title: Presenilin deficiency or lysosomal inhibition enhances Wnt signaling through relocalization of GSK3 to the late-endosomal compartment.
abstract: Sustained canonical Wnt signaling requires the inhibition of glycogen synthase kinase 3 (GSK3) activity by sequestration of GSK3 inside multivesicular endosomes (MVEs). Here, we show that Wnt signaling is increased by the lysosomal inhibitor chloroquine, which causes accumulation of MVEs. A similar MVE expansion and increased Wnt responsiveness was found in cells deficient in presenilin, a protein associated with Alzheimer's disease. The Wnt-enhancing effects were entirely dependent on the functional endosomal sorting complex required for transport (ESCRT), which is needed for the formation of intraluminal vesicles in MVEs. We suggest that accumulation of late endosomal structures leads to enhanced canonical Wnt signaling through increased Wnt-receptor/GSK3 sequestration. The decrease in GSK3 cytosolic activity stabilized cytoplasmic GSK3 substrates such as β-catenin, the microtubule-associated protein Tau, and other proteins. These results underscore the importance of the endosomal pathway in canonical Wnt signaling and reveal a mechanism for regulation of Wnt signaling by presenilin deficiency.
authors.affiliation: Howard Hughes Medical Institute and Department of Biological Chemistry, University of California, Los Angeles, CA 90095-1662, USA.
authors.forename: Radek
authors.initials: R
authors.lastname: Dobrowolski
authors.forename: Philipp
authors.initials: P
authors.lastname: Vick
authors.forename: Diego
authors.initials: D
authors.lastname: Ploper
authors.forename: Iwona
authors.initials: I
authors.lastname: Gumper
authors.forename: Harriet
authors.initials: H
authors.lastname: Snitkin
authors.forename: David D
authors.initials: DD
authors.lastname: Sabatini
authors.forename: Edward M
authors.initials: EM
authors.lastname: De Robertis
mesh_terms: D016475:3T3 Cells; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology; D002460:Cell Line; D002738:Chloroquine / Q000494:pharmacology; D056827:Endosomal Sorting Complexes Required for Transport; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism*; D018942:Macrolides / Q000494:pharmacology; D051379:Mice; D057146:Multivesicular Bodies / Q000201:enzymology*; D053763:Presenilins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D060149:Tetraspanin 30 / Q000378:metabolism; D051153:Wnt Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000378:metabolism; D000090802:rab7 GTP-Binding Proteins; D016875:tau Proteins / Q000378:metabolism
chemical_list: D000962:Antimalarials; D056827:Endosomal Sorting Complexes Required for Transport; C555475:LRP6 protein, human; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D018942:Macrolides; D053763:Presenilins; D034741:RNA, Small Interfering; D060149:Tetraspanin 30; D051153:Wnt Proteins; D051176:beta Catenin; D000090802:rab7 GTP-Binding Proteins; D016875:tau Proteins; C057620:bafilomycin A; D002738:Chloroquine; D038362:Glycogen Synthase Kinase 3; D020691:rab GTP-Binding Proteins