γ-Secretase Mediated Proteolysis: At the Cutting Edge of Notch Signaling

  • Ma. Xenia G. Ilagan
  • Dilip Chandu
  • Raphael Kopan
Part of the Proteases in Biology and Disease book series (PBAD, volume 6)


Notch proteins are evolutionary conserved transmembrane receptors used by metazoans to direct cell fate decisions, proliferation, differentiation and cell death at all stages of development, including self-renewing adult tissues. Notch signaling is a well-established example of a pathway that is mediated by Regulated Intramembrane Proteolysis (RIP). Upon binding of ligand, the Notch receptor undergoes successive proteolytic cleavages – an ectodomain shedding cleavage followed by intramembrane proteolysis by γ-secretase. This process releases the Notch intracellular domain, which translocates to the nucleus to activate its target genes. Deciphering the proteolytic mechanism for Notch activation relied on the convergence of previously independent fields of research, revealing that the Notch receptor resembled another Type I membrane protein, the amyloid-γ precursor protein, in that both are proteolytically cleaved within their transmembrane domains (TMDs) by the same protease, γ-secretase, whose catalytic center resided in the protein Presenilin. Intramembrane proteolysis has continued to emerge as an exciting research area in cell biology. Recent studies on γ-secretase function have begun to reveal the molecular details involved in ectodomain shedding and intramembrane cleavage events as well as the importance of endocytosis and endosomal sorting as key regulators of γ-secretase cleavage of Notch


Notch γ-secretase RIP ectodomain shedding endocytosis 


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Copyright information

© Springer 2007

Authors and Affiliations

  • Ma. Xenia G. Ilagan
    • 1
  • Dilip Chandu
    • 1
  • Raphael Kopan
    • 1
  1. 1.Department of Molecular Biology and PharmacologyWashington University School of MedicineSt. LouisUSA 63110

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