Nicastrin is required for gamma-secretase cleavage of the Drosophila Notch receptor.
Nicastrin is genetically linked to Notch/lin-12 signaling in C. elegans and is part of a large multiprotein complex along with Presenilin. Here we describe the isolation and characterization of Drosophila Nicastrin (Nic) mutants. Nic mutants and tissue clones display characteristic Notch-like phenotypes. Genetic and inhibitor studies indicate a function for Nicastrin in the gamma-secretase step of Notch processing, similar to Presenilin. Further, Nicastrin is genetically required for signaling from membrane-anchored activated Notch. In the absence of Nicastrin, Presenilin is destabilized and mature C-terminal subunits are absent. Nicastrin might recruit gamma-secretase substrates into the proteolytic complex as a prerequisite for Presenilin maturation and active complex assembly.
Hu
Yue
Y
Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Ye
Yihong
Y
Fortini
Mark E
ME
D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D004330:Drosophila / Q000235:genetics*; D029721:Drosophila Proteins; D010450:Endopeptidases / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D009154:Mutation / Q000502:physiology; D053764:Presenilin-1; D051880:Receptors, Notch; D015398:Signal Transduction / Q000502:physiology
D029721:Drosophila Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; C497759:N protein, Drosophila; D053764:Presenilin-1; D051880:Receptors, Notch; C413604:nicastrin protein; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases