Out, in and back again: PtdIns(4,5)P2 regulates cadherin trafficking in epithelial morphogenesis

Abstract

The morphogenesis of epithelial cells in the tissue microenviron-ment depends on the regulation of the forces and structures that keep cells in contact with their neighbours. The formation of cell– cell contacts is integral to the establishment and maintenance of epithelial morphogenesis. In epithelial tissues, the misregulation of the signalling pathways that control epithelial polarization induces migratory and invasive cellular phenotypes. Many cellular processes influence cadherin targeting and function, including exocytosis, endocytosis and recycling. However, the localized generation of the lipid messenger PtdIns(4,5)P2 is emerging as a fundamental signal controlling all of these processes. The PtdIns(4,5)P2-generating enzymes, PIPKs (phosphatidylinositol phosphate kinases) are therefore integral to these pathways. By the spatial and temporal targeting of PIPKs via the actions of its functional protein associates, PtdIns(4,5)P2 is generated at discrete cellular locales to provide the cadherin-trafficking machinery with its required lipid messenger. In the present review, we discuss the involvement of PtdIns(4,5)P2 and the PIPKs in the regulation of the E-cadherin (epithelial cadherin) exocytic and endocytic machinery, the modulation of actin structures at sites of adhesion, and the direction of cellular pathways which determine the fate of E-cadherin and cell–cell junctions. Recent work is also described that has defined phosphoinositide-mediated E-cadherin regulatory pathways by the use of organismal models.

Transcytosis ofListeria monocytogenesacross the intestinal barrier upon specific targeting of goblet cell accessible E-cadherin

“…We indeed observed a reorganized apical actin network at sites with accessible Ecad (Fig. S4 M), a result which is consistent with the well-established importance of the actin cytoskeleton in maintaining cell junction integrity by stabilizing Ecad clusters (Hagen and Trier, 1988;Cavey et al, 2008;Schill and Anderson, 2009). Finally, we also show that Ecad is luminally accessible in villus intestinal folds ( Fig.…”

Tuning Collective Cell Migration by Cell–Cell Junction Regulation

“…The stability of AJs is controlled by several mechanisms, including endocytosis and cytoskeletal regulation. Endocytosis of AJ receptors and adapters occurs both by clathrin-dependent and -independent mechanisms (Delva and Kowalczyk 2009;Schill and Anderson 2009), which cooperate with regulation by Rho family GTPases. For example, Cdc42 works upstream of Par6/aPKC and Cdc42-interacting protein 4 (CIP4), which control actin dynamics at the internalization site (Harris and Tepass 2010).…”

PIPKIγi5 regulates the endosomal trafficking and degradation of E-cadherin

“…The unique intracellular targeting of each member allows for the spatial and temporal control of the synthesis of PI(4,5)P 2 , thereby regulating specific processes, such as endocytosis, actin assembly, formation of cell-cell contacts and adhesion to the extracellular matrix Heck et al, 2007;Ling et al, 2006;Schill and Anderson, 2009a). PI(4,5)P 2 influences physiological processes by binding to proteins containing domains such as the pleckstrin-homology (PH) domain, phox-homology (PX) domain, band 4.1 ezrin radixin moesin homology (FERM) domain or the Bin/ Amphiphysin/Rvs (BAR) domain to modulate their activities (Betson et al, 2002;Harlan et al, 1994;Lemmon et al, 2002;Toker, 2002;Yoon et al, 2012).…”

“…PI(4,5)P 2 influences physiological processes by binding to proteins containing domains such as the pleckstrin-homology (PH) domain, phox-homology (PX) domain, band 4.1 ezrin radixin moesin homology (FERM) domain or the Bin/ Amphiphysin/Rvs (BAR) domain to modulate their activities (Betson et al, 2002;Harlan et al, 1994;Lemmon et al, 2002;Toker, 2002;Yoon et al, 2012). In particular, PI(4,5)P 2 regulates various components of the endocytic and endosomal trafficking pathways, including epsin, AP180, dynamin, sorting nexins (SNXs), ARFs and clathrin adaptor protein complexes Martin, 2001;Schill and Anderson, 2009a;Seet and Hong, 2006). Collectively, PI(4,5)P 2 is a potent regulatory molecule in diverse cellular signaling pathways, with broad effects on cellular function.…”