Lgl Regulates Notch Signaling via Endocytosis, Independently of the Apical aPKC-Par6-Baz Polarity Complex

Abstract

Altogether, our data show that Lgl regulates endocytosis to restrict vesicle acidification and prevent ectopic ligand-dependent Notch signaling. This Lgl function is independent of the aPKC-Par6-Baz polarity complex and uncovers a novel attenuation mechanism of ligand-activated Notch signaling during Drosophila eye development.

Regulation of Notch signaling and endocytosis by the Lgl neoplastic tumor suppressor

“…Elevated Notch signalling in lgl -is correlated with defects in endosomal trafficking (Avl + (Syx7) EEs, Rab11 + recycling endosomes (REs) and Hrs + (Escrt 0) early-MVBs accumulated) and with increased acidic vesicles. 24 In wildtype cells, we found that Lgl colocalizes with Notch and endocytic markers, consistent with Lgl playing a direct role in the regulation of endocytic trafficking. Based on these findings, we hypothesized that Lgl might regulate a step in endosomal maturation or in vesicle acidification that led to elevated Notch signalling.…”

“…15,[17][18][19][20][21] However, Drosophila Dlg and Scrib do not directly regulate the Hippo pathway, although once cell polarity is lost the Hippo pathway is impaired, most likely due to the aberrant aPKC activity. 9,16,22,23 In our recent study, 24 we have discovered a role for Drosophila Lgl in the regulation of the Notch signalling pathway (Fig 1). The Notch pathway is an important cell-cell communication pathway required for cell-fate decisions during development, which is commonly deregulated in human cancer (reviewed by 25,[26][27][28] 29,[30][31][32][33].…”

Position- and polarity-dependent Hippo signaling regulates cell fates in preimplantation mouse embryos

“…For example, it is unclear how Notch signaling establishes positiondependency. Is this process regulated by Lgl as found in Drosophila [89]? Does cross-talk occur between Hippo and Notch signaling, as with other systems (reviewed in [90])?…”

Role of vacuolar-type proton ATPase in signal transduction

“…Drosophila mutants that show impaired endocytic trafficking and acidification due to altered V-ATPase activity have dysregulated Notch signaling [23,37]. On the other hand, accumulation of acidic vesicles in a Drosophila Lgl mutant induced the upregulation of Notch signaling [38]. Although the underlying mechanisms are as yet unclear, it was proposed that V-ATPase-dependent acidification creates an environment favorable for Notch signaling in multiple indirect steps, including the regulation of traffic between early and late endosomes, establishment of low luminal pH for optimal γ-secretase activity, and control of the maturation and localization of γ-secretase.…”