUNX1 via a novel regulatory DNA element within the locus, and we examined its involvement in Megakaryocytes (MKs) generation

cell & other

REGULATION

activated by

delta (DLK1) jagged (JAG*)

induced by

MAML1, MAML2 and MAML3 which act as transcriptional coactivators for NOTCH4

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)

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral     --low   in endometrial cancer constitutional     --over   in proliferating hemangiomas tumoral     --low   in colorectal cancer (CRC), which could determine tumor proliferation, relapse, and prognosis

Susceptibility

schizophrenia (minor locus) alopecia areata(ALPCA) to rheumatoid arthritis to variation of characteristics of migraine

Variant & Polymorphism SNP	A>G 5 utr,(CTG)10 alleles (exon 1)
	variants in the NOTCH4 Gene influence the clinical features of migraine

Candidate gene
Marker	NOTCH4 mRNA level could be an independent prognostic factor for both disease-free and overall survival of colorectal cancer (CRC) patients
Therapy target

ANIMAL & CELL MODELS

Notch4 null mice exhibited slightly delayed vessel growth in the retina