A Molecular Switch for the Orientation of Epithelial Cell Polarization

Abstract

SUMMARY The formation of epithelial tissues containing lumens requires not only the apical-basolateral polarization of cells, but also the coordinated orientation of this polarity such that the apical surfaces of neighboring cells all point toward the central lumen. Defects in extracellular matrix (ECM) signaling lead to inverted polarity so that the apical surfaces face the surrounding ECM. We report a molecular switch mechanism controlling polarity orientation. ECM signals through a β1-integrin/FAK/p190RhoGAP complex to down-regulate a RhoA/ROCK/Ezrin pathway at the ECM interface. PKCβII phosphorylates the apical identity-promoting Podocalyxin/NHERF1/Ezrin complex, removing Podocalyxin from the ECM-abutting cell surface and initiating its transcytosis to an apical membrane initiation site for lumen formation. Inhibition of this switch mechanism results in the retention of Podocalyxin at the ECM interface and the development instead of collective front-rear polarization and motility. Thus, ECM-derived signals control the morphogenesis of epithelial tissues by controlling the collective orientation of epithelial polarization.

Integrin signalling regulates YAP and TAZ to control skin homeostasis

“…Thus, our results show that antagonistic apical and basal polarity signals serve as the primary control mechanism that determines YAP subcellular localisation in vivo. In a striking parallel, the same apical and basal polarity determinants act antagonistically in epithelial membrane polarisation, with integrin and PI3K signalling localising PtdIns(3,4,5)P3 basally, and helping to restrict and/or orient PtdIns(4,5)P2, CDC42 and the CRB3 complex apically (Akhtar and Streuli, 2013;Bryant et al, 2014;Fletcher et al, 2012;Martin-Belmonte et al, 2007;Thompson, 2013). Further work will be necessary to fully elaborate the molecular interactions that mediate the antagonistic relationship between apical and basal signals in cell polarisation and nuclear signalling via YAP.…”

Embryoids, organoids and gastruloids: new approaches to understanding embryogenesis

“…2C) due to interactions with the ECM (Bedzhov and ZernickaGoetz, 2014;Kadoshima et al, 2013;Taniguchi et al, 2015), in the same way as shown previously for Madin-Darby canine kidney (MDCK) and human colorectal cancer cells, both of which are common models of epithelia (Martin-Belmonte and Mostov, 2008;Rodriguez-Fraticelli and Martin-Belmonte, 2013). In the case of developing MDCK cysts, actin-associating proteins such as ezrin are trafficked to the cytokinetic plane as single cells first divide (Bryant et al, 2014), forming an actin-rich site and marking the initiation region for the apical membrane (Apodaca et al, 2012). Cells then self-organize into an epithelium, forming a lumen at their apical sides.…”

Tuning Collective Cell Migration by Cell–Cell Junction Regulation

“…EMT also up-regulates the expression of stromal proteases, which cleave cadherins; deregulates integrin adhesion systems, for example, by switching b1 to b3 integrin expression and enhancing aV integrin signaling; and can redirect Rho-mediated actomyosin contractility from cell -cell junctions toward cell -matrix interactions (Kalluri and Weinberg 2009;Parvani et al 2013;Truong et al 2014). These molecular reprogramming events result in deregulated cellcell contacts, loss of apicobasal polarity, including degeneration of the lumen of otherwise ductal and glandular structures, gain of frontrear polarity, and ultimately favor the gradual transition from epithelial to mesenchymal migration modes (Bryant et al 2014).…”