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The NOTCH diagram was created by Rockland scientists to provide an overview of this important signaling pathway. The proteins are linked to the related Rockland antibody products.
To download a PDF version of the NOTCH Signaling Pathway, click here.
NOTCH Pathway Description:
The evolutionary highly conserved notch signaling pathway regulates cell-fate determination during development and maintains adult tissue homeostasis.
Notch signaling is mediated by proteolysis. Regulation of the amount and timing of the notch signal is managed by posttranslational modifications to ligands and receptors and their trafficking.
The Notch receptors (NOTCH, dark green) are single pass type I transmembrane heterodimer proteins. They encompass a functional extracellular truncation (NEXT), transmembrane (TM), and intracellular (NICD) domain. The Notch receptor is activated by binding to a ligand presented by a neighboring cell.
Maturation of Notch happens in the ER and Golgi. Protein fucosylation is essential for the functional receptor and occurs via the chaperone O-fut1 (O-Fut1, red triangle, ER). Different patterns of fucose on Notch changes the aptitude of specific ligands to activate Notch. Fucose extension is performed by Fringe (red triangle, Golgi). Upon proteolytic cleavage by Furin (red triangle, Golg) at site 1 (S1) Notch is transported to the cell surface.
Delta and Jagged (yellow) are the major classes of Notch ligands (yellow). They are type I transmembrane proteins and are ubiquitinated by Neur and Mib (E3 ubiquitin ligases, red), triggering Epsin (green) mediated endocytosis. Modification of the Notch ligands induces recycling of the ligand to the cell surface in a Rab11 (red triangle) dependent process. Fruitful receptor-ligand interactions depend on the glycosylation state of Notch. Ligand endocytosis is thought to produce partial or complete domain dissociation, thereby exposing Notch to cleavage at site S2 by ADAM metalloproteases (red). Upon cleavage the Notch extracellular domain is transendocytosed into the signal-sending cell (neighboring cell). The membrane-anchored NEXT fragment is recognized by Nicastrin (NCT, red triangle), which transfers NEXT to the active site of γ-secretase (red triangle). γ-secretase is an enzymatic complex composed of presenilin (PS), NCT, PEN2, and APH1. γ-secretase cleaves the Notch transmembrane domain sequentially starting near the cytosolic surface (sites S3 and S4) to release the Notch intracellulardomain (NICD) and Nβ peptides, respectively.
NICD enters the nucleus to facilitate transcription. NICD binding to the DNA-binding protein CSL triggers an allosteric change that facilitates displacement of transcriptional repressors. The NICD/CSL interface is recognized by Mastermind (MAM, light blue), and this complex recruits Co-activators (Co-A, yellow) like histone acetylases (HATs), to assemble an active transcription complex on target promoters. When NICD is not present, CSL associates with ubiquitous Co-repressor proteins (Co-R, orange) and histone deacetylases (HDACs) to block transcription of target genes.
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