History and Nomenclature: The notch1 gene, previously referred to as TAN1, was first described in 1917 by American giant of genetics and embryology Thomas Hunt Morgan in a strain of the fruit fly Drosophila melanogaster with "notches" apparent in their wings. Molecular study of the notch1 gene product and sequencing was carried out in the 1980s.
The following discussion will refer to the notch1 gene as "notch1" and the functional gene product (protein) as "NOTCH1".

Notch1 encompasses 51,418 bp of DNA on chromosome 9 (9q34.3) between 138,508,717 and 138,508,135 bp from pter.

The notch1 RNA transcript contains 34 exons and is 9,371 bp in length.

The notch1 gene product NOTCH1 (2,556 amino acids; 272,500 Da) consists of a large extracellular unit which associates in a calcium-dependent, non-covalent interaction with a second unit consisting of the following: a small extracellular region, a single transmembrane spanning region, and a small intracellular region.
The NOTCH1 extracellular domain is composed primarily of 36 small cysteine knot motifs called EGF-like repeats. Each EGF-like repeat is approximately 40 amino acids, and its structure is defined largely by six conserved cysteine residues that form three conserved disulfide bonds. This feature is critical in ligand binding. The extracellular domain also contains three cysteine-rich Notch/Lin12 (LN) repeats required for the blockage of signaling in the absence of ligand.
The NOTCH1 intracellular domain (NICD) contains a RAM23 domain, six ankyrin/cdc10 repeats involved in protein-protein interactions, two nuclear localization signals (N1 and N2), a transcriptional activation domain (TAD), and a PEST (proline-, glutamic acid-, serine-, and threonine- rich) sequence that negatively regulates protein stability. NOTCH1 undergoes an initial proteolytic cleavage by furin (PACE1) in the Golgi during trafficking to the cell surface.
NOTCH1 is subject to several important post-translational modifications. An O-glucose sugar may be added between the first and second conserved cysteine, and an O-fucose may be added between the second and third conserved cysteine. These sugars are added by an as yet unidentified O-glucosyltransferase, and GDP-fucose protein O-fucosyltransferase 1 (POFUT1) respectively. The addition of O-fucose by POFUT1 is crucial for NOTCH1 function, and without its addition NOTCH1 proteins fail to function properly. As yet, the manner in which the glycosylation of NOTCH1 affects function is not completely understood.
The O-glucose on NOTCH1 can be further elongated to a trisaccharide with the addition of two xylose sugars by xylosyltransferases, and the O-fucose can be elongated to a tetrasaccharide by the ordered addition of an N-acetylglucosamine (GlcNAc) sugar by an N-Acetylglucosaminyltransferase called Fringe, the addition of a galactose by a galactosyltransferase, and the addition of a sialic acid by a sialyltransferase.
The NOTCH1 ligands are single-pass transmembrane proteins and are members of the DSL (Delta/Serrate/LAG-2) family of proteins. In Drosophila there are two involved ligands named Delta and Serrate. In mammals, the corresponding names are Delta-like and Jagged. In mammals there are multiple Delta-like and Jagged ligands, as well as probably a variety of other ligands, such as F3/contactin.

NOTCH1: Cell membrane. Single pass type I membrane protein.
NICD: Internal surface of cell membrane translocating to the nucleus upon ligand binding.

The NOTCH1 cell signaling mechanism is conserved in most multicellular organisms including all metazoans (and thus vertebrates). NOTCH1 functions as a receptor for membrane-bound ligands Jagged1, Jagged2, and Delta1 in regulation of cell-fate determination.
Once the NOTCH1 extracellular domain interacts with a ligand, an ADAM-family metalloprotease called TACE (Tumor Necrosis Factor Alpha Converting Enzyme) cleaves the NOTCH1 protein just outside the membrane. Consequently, the extracellular portion of NOTCH1 is released and continues to interact with the ligand. The ligand plus the NOTCH1 extracellular domain is then endocytosed by the ligand-expressing cell. There may be signaling effects in the ligand-expressing cell after endocytosis, however currently these effects are not well understood.
Upon ligand activation and cleavage via gamma secretase, the released notch intracellular domain (NICD) forms a transcriptional activator complex via its RAM23 domain with the transcription factor CSL (CBF1 in humans, RBP-JK in mice, Suppressor of Hairless in Drosophila, LAG in Caenorhabditis elegans). In the absence of NOTCH1, CSL proteins bind to promoters of target genes and recruit histone deacetylases and corepressors (CoR) that inhibit transcription of these genes. Among known corepressor molecules are SMRT/NcoR and SHARP/MINT/SPEN. The NICD/CSL interaction converts CSL from a transcriptional repressor into a transcriptional activator (CBF1 binding complex in humans) by displacing the corepressor complex and recruiting coactivators such as Mastermind-Like 1 (MAM) and histone acetyltransferase. Several other proteins are known to affect NOTCH1 signaling, including the RING-domain E3 ubiquitin ligase deltex and the phosphotyrosine binding domain (PTB)-containing proteins numb and numblike, which act as context-dependent negative or positive Notch1 regulators.
In mammals there are three Fringe N-acetylglucosamine (GlcNAc)-transferase enzymes named Lunatic Fringe, Manic Fringe, and Radical Fringe, which are responsible for something called the "Fringe Effect" on NOTCH1 signaling. If Fringe adds a GlcNAc to the O-fucose sugar, then addition of a galactose and sialic acid will occur. In the presence of this tetrasaccharide, NOTCH1 signals strongly when it interacts with the Delta ligand, but is inhibited when interacting with the Jagged ligand. The means by which this addition of sugar inhibits signaling through one ligand, and potentiates signaling through another is not clearly understood.
Known target genes of NOTCH1 signaling include: members of the basic helix-loop-helix (bHLH) hairy/enhancer of split (Hes) family, the related HRT/Herp (Hes-related repressor protein) transcription factor family, the cell cycle regulator p21, the Notch pathway element Notch-regulated ankyrin repeat protein (Nrarp), deltex1, and the pre-T cell receptor-alpha gene. The NOTCH1 signaling pathway is important for cell-cell communication, involving gene regulation mechanisms that control multiple cell differentiation processes during embryonic and adult life. NOTCH1 signaling is known to play a role in the following processes:

Neuronal function and development: Via lateral inhibition, NOTCH1 in the embryo generates molecular differences between adjacent cells. In the central nervous system, NOTCH1 activity maintains the neural progenitor state and inhibits differentiation. During gliogenesis, NOTCH1 has an instructive role, directly promoting the differentiation of different glial subtypes. More detailed analyses have also revealed that Notch regulates progenitor pool diversification and neuronal maturation. New data suggests that NOTCH1 activity has a role in neuronal function of the adult brain.

Modulating arterial endothelial fate and angiogenesis: Expression of NOTCH1 and its ligand in vascular endothelium and defects in vascular phenotypes of targeted mutants in the NOTCH1 pathway suggest a critical role for NOTCH1 signaling in vasculogenesis and angiogenesis. Vascular endothelial growth factor (VEGF) can induce gene expression of NOTCH1 and its ligand, Delta-like 4 (Dll4), in human arterial endothelial cells. The VEGF-induced specific signaling is mediated through VEGF receptors 1 and 2 (FLT1/VEGFR1 and KDR/VEGFR2) and is transmitted via the phosphatidylinositol 3-kinase/Akt pathway. Constitutive activation of NOTCH1 signaling stabilizes network formation of endothelial cells on Matrigel and enhances formation of vessel-like structures in a three-dimensional angiogenesis model. Blocking Notch signaling can inhibit network formation.

Regulating cell communication events between endocardium and myocardium during ventricular chamber formation: Ventricular chamber morphogenesis is critical for proper cardiac function and embryonic viability and depends on cellular interactions between the endocardium and myocardium. Ventricular Notch1 activity is highest at presumptive trabecular endocardium. RBPJk and Notch1 mutants show impaired trabeculation and marker expression, weakened EphrinB2, NRG1, and BMP10 expression and signaling, and decreased myocardial proliferation. Functional and molecular analyses have shown that Notch1 inhibition prevents EphrinB2 expression, and that EphrinB2 is a direct Notch1 target acting upstream of NRG1 in the ventricles.

Cell lineage specification of both endocrine and exocrine pancreas: Multiple cell types of the pancreas appear asynchronously during embryogenesis, which requires that pancreatic progenitor cell potential changes over time. Loss-of-function studies have shown that NOTCH1 signaling modulates the differentiation of these progenitors. It has been demonstrated that misexpression of activated NOTCH1 in Pdx1-expressing progenitor cells prevents differentiation of both exocrine and endocrine lineages. Progenitors remained trapped in an undifferentiated state even if notch1 activation occurred long after the pancreas was specified. Endocrine differentiation is associated with escape from this activity, as Ngn3-expressing endocrine precursors were susceptible to notch1 inhibition, whereas fully differentiated endocrine cells were resistant.

Notch1-dependent bone morphogenic protein (BMP) signaling: NOTCH1 enhances BMP2-induced commitment to the osteoblastic lineage during bone development.

Regulation of cell-fate decision in the mammary gland: It has been suggested that Notch1 signaling plays a critical role in normal human mammary development by acting on both stem cells and progenitor cells, affecting self-renewal and lineage-specific differentiation. Notch signaling can act on mammary stem cells to promote self renewal and on early progenitor cells to promote their proliferation, as demonstrated in one study by a 10-fold increase in secondary mammosphere formation upon addition of a Notch activating DSL peptide. The same study showed that in addition to acting on stem cells, Notch signaling is also able to act on multipotent progenitor cells, facilitating myoepithelial lineage-specific commitment and proliferation. Stimulation of this pathway also promotes branching morphogenesis in three-dimensional Matrigel cultures. Notch1 signaling has no such effect on fully committed, differentiated, mammary epithelial cells.

Cytoskeletal component formation: It has been suggested that NOTCH1 signaling, via some non-nuclear mechanisms, controls the actin cytoskeleton through the tyrosine kinase Abl.

Normal lymphocyte function: NOTCH1 signaling is involved in the maturation of both CD4+ and CD8+ cells in the thymus. In altered form, NOTCH1 may contribute to transformation or progression in some T-cell neoplasms. NOTCH1 may be important for follicular differentiation and possibly cell fate selection within the follicle.

Regulation of fate choices in the inner ear.

Induction of left-right asymmetry.

Regulation of limb bud development.

Regulation of kidney development.

Notch1 mutant mice display defects in somite morphology.
Mutations in the NOTCH1 ligand affect the development of many organs, including that of the liver, skeleton, heart and eye.
Mutations in the NOTCH1 ligand DLL3 result in rib fusions and trunk dwarfism.
Notch1 mutations play a dual role in carcinogenesis as either a tumor suppressor or an oncogene. The role of NOTCH1 within and between cells depends on signal strength, timing, cell type, and context.
Notch1 mutant cells infected with a retrovirus transducing the ras oncogene and injected subcutaneously into nude mice form aggressive squamous cell carcinoma (SCC), whereas wild-type cells do not. Loss of notch1 activity may thus cooperate with ras oncogene transformation in keratinocyte tumor development.
In humans, aberrant NOTCH1 expression has been identified as a causative factor in the development of T-cell acute lymphoblastic leukemia and lymphoma (T-ALL). Recurrent t(7;9) translocation that involves the extracellular heterodimerization domain and/or the C-terminal PEST domain of NOTCH1 is associated with T-ALL. The t (7; 9) translocation in T-ALL patients is characterized by juxtaposition of the 3 portion of the human notch1 gene with the T cell receptor beta (TCRB) locus. This leads to expression of truncated NOTCH1 transcripts and consequent production of dominant active, ligand-independent forms of the NOTCH1 receptor, causing T-ALL. Less than 1% of human T-ALLs exhibit the t(7;9) translocation, however, activating mutations in notch1 independent of t(7;9) have been identified in more than 50% of human T-ALL.
Cells that are mutant for notch1 form skin and corneal tumors in mice, indicating that Notch1 signaling suppresses tumorigenesis in these instances.
Notch1 mutations cause an early developmental defect in the aortic valve and a later derepression of calcium deposition that causes progressive aortic valve disease.
Many other human and murine cancers, including certain neuroblastomas, mammary, skin, cervical and prostate cancers are correlated with alterations in expression of Notch proteins and/or ligands. These cases await better characterization, but these observations suggest broad roles for Notch dysfunction in a wide range of neoplasms.
Based on analysis of neuroendocrine tumors and cell lines, NOTCH1 appears to be absent in this type of cancer. Expression of ectopic NOTCH1 in human medullary thyroid carcinoma and carcinoid tumor cell lines resulted in suppression of cancer cell growth. These data suggest that in neuroendocrine malignancies notch1 may act as a tumor suppressor.