Abstract
Epithelial cell polarity defects support cancer progression. It is thus crucial to decipher the functional interactions within the polarity protein network. Here we show that Drosophila Girdin and its human ortholog (GIRDIN) sustain the function of crucial lateral polarity proteins by inhibiting the apical kinase aPKC. Loss of GIRDIN expression is also associated with overgrowth of disorganized cell cysts. Moreover, we observed cell dissemination from GIRDIN knockdown cysts and tumorspheres, thereby showing that GIRDIN supports the cohesion of multicellular epithelial structures. Consistent with these observations, alteration of GIRDIN expression is associated with poor overall survival in subtypes of breast and lung cancers. Overall, we discovered a core mechanism contributing to epithelial cell polarization from flies to humans. Our data also indicate that GIRDIN has the potential to impair the progression of epithelial cancers by preserving cell polarity and restricting cell dissemination.
Highlights
The ability of epithelia to form physical barriers is provided by specialized cell-cell junctions, including the zonula adherens (ZA)
We show that the protein Girdin and its human ortholog (GIRDIN) is essential to maintain epithelial polarity in fruit flies and human cells
To explore the role of Girdin in epithelial cell polarity regulation, we investigated its functional relationship with Yrt and Lethal (2) giant larvae (Lgl), which are known polarity regulators in Drosophila embryos
Summary
The ability of epithelia to form physical barriers is provided by specialized cell-cell junctions, including the zonula adherens (ZA) The latter is a belt-like adherens junction composed primarily of the transmembrane homotypic receptor E-cadherin, which is linked indirectly to circumferential F-actin bundles through adaptor proteins such as β-catenin and α-catenin [1,2]. In Drosophila embryonic epithelia, the protein Girdin stabilizes the ZA by reinforcing the association of the cadherin–catenin complex with the actin cytoskeleton [3]. This function in cell– cell adhesion is preserved in mammals, and supports collective cell migration [4,5]. The apical exclusion of Baz is essential to the positioning of the ZA along the apical-basal axis [18], and for full aPKC activation [20,21,22]
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