NOTCH4 notch receptor 4 [Homo sapiens (human)] - Gene

Summary

Official Symbol: NOTCH4provided by HGNC
Official Full Name: notch receptor 4provided by HGNC
Primary source: HGNC:HGNC:7884
See related: Ensembl:ENSG00000204301 MIM:164951; AllianceGenome:HGNC:7884
Gene type: protein coding
RefSeq status: REVIEWED
Organism: Homo sapiens
Lineage: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
Also known as: INT3
Summary: 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. [provided by RefSeq, Jan 2016]
Expression: Broad expression in fat (RPKM 20.5), lung (RPKM 16.6) and 21 other tissues See more
Orthologs: mouse all
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Genomic context

Location:: 6p21.32

Exon count:: 31

Annotation release	Status	Assembly	Chr	Location
RS_2024_08	current	GRCh38.p14 (GCF_000001405.40)	6	NC_000006.12 (32194843..32224067, complement)
RS_2024_08	current	T2T-CHM13v2.0 (GCF_009914755.1)	6	NC_060930.1 (32048032..32077265, complement)
RS_2024_09	previous assembly	GRCh37.p13 (GCF_000001405.25)	6	NC_000006.11 (32162620..32191844, complement)

Chromosome 6 - NC_000006.12 Genomic Context describing neighboring genes

Genomic regions, transcripts, and products

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Go to reference sequence details

Genomic Sequence:

Go to nucleotide: Graphics FASTA GenBank

Expression

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See details

Project title: HPA RNA-seq normal tissues HPA RNA-seq normal tissues
Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
BioProject: PRJEB4337
Publication: PMID 24309898
Analysis date: Wed Apr 4 07:08:55 2018

Bibliography

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GeneRIFs: Gene References Into Functions

What's a GeneRIF?

Inhibition of NOTCH4 sensitizes FLT3/ITD acute myeloid leukemia cells to FLT3 tyrosine kinase inhibition.
Title: Inhibition of NOTCH4 sensitizes FLT3/ITD acute myeloid leukemia cells to FLT3 tyrosine kinase inhibition.
NOTCH4 potentiates the IL-13 induced genetic program in M2 alternative macrophages through the AP1 and IRF4-JMJD3 axis.
Title: NOTCH4 potentiates the IL-13 induced genetic program in M2 alternative macrophages through the AP1 and IRF4-JMJD3 axis.
Association of NOTCH4 and ACHE gene polymorphism in Alzheimer's disease of Gujarat cohort.
Title: Association of NOTCH4 and ACHE gene polymorphism in Alzheimer's disease of Gujarat cohort.
NOTCH4[DeltaL12_16] sensitizes lung adenocarcinomas to EGFR-TKIs through transcriptional down-regulation of HES1.
Title: NOTCH4(ΔL12_16) sensitizes lung adenocarcinomas to EGFR-TKIs through transcriptional down-regulation of HES1.
NOTCH4 Single-Nucleotide Polymorphism Is Associated with Brain Arteriovenous Malformation in a Chinese Han Population.
Title: NOTCH4 Single-Nucleotide Polymorphism Is Associated with Brain Arteriovenous Malformation in a Chinese Han Population.
Polymorphisms and gene expression of Notch4 in pulmonary tuberculosis.
Title: Polymorphisms and gene expression of Notch4 in pulmonary tuberculosis.
JAG1-NOTCH4 mechanosensing drives atherosclerosis.
Title: JAG1-NOTCH4 mechanosensing drives atherosclerosis.
NOTCH4 mutation as predictive biomarker for immunotherapy benefits in NRAS wildtype melanoma.
Title: NOTCH4 mutation as predictive biomarker for immunotherapy benefits in NRAS wildtype melanoma.
Expression of NOTCH1, NOTCH4, HLA-DMA and HLA-DRA is synergistically associated with T cell exclusion, immune checkpoint blockade efficacy and recurrence risk in ER-negative breast cancer.
Title: Expression of NOTCH1, NOTCH4, HLA-DMA and HLA-DRA is synergistically associated with T cell exclusion, immune checkpoint blockade efficacy and recurrence risk in ER-negative breast cancer.
Convergent lines of evidence support NOTCH4 as a schizophrenia risk gene.
Title: Convergent lines of evidence support NOTCH4 as a schizophrenia risk gene.

Submit: New GeneRIF Correction See all GeneRIFs (129)

Phenotypes

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Find tests for this gene in the NIH Genetic Testing Registry (GTR)

Review eQTL and phenotype association data in this region using PheGenI

EBI GWAS Catalog

Description
A comprehensive family-based replication study of schizophrenia genes. EBI GWAS Catalog EBI GWAS CatalogPubMed
A genome-wide association study identifies 2 susceptibility Loci for Crohn's disease in a Japanese population. EBI GWAS Catalog EBI GWAS CatalogPubMed
A genome-wide integrative genomic study localizes genetic factors influencing antibodies against Epstein-Barr virus nuclear antigen 1 (EBNA-1). EBI GWAS Catalog EBI GWAS CatalogPubMed
Common genetic variation and the control of HIV-1 in humans. EBI GWAS Catalog EBI GWAS CatalogPubMed
Common variants conferring risk of schizophrenia. EBI GWAS Catalog EBI GWAS CatalogPubMed
Differential genetic associations for systemic lupus erythematosus based on anti-dsDNA autoantibody production. EBI GWAS Catalog EBI GWAS CatalogPubMed
Genome-wide and gene-centric analyses of circulating myeloperoxidase levels in the charge and care consortia. EBI GWAS Catalog EBI GWAS CatalogPubMed
Genome-wide association scan in north Indians reveals three novel HLA-independent risk loci for ulcerative colitis. EBI GWAS Catalog EBI GWAS CatalogPubMed
Genome-wide association study for serum complement C3 and C4 levels in healthy Chinese subjects. EBI GWAS Catalog EBI GWAS CatalogPubMed
Genome-wide association study identifies multiple susceptibility loci for pulmonary fibrosis. EBI GWAS Catalog EBI GWAS CatalogPubMed
Genome-wide association study identifies three new susceptibility loci for adult asthma in the Japanese population. EBI GWAS Catalog EBI GWAS CatalogPubMed
Genome-wide association study of age-related macular degeneration identifies associated variants in the TNXB-FKBPL-NOTCH4 region of chromosome 6p21.3. EBI GWAS Catalog EBI GWAS CatalogPubMed
Genome-wide association study of hepatitis C virus- and cryoglobulin-related vasculitis. EBI GWAS Catalog EBI GWAS CatalogPubMed
Genome-wide genetic and transcriptomic investigation of variation in antibody response to dietary antigens. EBI GWAS Catalog EBI GWAS CatalogPubMed
Identification of 23 new prostate cancer susceptibility loci using the iCOGS custom genotyping array. EBI GWAS Catalog EBI GWAS CatalogPubMed
Identification of novel genetic markers associated with clinical phenotypes of systemic sclerosis through a genome-wide association strategy. EBI GWAS Catalog EBI GWAS CatalogPubMed
Novel genetic loci identified for the pathophysiology of childhood obesity in the Hispanic population. EBI GWAS Catalog EBI GWAS CatalogPubMed

Variation

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See variants in ClinVar

See studies and variants in dbVar

See Variation Viewer (GRCh37.p13)

See Variation Viewer (GRCh38)

Interactions

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Products	Interactant	Other Gene	Complex	Source	Pubs	Description

General gene information

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Markers

WI-12121 (e-PCR)
- UniSTS:81412

SHGC-145102 (e-PCR)
- UniSTS:184357

PMC140667P2 (e-PCR)
- UniSTS:270957

D15S1477 (e-PCR)
- UniSTS:474482

D6S1014 (e-PCR)
- UniSTS:54644

AF021125 (e-PCR)
- UniSTS:12170

AF021123 (e-PCR)
- UniSTS:79801

CTG-NotCH4 (e-PCR)
- UniSTS:239059

D6S1014 (e-PCR)
- UniSTS:256725

Gene Ontology Provided by GOA

Function	Evidence Code	Pubs
enables DNA-binding transcription activator activity, RNA polymerase II-specific	IDA Inferred from Direct Assay more info	PubMed
enables Notch binding	IBA Inferred from Biological aspect of Ancestor more info
enables calcium ion binding	TAS Traceable Author Statement more info	PubMed
enables cis-regulatory region sequence-specific DNA binding	IDA Inferred from Direct Assay more info	PubMed
enables protein binding	IPI Inferred from Physical Interaction more info	PubMed
enables signaling receptor activity	TAS Traceable Author Statement more info	PubMed

Process	Evidence Code	Pubs
involved_in branching involved in blood vessel morphogenesis	ISS Inferred from Sequence or Structural Similarity more info
involved_in cell differentiation	NAS Non-traceable Author Statement more info	PubMed
involved_in cell fate determination	TAS Traceable Author Statement more info	PubMed
involved_in epithelial to mesenchymal transition	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in hemopoiesis	TAS Traceable Author Statement more info	PubMed
involved_in mammary gland development	IDA Inferred from Direct Assay more info	PubMed
involved_in morphogenesis of a branching structure	ISS Inferred from Sequence or Structural Similarity more info
involved_in negative regulation of cell adhesion molecule production	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in negative regulation of cell differentiation	NAS Non-traceable Author Statement more info	PubMed
involved_in negative regulation of cell-cell adhesion mediated by cadherin	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in negative regulation of endothelial cell differentiation	ISS Inferred from Sequence or Structural Similarity more info
involved_in negative regulation of transcription by RNA polymerase II	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in positive regulation of DNA-templated transcription	TAS Traceable Author Statement more info	PubMed
involved_in positive regulation of smooth muscle cell differentiation	IDA Inferred from Direct Assay more info	PubMed
involved_in positive regulation of transcription by RNA polymerase II	IDA Inferred from Direct Assay more info	PubMed
involved_in positive regulation of transcription of Notch receptor target	TAS Traceable Author Statement more info	PubMed
involved_in vasculature development	ISS Inferred from Sequence or Structural Similarity more info
involved_in wound healing	IEA Inferred from Electronic Annotation more info

Component	Evidence Code	Pubs
located_in Golgi membrane	TAS Traceable Author Statement more info
located_in cell surface	IDA Inferred from Direct Assay more info	PubMed
located_in cytosol	TAS Traceable Author Statement more info
located_in endoplasmic reticulum membrane	TAS Traceable Author Statement more info
located_in extracellular region	TAS Traceable Author Statement more info
located_in nucleoplasm	TAS Traceable Author Statement more info
located_in nucleus	TAS Traceable Author Statement more info	PubMed
located_in plasma membrane	TAS Traceable Author Statement more info	PubMed

General protein information

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Preferred Names: neurogenic locus notch homolog protein 4

Names: Notch homolog 4; notch 4

NCBI Reference Sequences (RefSeq)

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RefSeqs maintained independently of Annotated Genomes

These reference sequences exist independently of genome builds. Explain

These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

Genomic

NG_028190.1 RefSeqGene

Range

5001..34225

Download

GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

NM_004557.4 → NP_004548.3 neurogenic locus notch homolog protein 4 preproprotein

See identical proteins and their annotated locations for NP_004548.3

Status: REVIEWED

Description

Transcript Variant: This variant (1) represents the longest transcript and encodes the protein.

Source sequence(s)

AL705928, BQ023880, D63395, U95299

Consensus CDS

CCDS34420.1

UniProtKB/Swiss-Prot

B0V183, B0V1X5, O00306, Q5SSY7, Q99458, Q99466, Q99940, Q9H3S8, Q9UII9, Q9UIJ0

UniProtKB/TrEMBL

A0A1U9X938, A0A1U9X983, A0A1U9X986, B2RTR4

Related

ENSP00000364163.3, ENST00000375023.3

Conserved Domains (8) summary

smart00004
Location:1207 → 1245

NL; Domain found in Notch and Lin-12

cd00054
Location:432 → 473

EGF_CA; Calcium-binding EGF-like domain, present in a large number of membrane-bound and extracellular (mostly animal) proteins. Many of these proteins require calcium for their biological function and calcium-binding sites have been found to be located at the ...

cd00204
Location:1661 → 1787

ANK; ankyrin repeats; ankyrin repeats mediate protein-protein interactions in very diverse families of proteins. The number of ANK repeats in a protein can range from 2 to over 20 (ankyrins, for example). ANK repeats may occur in combinations with other ...

sd00045
Location:1634 → 1664

ANK; ANK repeat [structural motif]

pfam00066
Location:1249 → 1285

Notch; LNR domain

pfam07684
Location:1380 → 1420

NODP; NOTCH protein

cl02419
Location:1165 → 1203

Notch; LNR domain

cl26072
Location:1753 → 1851

Ank_5; Ankyrin repeats (many copies)

RNA

NR_134949.2 RNA Sequence

Status: REVIEWED

Description

Transcript Variant: This variant (2) includes an alternate internal exon and lacks an alternate internal exon compared to variant 1. This variant is represented as non-coding because the use of the 5'-most expected translational start codon renders the transcript a candidate for nonsense-mediated mRNA decay (NMD).

Source sequence(s)

AK290785, AL662884, BC033869, BC144540, U95299
NR_134950.2 RNA Sequence

Status: REVIEWED

Description

Transcript Variant: This variant (3) lacks an alternate internal exon and uses an alternate splice site at an internal exon compared to variant 1. This variant is represented as non-coding because the use of the 5'-most expected translational start codon renders the transcript a candidate for nonsense-mediated mRNA decay (NMD).

Source sequence(s)

AK290785, BC033869, BC144540, BC144541, U95299