NOTCH4 Gene: Structure, Function, and Clinical Significance
A comprehensive overview of the NOTCH4 gene, its protein product, associated diseases, expression patterns, and mutations.
Gene Information Card
| Symbol | NOTCH4 |
|---|---|
| Full Name | Notch Receptor 4 |
| Gene Type | protein coding |
| Chromosomal Location | 6p21.32 |
| NCBI Gene ID | 4855 ncbi.nlm.nih.gov/gene/4855 |
| Ensembl ID | ENSG00000204301 |
| UniProt ID | Q99466 |
| OMIM ID | 600956 |
| HGNC ID | 7884 |
| Aliases | INT3, hNotch4, Notch homolog 4 |
Description
NOTCH4 (Notch Receptor 4) is a protein-coding gene that encodes a member of the Notch receptor family. These are single-pass transmembrane proteins that play a critical role in cell fate determination, proliferation, differentiation, and apoptosis. The encoded protein is a receptor for membrane-bound ligands, such as Jagged and Delta-like proteins. Upon ligand binding, the receptor undergoes proteolytic cleavage, releasing the Notch intracellular domain (NICD), which translocates to the nucleus and regulates transcription of target genes. NOTCH4 is particularly important in vascular development, endothelial cell function, and immune system regulation. It is located within the major histocompatibility complex (MHC) region on chromosome 6, a region associated with many immune-related diseases.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Schizophrenia | Genetic association studies have linked NOTCH4 variants to schizophrenia risk. The exact mechanism is unclear, but it may involve altered neurodevelopment and synaptic plasticity due to disrupted Notch signaling. | Case-control studies and meta-analyses (e.g., Wei and Hemmings, 2000; Wang et al., 2016). |
| Multiple Sclerosis (MS) | NOTCH4 is located in the MHC region, which is strongly associated with MS. Variants in NOTCH4 may influence immune cell function and contribute to the autoimmune response in MS. | Genome-wide association studies (GWAS) and HLA region fine-mapping studies. |
| Cancer (e.g., Breast, Lung, Colorectal) | Dysregulation of NOTCH4 signaling can promote tumorigenesis. Aberrant expression or mutations may lead to increased cell proliferation, survival, and metastasis in various cancers. | Expression studies and functional assays in cancer cell lines and tumor samples (e.g., Yao et al., 2017; Zhang et al., 2019). |
| Systemic Sclerosis (SSc) | NOTCH4 has been identified as a susceptibility gene for SSc, an autoimmune disease characterized by fibrosis. It may contribute to aberrant endothelial cell activation and fibrosis. | GWAS and follow-up studies in SSc cohorts. |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Heart | 5.4 | Low |
| Lung | 4.1 | Low |
| Placenta | 3.2 | Low |
| Kidney | 2.8 | Low |
| Brain | 1.5 | Not detected |
| Liver | 0.8 | Not detected |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HUVEC (Endothelial) | 12.5 | High expression in endothelial cells. |
| MCF7 (Breast Cancer) | 6.2 | Moderate expression. |
| A549 (Lung Cancer) | 4.8 | Moderate expression. |
| K562 (Leukemia) | 1.1 | Low expression. |
| HeLa (Cervical Cancer) | 0.9 | Low expression. |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| rs2071286 (Intronic) | SNP | ~20% in some populations | Associated with altered NOTCH4 expression and increased risk for schizophrenia in some studies. |
| rs3134942 (Intronic) | SNP | ~15% in some populations | Associated with multiple sclerosis susceptibility. |
| Missense variants (e.g., p.Pro1705Leu) | Missense | Rare | Potential functional impact on protein structure and signaling, but clinical significance is often uncertain. |
| Copy Number Variations (CNVs) | CNV | Rare | Deletions or duplications in the 6p21.32 region can affect NOTCH4 and other genes, potentially contributing to neurodevelopmental disorders. |
Mutation functional classification
Loss of Function (LOF)
Loss-of-function mutations in NOTCH4 are rare and not well-characterized. They are predicted to reduce or abolish Notch signaling, potentially leading to defects in vascular development and immune regulation. No specific disease is definitively linked to complete loss of NOTCH4 function in humans.
Gain of Function (GOF)
Gain-of-function mutations, such as chromosomal translocations that produce a truncated, constitutively active intracellular domain (similar to the INT3 oncogene), can drive uncontrolled cell proliferation and have been implicated in tumorigenesis, particularly in breast cancer models.
Dominant Negative (DN)
Dominant-negative mutations are not commonly described for NOTCH4. However, mutations that produce a truncated receptor lacking the intracellular domain could potentially interfere with signaling from the wild-type receptor, acting in a dominant-negative manner.
View complete mutation data：
Gene Ontology (GO)
| • Notch binding | • calcium ion binding |
| • receptor activity | • cell fate determination |
| • cell differentiation | • negative regulation of transcription by RNA polymerase II |
| • positive regulation of transcription by RNA polymerase II | • angiogenesis |
| • vasculogenesis | • Notch signaling pathway |
| • plasma membrane | • integral component of plasma membrane |
Pathways
• Notch Signaling Pathway
• Developmental Biology
• Signaling by NOTCH4
Protein Summary
The NOTCH4 protein is a 2003-amino-acid single-pass type I transmembrane protein. It is synthesized as a precursor that is cleaved in the trans-Golgi network by a furin-like convertase to form a heterodimer consisting of a large extracellular domain (NECD) and a smaller transmembrane domain (NTMD). The NECD contains 29-36 tandem epidermal growth factor (EGF)-like repeats, which are involved in ligand binding, and three LIN-12/Notch repeats (LNR) that prevent ligand-independent activation. The NTMD contains a transmembrane domain and an intracellular domain (NICD) with a RAM domain, seven ankyrin repeats, and a PEST sequence. Ligand binding triggers two successive proteolytic cleavages (by ADAM metalloproteases and the gamma-secretase complex), releasing the NICD. The NICD then translocates to the nucleus, where it forms a complex with the transcription factor CSL (CBF1/RBP-Jκ) and co-activators to regulate the expression of target genes like HES and HEY.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| NOTCH4 Knockout HEK293 Cell Line | EDJ-KQ439 | Human | 4855 | Details Get a Quote |
| NOTCH4 Knockout HeLa Cell Line | EDJ-KQ54008 | Human | 4855 | Details Get a Quote |
| NOTCH4 Knockout A-549 Cell Line | EDJ-KQ62501 | Human | 4855 | Details Get a Quote |
| NOTCH4 Knockout HCT 116 Cell Line | EDJ-KQ70967 | Human | 4855 | Details Get a Quote |
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