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Lgl reduces endosomal vesicle acidification and Notch signaling by promoting the interaction between Vap33 and the V-ATPase complex
Science Signaling ( IF 7.3 ) Pub Date : 2018-06-05 , DOI: 10.1126/scisignal.aar1976
Marta Portela 1, 2, 3 , Liu Yang 4 , Sayantanee Paul 4 , Xia Li 5 , Alexey Veraksa 4 , Linda M. Parsons 2, 6 , Helena E. Richardson 1, 2, 7
Affiliation  

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.



中文翻译:

Lgl通过促进Vap33和V-ATPase复合物之间的相互作用来减少内体小泡酸化和Notch信号传导

上皮细胞极性与组织生长和肿瘤发生的控制有关。肿瘤抑制因子和细胞极性蛋白致死性2巨型幼虫(Lgl)促进了Hippo信号传导并抑制Notch信号传导,从而限制了果蝇的组织生长。lgl突变组织中的Notch信号比野生型组织中的Notch信号更大,这是因为内体小泡的酸化增加,这促进了蛋白水解过程和由γ-分泌酶激活的Notch。我们显示lgl的Notch信号传导增加和组织生长缺陷突变体组织依赖于液泡腺苷三磷酸酶(V-ATPase)介导的内体囊泡酸化。Lgl通过与Vap33(33 kDa的VAMP相关蛋白)相互作用来促进V-ATPase的活性。Vap33在物理和遗传上与Lgl和V-ATPase亚基相互作用,并抑制了V-ATPase介导的内体囊泡酸化和Notch信号传导。Vap33的过表达降低了V-ATPase组分Vha44的丰度,而Lg1的敲低降低了Vap33与V-ATPase组分Vha68-3的结合。我们的数据表明Lgl促进Vap33与V-ATPase的结合,从而抑制V-ATPase介导的内体囊泡酸化,从而降低γ-分泌酶的活性,Notch信号传导和组织生长。

更新日期:2018-06-06
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