title: Overexpression of human CRB1 or related isoforms, CRB2 and CRB3, does not regulate the human presenilin complex in culture cells.
abstract: The presenilin proteins (PS1 and PS2) with their partners (NCT, Aph1, and Pen2) are the major components of the high molecular weight gamma-secretase complex which facilitates the intramembraneous cleavage of various type 1 transmembrane proteins, including the amyloid-beta precursor protein (APP) and the Notch receptor. Additional gamma-secretase complex components may be involved in regulation of its activity and specificity. A recent investigation indicated that the Crumbs protein is a negative regulator of Notch signaling and may act by repressing gamma/epsilon-secretase activity in Drosophila [Herranz, H., Stamataki, E., Feiguin, F., and Milan, M. (2006) EMBO Rep. 7, 297-302]. To address this question, we investigated potential functional interactions between the human Crumbs homologues (CRB1, CRB2, and CRB3) and presenilin complexes which mediate gamma/epsilon-secretase cleavage of APP and Notch. We found no evidence for direct interaction between CRB1, CRB2, or CRB3 and presenilin complex components. Furthermore, overexpression of human CRB1 and related isoforms, CRB2 and CRB3, had no effect on the levels of presenilin complex components, on NCT maturation or on PS endoproteolysis, and did not alter Abeta AICD or NICD production. These results suggest that, in mammalian cells at least, Crumbs is unlikely to be a significant direct modulator of presenilin-dependent gamma/epsilon-secretase activity.
authors.affiliation: Centre for Research in Neurodegenerative Diseases, 6 Queen's Park Crescent West, Toronto, Ontario M5S 3H2, Canada. raphaelle.pardossi.piquard@utoronto.ca
authors.forename: Raphaëlle
authors.initials: R
authors.lastname: Pardossi-Piquard
authors.forename: Fusheng
authors.initials: F
authors.lastname: Chen
authors.forename: Nancy F
authors.initials: NF
authors.lastname: Silva-Gagliardi
authors.forename: Michael
authors.initials: M
authors.lastname: Szego
authors.forename: Roderick
authors.initials: R
authors.lastname: McInnes
authors.forename: C Jane
authors.initials: CJ
authors.lastname: McGlade
authors.forename: Peter
authors.initials: P
authors.lastname: St George-Hyslop
authors.forename: Paul E
authors.initials: PE
authors.lastname: Fraser
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D004591:Electrophoresis, Polyacrylamide Gel; D004797:Enzyme-Linked Immunosorbent Assay; D005136:Eye Proteins / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D006801:Humans; D047468:Immunoprecipitation; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D053763:Presenilins / Q000378:metabolism*
chemical_list: C448939:CRB1 protein, human; C492531:CRB2 protein, human; C472002:CRB3 protein, human; D002352:Carrier Proteins; D005136:Eye Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D053763:Presenilins