However, little is known neither about the basic regulatory mechanisms underlying TJ and permeability barrier formation in the lung epithelium, nor how Eya1-controlled cell polarity affects TJ protein assembly, in particular this is still unknown in the lung distal epithelium.Įya1 deletion causes TJ protein disassembly in lung distal epithelium. We recently reported mechanisms of cell polarity control by Eya1 protein phosphatase that regulates aPKCζ activity and Par subcellular localization in the lung distal epithelium ( El-Hashash et al., 2011a). These polarity proteins also maintain TJ structure by modulating targeted insertion of newly synthesized proteins to the junctional complex ( Shin et al., 2006). The aPKCζ/Par polarity complex, together with several scaffolding/adhesion molecules, promotes TJ formation and designates the site of TJ assembly that defines the apical and basolateral membrane domains. In epithelial cells, the assembly and maintenance of TJs are inextricably linked to the preservation of polarity, and is highly coordinated by proteins that regulate epithelial cell polarity, including aPKCζ/Par complex ( Shin et al., 2006). These findings uncover novel functions for the Eya1–aPKCζ–Notch1–Cdc42 pathway as a crucial regulatory mechanism of TJ assembly and polarity of the lung epithelium, providing a conceptual framework for future mechanistic and translational studies in this area. Moreover, genetic activation of Notch1 rescues Eya1 −/− lung epithelial TJ defects. These effects are reversed by reintroduction of wild-type Eya1 or partially inhibiting aPKCζ in Eya1siRNA cells. Thus, TJs are disassembled after interfering with Eya1 function in vivo or during calcium-induced TJ assembly in vitro. Here, we have extended these observations to TJ formation to demonstrate that Eya1 is crucial for the maintenance of TJ protein assembly in the lung epithelium, probably by controlling aPKCζ phosphorylation levels, aPKCζ-mediated TJ protein phosphorylation and Notch1–Cdc42 activity. We recently reported that Eya1 phosphatase functions through aPKCζ–Notch1 signaling to control cell polarity in the lung epithelium. Little is known about the regulatory mechanisms underlying lung epithelial tight junction (TJ) assembly, which is inextricably linked to the preservation of epithelial polarity, and is highly coordinated by proteins that regulate epithelial cell polarity, such as aPKCζ.
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