NOTCH1
GeneName
NOTCH1
Summary
NOTCH1, also known as p300 or Notch-1, is a 273kDa transmembrane receptor that plays a pivotal role in cell signalling and is involved in various developmental processes. It is expressed in multiple tissues, including the heart, nervous system, and various epithelial tissues. NOTCH1 is integral to the Notch signalling pathway, which regulates cell differentiation, proliferation, and apoptosis. The protein is localised to several cellular components, including the plasma membrane, nucleus, and adherens junctions, and is known for its ability to bind calcium ions and DNA, functioning as a transcriptional regulator and coactivator in response to specific signalling cues.
Importance
NOTCH1 is relevant to: - Developmental biology, particularly in organogenesis and cell fate determination, influencing processes such as heart and neural development. - Cancer research, as aberrant Notch signalling is implicated in various malignancies, making it a potential therapeutic target. - Regenerative medicine, given its role in tissue regeneration and repair mechanisms. - Cardiovascular research, due to its involvement in cardiac morphogenesis and endothelial cell differentiation.
Top Products
For researchers investigating NOTCH1, we highly recommend the top-selling recombinant antibody, Anti-Notch1 antibody [EP1238Y] (ab52627). This well-cited antibody has garnered 258 citations, reflecting its strong reputation in the field. It has been validated in knockout models and is suitable for a variety of applications, including Western blotting (WB), immunohistochemistry (IHC), immunocytochemistry (ICC), and flow cytometry (FC). This versatility makes it an excellent choice for those seeking reliable and consistent results in their NOTCH1 studies. The Anti-Notch1 antibody [E6] ELISA Kit (ab245686) is an excellent option for researchers looking to study Notch1 in their experiments.
Abcam Product Citation Summary
The data indicates that NOTCH1 is a significant target in various studies related to cell growth, motility, and signalling pathways, particularly in the context of cancer and tissue injury. The use of Abcam antibodies in both Western blotting and immunohistochemistry highlights the importance of NOTCH1 in understanding cellular mechanisms in different species, including mouse and rat models, as well as human cancer tissues.
Abcam Product Citation Table
Domain
Interaction with PSEN1 causes partial unwinding of the transmembrane helix, facilitating access to the scissile peptide bond.
Function
Functions as a receptor for membrane-bound ligands Jagged-1 (JAG1), Jagged-2 (JAG2) and Delta-1 (DLL1) to regulate cell-fate determination. Upon ligand activation through the released notch intracellular domain (NICD) it forms a transcriptional activator complex with RBPJ/RBPSUH and activates genes of the enhancer of split locus. Affects the implementation of differentiation, proliferation and apoptotic programs. Involved in angiogenesis; negatively regulates endothelial cell proliferation and migration and angiogenic sprouting. Involved in the maturation of both CD4(+) and CD8(+) cells in the thymus. Important for follicular differentiation and possibly cell fate selection within the follicle. During cerebellar development, functions as a receptor for neuronal DNER and is involved in the differentiation of Bergmann glia. Represses neuronal and myogenic differentiation. May play an essential role in postimplantation development, probably in some aspect of cell specification and/or differentiation. May be involved in mesoderm development, somite formation and neurogenesis. May enhance HIF1A function by sequestering HIF1AN away from HIF1A. Required for the THBS4 function in regulating protective astrogenesis from the subventricular zone (SVZ) niche after injury. Involved in determination of left/right symmetry by modulating the balance between motile and immotile (sensory) cilia at the left-right organiser (LRO).
Involvement in disease
Aortic valve disease 1
AOVD1
A common defect in the aortic valve in which two rather than three leaflets are present. It is often associated with aortic valve calcification, stenosis and insufficiency. In extreme cases, the blood flow may be so restricted that the left ventricle fails to grow, resulting in hypoplastic left heart syndrome.
None
The disease is caused by variants affecting the gene represented in this entry.
Adams-Oliver syndrome 5
AOS5
A form of Adams-Oliver syndrome, a disorder characterized by the congenital absence of skin (aplasia cutis congenita) in combination with transverse limb defects. Aplasia cutis congenita can be located anywhere on the body, but in the vast majority of the cases, it is present on the posterior parietal region where it is often associated with an underlying defect of the parietal bones. Limb abnormalities are typically limb truncation defects affecting the distal phalanges or entire digits (true ectrodactyly). Only rarely, metatarsals/metacarpals or more proximal limb structures are also affected. Apart from transverse limb defects, syndactyly, most commonly of second and third toes, can also be observed. The clinical features are highly variable and can also include cardiovascular malformations, brain abnormalities and vascular defects such as cutis marmorata and dilated scalp veins.
None
The disease is caused by variants affecting the gene represented in this entry.
Post-translational modifications
Synthesized in the endoplasmic reticulum as an inactive form which is proteolytically cleaved by a furin-like convertase in the trans-Golgi network before it reaches the plasma membrane to yield an active, ligand-accessible form (By similarity). Cleavage results in a C-terminal fragment N(TM) and a N-terminal fragment N(EC). Following ligand binding, it is cleaved by ADAM17 to yield a membrane-associated intermediate fragment called notch extracellular truncation (NEXT) (PubMed:24226769). Following endocytosis, this fragment is then cleaved by one of the catalytic subunits of gamma-secretase (PSEN1 or PSEN2), to release a Notch-derived peptide containing the intracellular domain (NICD) from the membrane (PubMed:30598546).
Phosphorylated.
O-glycosylated on the EGF-like domains (PubMed:24226769). O-glucosylated at Ser-435 by KDELC1 and KDELC2 (PubMed:30127001). Contains both O-linked fucose and O-linked glucose in the EGF-like domains 11, 12 and 13, which are interacting with the residues on DLL4 (By similarity). O-linked glycosylation by GALNT11 is involved in determination of left/right symmetry: glycosylation promotes activation of NOTCH1, possibly by promoting cleavage by ADAM17, modulating the balance between motile and immotile (sensory) cilia at the left-right organiser (LRO) (PubMed:24226769). MFNG-, RFNG- and LFNG-mediated modification of O-fucose residues at specific EGF-like domains results in inhibition of its activation by JAG1 and enhancement of its activation by DLL1 via an increased binding to DLL1 (By similarity).
Ubiquitinated. Undergoes 'Lys-29'-linked polyubiquitination by ITCH; promotes the lysosomal degradation of non-activated internalized NOTCH1 (PubMed:18628966, PubMed:23886940). Deubiquitination by USP12 is required for transport of internalized non-activated receptor from late endosomes to lysosomes for degradation (PubMed:22778262). Monoubiquitination at Lys-1759 is required for activation by gamma-secretase cleavage, it promotes interaction with AAK1, which stabilizes it. Deubiquitination by EIF3F is necessary for nuclear import of activated Notch (PubMed:24226769).
Hydroxylated at Asn-1955 by HIF1AN. Hydroxylated at Asn-2022 by HIF1AN (By similarity). Hydroxylation reduces affinity for HI1AN and may thus indirectly modulate negative regulation of NICD (By similarity).
Sequence Similarities
Belongs to the NOTCH family.
Tissue Specificity
In fetal tissues most abundant in spleen, brain stem and lung. Also present in most adult tissues where it is found mainly in lymphoid tissues.
Cellular localization
- Cell membrane
- Single-pass type I membrane protein
- Late endosome membrane
- Single-pass type I membrane protein
- Non-activated receptor is targeted for lysosomal degradation via the endosomal pathway; transport from late endosomes to lysosomes requires deuibiquitination by USP12.
- Notch 1 intracellular domain
- Nucleus
- Following proteolytical processing NICD is translocated to the nucleus. Nuclear location may require MEGF10.
Alternative names
TAN1, NOTCH1, Neurogenic locus notch homolog protein 1, Notch 1, hN1, Translocation-associated notch protein TAN-1
Database links
swissprot:P46531 omim:190198 entrezGene:4851
Other research areas
- Immuno-oncology
- Neuroscience