Establishment of epithelial polarity – GEF who's minding the GAP?

Abstract

Cell polarization is a fundamental process that underlies epithelial morphogenesis, cell motility, cell division and organogenesis. Loss of polarity predisposes tissues to developmental disorders and contributes to cancer progression. The formation and establishment of epithelial cell polarity is mediated by the cooperation of polarity protein complexes, namely the Crumbs, partitioning defective (Par) and Scribble complexes, with Rho family GTPases, including RhoA, Rac1 and Cdc42. The activation of different GTPases triggers distinct downstream signaling pathways to modulate protein–protein interactions and cytoskeletal remodeling. The spatio-temporal activation and inactivation of these small GTPases is tightly controlled by a complex interconnected network of different regulatory proteins, including guanine-nucleotide-exchange factors (GEFs), GTPase-activating proteins (GAPs), and guanine-nucleotide-dissociation inhibitors (GDIs). In this Commentary, we focus on current understanding on how polarity complexes interact with GEFs and GAPs to control the precise location and activation of Rho GTPases (Crumbs for RhoA, Par for Rac1, and Scribble for Cdc42) to promote apical–basal polarization in mammalian epithelial cells. The mutual exclusion of GTPase activities, especially that of RhoA and Rac1, which is well established, provides a mechanism through which polarity complexes that act through distinct Rho GTPases function as cellular rheostats to fine-tune specific downstream pathways to differentiate and preserve the apical and basolateral domains. This article is part of a Minifocus on Establishing polarity. For further reading, please see related articles: ‘ERM proteins at a glance’ by Andrea McClatchey (J. Cell Sci. 127, [098343]). ‘Integrins and epithelial cell polarity’ by Jessica Lee and Charles Streuli (J. Cell Sci. 127, [146142]).

On the Tricks Alveolar Epithelial Cells Play to Make a Good Lung

“…The question is how this is compatible with the concept that the basal-apical polarity and the structure of the apical plate are controlled from the basal membrane area (34). These mechanisms are presumably determined by cross-talk of the apical plate processes with the basal membrane (36).…”

The polarity protein Scribble positions DLC3 at adherens junctions to regulate Rho signaling

“…Cell polarization requires spatially restricted cytoskeleton remodeling, which is mediated by the cooperation of polarity proteins and small GTPases of the Rho family (Iden and Collard, 2008;Ngok et al, 2014). Rho GTPases, including RhoA, Rac and Cdc42 as the best-characterized members, function as key regulators of actin and microtubule dynamics and are involved in the control of cell polarity, adhesion and migration (Jaffe and Hall, 2005).…”

Development and dynamics of cell polarity at a glance

“…Ultimately, polarity complexes build signaling centers that scaffold Rho GTPases to specific membrane domains. This in turn controls cell shape and function by regulating the actomyosin cytoskeleton (EtienneManneville and Hall, 2003;Ngok et al, 2014), directing recycling endosome traffic (Harris and Tepass, 2010a;Shivas et al, 2010), and controlling E-cadherin distribution and stability in adherens junctions (Bilder et al, 2000;Harris and Tepass, 2010b;Rodriguez-Boulan and Macara, 2014).…”