The Canonical Notch Signaling Pathway: Unfolding the Activation Mechanism

By Raphael Kopan, M. Ilagan. Cell, 2009

3,591 citations recorded by the source corpus.

Notch signaling regulates many aspects of metazoan development and tissue renewal. Accordingly, misregulation or loss of Notch signaling underlies multiple human disorders, from developmental syndromes to adult onset diseases and cancer. Notch receptor activation is irreversible as it involves proteolysis-mediated release of the Notch intracellular domain, translocation to the nucleus, and association with a DNA-bound protein. Even though each Notch molecule signals only once without amplification by secondary messenger cascades, Notch signaling is remarkably robust in most tissues. In this review, we highlight the recent studies that reveal new molecular details involved in regulating ligand-mediated activation, receptor proteolysis and target selection.

Subfields: Global and Planetary Change, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/825619b4fedbf4cc3141a4b08e9a19d73ab53748

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Citations in the corpus

PI5P4Kγ functions in DTX1-mediated Notch signaling (2018, background): “In mammals, signaling is initiated when Notch binds to one of several ligands (Delta-like 1, 3, and 4 or Jagged 1 and 2) expressed on the surface of neighboring cells (2).”
Differentiation of Effector CD4 T Cell Populations (2010, neutral): “NICD translocates into the nucleus, where it displaces a corepressor complex from CBF1/Su(H)/Lag-1 (CSL, also known as RBP-J) and recruits a coactivator complex, leading to Notch-dependent gene transcription (225).”
Master Transcription Factors Determine Cell-Type-Specific Responses to TGF-β Signaling (2011, positive): “It is notable that any one signaling pathway can direct very different responses in different cell types (Clevers, 2006; Guasconi and Puri, 2009; Kopan and Ilagan, 2009; Massagué et al., 2005; O’Shea et al., 2002).”
Neurodegenerative disease and adult neurogenesis (2011, background): “…in neurogenic areas such as the dentate gyrus (DG) and subventricular zone (SVZ) ⁄ olfactory bulb (OB) system parallel the early or premotor symptoms that are seen in the early stages of neurodegenerative disease, such as depression, anxiety or olfactory dysfunction (Simuni & Sethi, 2008).”
Hydrogen peroxide sensing, signaling and regulation of transcription factors (2014, background): “16 families of ligands, Jagged (Jagged1 and Jagged2) and Delta-like (Dll1, Dll3 and Dll4) [110].”
Notch signalling in solid tumours: a little bit of everything but not all the time (2011, background): “The S3 cleavage results in the release of the active NICD from the plasma membrane and its subsequent translocation into thenucleu”
Much More than M1 and M2 Macrophages, There are also CD169+ and TCR+ Macrophages (2015, methodology): “NotchRBP-J and TLR-4 pathways synergistically induce expression of IRF8 protein that plays a role in activation of M1 macrophage polarization, autophagy, and clearance of L. monocytogenes (89, 90).”
Engineering Customized Cell Sensing and Response Behaviors Using Synthetic Notch Receptors (2016, background): “…of the Notch receptor with its ligand—Delta family proteins that are presented on the surface of partner cells— leads to intramembrane proteolysis (sequential proteolysis by a disintegrin and metalloproteinase (ADAM) metalloprotease and the gamma-secretase complex; Kopan and Ilagan, 2009).”
Balancing forces: architectural control of mechanotransduction (2011, neutral): “Given that the ligand-binding domain of Notch is in close proximity to the protective Lin12–Notch repeat (LNR) modules, this coincides with data showing that ligand-binding confers sufficient force to peel away the LNR modules, providing the 'lift' that exposes the metalloprotease cleavage site wher”