Review
Control of polarized cell morphology and motility by adherens junctions

https://doi.org/10.1016/j.semcdb.2011.07.023Get rights and content

Abstract

Cell–cell interactions play a key role in tissue homeostasis. Intercellular adhesions share the complex task of establishing and maintaining tissue architecture while allowing tissue growth, renewal and repair. In particular, adherens junctions (AJs) have been implicated in the formation of diverse tissues and organs like epitheliums, blood vessels or the central nervous system. At the cellular level, AJs are well known for their essential role in epithelial cell differentiation and baso-apical polarity. They also contribute to the control of cell polarity to promote neuronal morphogenesis, growth cone guidance and directed migration in a variety of cell types during embryonic development. AJs based on classical cadherin- and nectin-mediated cell–cell interactions control local membrane dynamics to polarize cell morphology and motility at the single cell level and to coordinate cell shape changes and motile behaviour at the tissue level. I review here the molecular mechanisms allowing control of polarized cell morphology and motility by AJs.

Highlights

Cadherins and nectins transmit information that influences cell polarity. ► AJs-mediated signalling locally influences cytoskeleton organization and membrane dynamics. ► AJs direct neuron and epithelial polarized growth. ► Cadherins support polarized cell motility.

Introduction

In multicellular organisms, cells behave in a coordinated manner and interact with their microenvironment through transmembrane receptors that recognize soluble factors, extracellular matrix proteins or neighbouring cells. Under external stress, such as tissue morphogenesis or body movement, cellular interactions maintain tissue architecture while allowing tissue growth, renewal or repair. One prominent component of cell–cell adhesion complexes is the adherens junction (AJ).

Classical cadherins are calcium-dependent adhesion receptors that form the core of AJs. They belong to a superfamily comprising approximately 80 members also including desmogleins, desmocollins, protocadherins, and fat-related cadherins [1]. Classical cadherins show distinct tissue distribution patterns and were originally named from the tissue in which they were predominantly expressed: E-cadherin in epithelium, N-cadherin in the nervous system and VE-cadherin in the vascular endothelium [2]. However, it is now clear that the expression pattern of each cadherin is not strictly restricted and that some cell types, like endothelial cells, express more than one type of classical cadherins. The 20 classical cadherins share a common domain organization which, in vertebrates, comprises an extracellular domain formed of five cadherin repeats (EC), a single transmembrane domain and a highly conserved cytoplasmic tail. Type I classical cadherins, including E-, N-, P- and R-cadherins, share a conserved HAV sequence in the amino terminal cadherin repeat (EC1) and mediate strong cell–cell adhesion. VE-cadherin, together with cadherin 6–12, 15, 18 and 19 are type II classical cadherins that lack the HAV motif. The EC1 domain confers the adhesive specificity of each cadherin [3], and promotes homophilic trans-cadherin binding. However, heterophilic interactions between classical cadherins have also been reported [4]. The juxtamembrane portion of the cytoplasmic domain binds p120catenin, and the carboxy-terminal half associates with β-catenin and γ-catenin (plakoglobin) (Fig. 2). These catenins interact with a number of cytoplasmic proteins that can affect the dynamics and strength of cadherin-mediated adhesion and mediate a wide variety of intracellular signalling pathways [5].

Nectin is another integral molecule of AJs [6]. The four members of the nectin family are calcium-independent immunoglobulin-like molecules [7]. In contrast with most cadherins, nectins can interact in either a homophilic or a heterophilic way and heterophilic adhesions seem to promote stronger cell–cell adhesion [8]. Their cytoplasmic domain associates with the actin-binding protein AF6/afadin [9]. Afadin can interact with α-catenin to provide a physical connection between the cadherin and the nectin complexes [10] (Fig. 2).

In addition to preventing tissue dissociation into their component cells, AJs promote cell-to-cell communication. Cadherins mediate intracellular signals that control cell division, apoptosis and differentiation (for reviews see [11], [12], [13]). Moreover, intercellular contacts serve as a polarity cue that regulates intracellular organization and leads to the orientation of the cell polarity axis along which the cell grows, resulting in shape changes and movement. In epithelial cells, tight junctions are essential for the maintenance of the polarized function of epitheliums. However, formation of E-cadherin mediated contacts is sufficient to initiate cell polarization [14] and endothelial cells, neurons, migrating fibroblasts or astrocytes, which do not have tight junctions, can polarize, revealing the general function of AJs in the regulation of cell polarity. AJs are not uniformly distributed over the cell surface but cluster in specific plasma membrane domains, which serve as signalling platforms. There, AJs directly connect with the cytoskeleton or signal through polarity proteins, RhoGTPases, tyrosine kinases and lipid modifications, to organize membrane traffic and promote polarized growth in regions that can be immediately adjacent or distant from AJs. In this review, I will summarize the observations showing how AJs transmit information that locally influences membrane dynamics, controls the establishment of polarized cell morphology and promotes polarized cell motility.

Section snippets

AJs and polarized cell morphology

The most classical and best characterized function of AJs is the control of epithelial cell morphology. AJs are one of the adhesive complexes that mediate the interactions between adjacent epithelial cells within the epithelium. Whereas in absence of cellular interaction, epithelial cells show a flattened morphology associated with multiple protrusions, groups of interacting epithelial cells exhibit a cobble-like regular shape with very little motile activity. In epithelial cells, E-cadherin is

AJs as a support for polarized cell motility

In addition to their role in the initial acquisition and the maintenance of a polarized morphology, AJs dynamically regulate cell motility. For example, cadherins contribute in different ways to growth cone navigation and pathfinding in the central nervous system,. Cadherin expression in neurons promotes neurite outgrowth and axon elongation [56], and cadherin expression in surrounding cells can serve as a target or repellent cue for growth cones [57].

Conclusion

Following the well-established role of E-cadherin in epithelial cell baso-apical polarity and morphogenesis, a general function of AJs and in particular of cadherin–catenin complexes in the regulation of polarity in numerous cell types has emerged. Classical cadherins and nectins appear as key regulators of the cytoskeleton and of membrane trafficking that control local membrane dynamics in response to cell–cell interactions. Although the molecular mechanisms underlying AJs associated

Acknowledgments

S.E.M. is a member of the EMBO YIP. This work was supported by the Institut National du Cancer, The Agence Nationale pour la Recherche, and La Ligue contre le Cancer.

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