Rab6 membrane association is dependent of Presenilin 1 and cellular phosphorylation events.
Processing of the amyloid precursor protein (APP) by alpha-secretase precludes the formation of beta-amyloid (Abeta). Therefore, the increase of cleavage by alpha-secretase upon stimulation by protein kinase C (PKC) is of potential therapeutic interest for Alzheimer's disease (AD). Unknown is whether phosphorylation by PKC increases alpha-secretase-mediated cleavage directly or indirectly, for example, by modulation of APP trafficking. Because modulation of Rab6-mediated transport has been shown to affect APP processing, we investigated the regulation of Rab6 membrane association by PKC and its relation to PS1. We show that in fibroblasts, Rab6 membrane association is PKC dependent, an effect strongly potentiated by inhibition of calcineurin. Moreover, we demonstrate that this regulation of Rab6 membrane association is dependent on PS1. The possible implications for APP processing and AD are discussed.
Scheper
Wiep
W
Neurogenetics Laboratory, Academic Medical Center, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands. w.scheper@amc.uva.nl
Zwart
Rob
R
Baas
Frank
F
D000818:Animals; D015153:Blotting, Western / Q000379:methods; D002462:Cell Membrane / Q000378:metabolism*; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology; D004622:Embryo, Mammalian; D004789:Enzyme Activation / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008959:Models, Neurological; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D010766:Phosphorylation; D053764:Presenilin-1; D020691:rab GTP-Binding Proteins / Q000378:metabolism*
D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D053764:Presenilin-1; C094135:Rab6 protein; D015240:Phorbol 12,13-Dibutyrate; D016572:Cyclosporine; D020691:rab GTP-Binding Proteins