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Lgl reduces endosomal vesicle acidification and Notch signaling by promoting the interaction between Vap33 and the V-ATPase complex

journal contribution
posted on 2022-03-25, 05:51 authored by Marta Portela-EstebanMarta Portela-Esteban, Liu Yang, Sayantanee Paul, Xia LiXia Li, Alexey Veraksa, Linda M Parsons, Helena RichardsonHelena Richardson
Epithelial cell polarity is linked to the control of tissue growth and tumorigenesis. The tumor suppressor and cell polarity protein lethal-2-giant larvae (Lgl) promotes Hippo signaling and inhibits Notch signaling to restrict tissue growth in Drosophila melanogaster. Notch signaling is greater in lgl mutant tissue than in wild-type tissue because of increased acidification of endosomal vesicles, which promotes the proteolytic processing and activation of Notch by γ-secretase. We showed that the increased Notch signaling and tissue growth defects of lgl mutant tissue depended on endosomal vesicle acidification mediated by the vacuolar adenosine triphosphatase (V-ATPase). Lgl promoted the activity of the V-ATPase by interacting with Vap33 (VAMP-associated protein of 33 kDa). Vap33 physically and genetically interacted with Lgl and V-ATPase subunits and repressed V-ATPase-mediated endosomal vesicle acidification and Notch signaling. Vap33 overexpression reduced the abundance of the V-ATPase component Vha44, whereas Lgl knockdown reduced the binding of Vap33 to the V-ATPase component Vha68-3. Our data indicate that Lgl promotes the binding of Vap33 to the V-ATPase, thus inhibiting V-ATPase-mediated endosomal vesicle acidification and thereby reducing γ-secretase activity, Notch signaling, and tissue growth. Our findings implicate the deregulation of Vap33 and V-ATPase activity in polarity-impaired epithelial cancers.


The project and M.P. were supported by Cancer Council Victoria grant APP1041817 (to H.E.R. and A.V.), a Juan de la Cierva-Incorporacion postdoctoral fellowship (IJCI-2014-19272) from the Spanish Ministerio de Ciencia e Innovacion (to M.P.), Contributing to Australian Scholarship and Science Foundation grant SM/14/5398 (to L.M.P.), and NIH grants HD085870 and GM123136 (to A.V.). H.E.R. was supported by a National Health and Medical Research Council Fellowship level B (APP1020056), a Bridging Fellowship from La Trobe University, and funds from the La Trobe Institute of Molecular Science.


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Science Signaling





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American Association for the Advancement of Science



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