Various studies using flies, nematodes, and mammalian epithelial cell cultures have suggested that regulated endocytic trafficking plays a fundamental role in establishing the cellular polarity. Subsequent studies on various organisms have revealed that these polarity complexes and their roles in establishing cell polarity are evolutionarily conserved in various species. In addition, the Rho family small guanosine triphosphate (GTP)-binding protein CDC42 is also considered to be a part of the Par/aPKC complex and plays key roles in regulating the assembly of polarity.

These complexes localize at distinct epithelial membrane domains and function in either a cooperative or antagonistic manner to induce cellular asymmetry as well as to establish apical-basal polarity. The establishment and maintenance of epithelial cell polarization is mainly controlled by the following three polarity complexes: Crumbs, 6) Par/aPKC (atypical protein kinase C, PKCζ, and ι in mammals), 7) and Scribble 8) ( Fig. Genetic approaches using Drosophila melanogaster and Caenorhabditis elegans have been instrumental in identifying genes that regulate cell polarity and epithelial morphogenesis. The mechanisms for establishing cell polarity and regulatory circuits underlying these mechanisms have been extensively studied over the past several decades (for review see 1– 5)). Polarity arises from the asymmetric distribution of proteins in cells. Morphogenesis of the polarity of epithelial cells requires various cellular processes, including asymmetric organization of cytoskeletons, polarized transport of proteins, and variation in lipid composition.Ģ. THE PRINCIPAL REGULATORS OF EPITHELIAL MORPHOGENESIS The apical-basal polarity of epithelial cells is required for their fundamental physiological functions, including secretion, selective absorption, protection, transcellular transport, and sensing. Mammalian V-ATPase contains accessory protein Ac45 and full-length Atp6ap2 protein, both of which are essential for enzyme function. Uppercase letters indicate the subunits of the V 1 sector and lowercase letters represent the V 0-sector subunits. The V-ATPase complex is composed of a peripheral domain (V 1) responsible for ATP hydrolysis and an integral domain (V 0) involved in proton translocation across the membrane. Furthermore, PAR-6 is regulated by the small GTPase Cdc42, which dynamically associates with the PAR complex.

The Crumbs complex consists of Crb, Pals1, and Patj or its paralog Mupp1 the Par complex consists of Par3, Par6, and aPKC and the Scribble complex is composed of Scrib, Dlg, and Lgl. Epithelial polarity is initiated and maintained mainly by three cell polarity complexes, namely the Crumbs, Par, and Scribble complexes. Simplified Scheme Depicting a Differentiated Epithelial Cell with Apical-Basal Polarity Regulators B. This review provides a brief overview of the relationship between the polarity of epithelial cells and V-ATPase as well as V-ATPase driven luminal acidification.įig. 1. Recently, several studies using genetic approaches have revealed the involvement of V-ATPase in the establishment and maintenance of apico-basal polarity. Various pharmacological analyses have suggested that acidic endocytic organelles are important for the maintenance of cell polarity. Emerging evidence indicates that the luminal acidic endocytic organelles and their trafficking may function as important hubs that connect and coordinate various signaling pathways. V-ATPase plays important roles in a wide range of cell biological processes and physiological functions by generating an acidic pH therefore, it has attracted much attention not only in basic research but also in pathological and clinical aspects. Subsequently, it was observed that the proton pump also participates in the acidification of extracellular compartments. Vacuolar-type H +-ATPase (V-ATPase) was first identified as an electrogenic proton pump that acidifies the lumen of intracellular organelles.

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