Abstract
The evolutionary conserved Notch signaling pathway is involved in cell fate specification and mediated by molecular interactions between the Notch receptors and the Notch ligands, Delta, Serrate, and Jagged. In this report, we demonstrate that like Notch, Delta1 and Jagged2 are subject to presenilin (PS)-dependent, intramembranous "gamma-secretase" processing, resulting in the production of soluble intracellular derivatives. Moreover, and paralleling the observation that expression of familial Alzheimer's disease-linked mutant PS1 compromises production of Notch S3/NICD, we show that the PS-dependent production of Delta1 cytoplasmic derivatives are also reduced in cells expressing mutant PS1. These studies led us to conclude that a similar molecular apparatus is responsible for intramembranous processing of Notch and it's ligands. To assess the potential role of the cytoplasmic derivative on nuclear transcriptional events, we expressed a Delta1-Gal4VP16 chimera and demonstrated marked transcriptional stimulation of a luciferase-based reporter. Our findings offer the proposal that Delta1 and Jagged2 play dual roles as activators of Notch receptor signaling and as receptors that mediate nuclear signaling events via gamma-secretase-generated cytoplasmic domains.
Highlights
The evolutionary conserved Notch signaling pathway is involved in cell fate specification and mediated by molecular interactions between the Notch receptors and the Notch ligands, Delta, Serrate, and Jagged
We show that a plasma membrane-resident ϳ40 kDa carboxyl-terminal fragment (CTF) that is presumably generated by a Kuzbanian-like activity serves as substrate for ␥-secretase, resulting in the liberation of a cytosolic, ϳ38-kDa CTF
Taken together with the curious observation that expression of familial Alzheimer’s disease (FAD)-linked PS1 variants leads to reduced processing at the Notch S3 and amyloid precursor protein (APP) ⑀ sites, our findings that production of the D-CTF2 derived from Delta1 is reduced by expression of mutant PS1 argues that a similar, if not identical, molecular apparatus is involved in substrate recognition and intramembranous processing of these functionally divergent membrane proteins
Summary
We demonstrate that like Notch, Delta and Jagged are subject to presenilin (PS)-dependent, intramembranous “␥-secretase” processing, resulting in the production of soluble intracellular derivatives. Paralleling the observation that expression of familial Alzheimer’s disease-linked mutant PS1 compromises production of Notch S3/NICD, we show that the PS-dependent production of Delta cytoplasmic derivatives are reduced in cells expressing mutant PS1 These studies led us to conclude that a similar molecular apparatus is responsible for intramembranous processing of Notch and it’s ligands. The precise role of Kuzbanian-dependent proteolytic processing of Delta is not fully understood, but recent studies suggest that this event down-regulates Delta-mediated Notch signaling (21) In this regard, ectodomain shedding of Jagged has not been described to date. Presenilin-dependent Cleavage of Notch Ligands responsible for intramembranous cleavage of Notch and it’s ligand, Delta
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