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Actin-Based Adhesion Modules Mediate Cell Interactions with the Extracellular Matrix and Neighboring Cells

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Actin-Based Adhesion Modules Mediate Cell Interactions with the Extracellular Matrix and Neighboring Cells Downloaded from http://cshperspectives.cshlp.org/ on October 3, 2021 - Published by Cold Spring Harbor Laboratory Press Actin-Based Adhesion Modules Mediate Cell Interactions with the Extracellular Matrix and Neighboring Cells Alexia I. Bachir,1,4 Alan Rick Horwitz,2 W. James Nelson,3 and Julie M. Bianchini3,4 1Protein and Cell Analysis, Biosciences Division, Thermo Fisher Scientific, Eugene, Oregon 97402 2Department of Cell Biology, University of Virginia, Charlottesville, Virginia 22903 3Department of Biology, Stanford University, Stanford, California 94305 Correspondence: [email protected] SUMMARY Cell adhesions link cells to the extracellular matrix (ECM) and to each other and depend on interactions with the actin cytoskeleton. Both cell–ECM and cell–cell adhesion sites contain discrete, yet overlapping, functional modules. These modules establish physical associations with the actin cytoskeleton, locally modulate actin organization and dynamics, and trigger intracellular signaling pathways. Interplay between these modules generates distinct actin architectures that underlie different stages, types, and functions of cell–ECM and cell–cell adhesions. Actomyosin contractility is required to generate mature, stable adhesions, as well as to sense and translate the mechanical properties of the cellular environment into changes in cell organization and behavior. Here, we review the organization and function of different adhesion modules and how they interact with the actin cytoskeleton. We highlight the mo- lecular mechanisms of mechanotransduction in adhesions and how adhesion molecules me- diate cross talk between cell–ECM and cell–cell adhesion sites. Outline 1 Introduction 6 Cell–ECM adhesions function as a molecular clutch 2 Cell adhesions link actin to the cellular microenvironment: A historical perspective 7 Cross talk between cell–ECM and cell–cell adhesions 3 Cell adhesions are modular and multifunctional structures 8 Conclusion 4 Adhesion architecture is dictated by actin References filament organization 5 Cell adhesions sense and transduce mechanical forces 4These authors made equal contributions. Editors: Thomas D. Pollard and Robert D. Goldman Additional Perspectives on The Cytoskeleton available at www.cshperspectives.org Copyright # 2017 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a023234 Cite this article as Cold Spring Harb Perspect Biol 2017;9:a023234 1 Downloaded from http://cshperspectives.cshlp.org/ on October 3, 2021 - Published by Cold Spring Harbor Laboratory Press A.I. Bachir et al. 1 INTRODUCTION density and correlated with the “close contacts” that had been observed by light microscopy (Izzard and Lochner Cell adhesion to the extracellular matrix (ECM) and to 1976; Heath and Dunn 1978). These sites were proposed neighboring cells is the hallmark of multicellularity and to serve as traction points that supported the translocation underlies the organization and distinct physiological func- of the cell body during migration (Izzard and Lochner tions of mammalian tissues (Gumbiner 1996). Aberrant 1980). Concurrent studies showed that fibronectin—an cell adhesion contributes to diverse pathologies, including ECM protein secreted by cells and implicated in cell attach- cancer metastasis, vascular disease, and inflammation ment to the substratum—localized adjacent to actin fila- (Hynes 2007; Ley et al. 2007; Friedl and Gilmour 2009). ment bundles and their termini (Hynes and Destree 1978; Discrete macromolecular complexes mediate cell adhe- Singer 1979). This suggested the presence of a transmem- sions and form a link between the actin cytoskeleton and brane linker molecule that connected the actin cytoskeleton either the ECM or adjacent cells. The organization of the and fibronectin and thereby served as an ECM adhesion actin cytoskeleton at adhesion sites (e.g., filament nucle- molecule. ation, cross-linking, bundling, and actomyosin contractil- ity) is tightly regulated and driven byadhesion proteins that are physically linked to the actin cytoskeleton (Schwarz and 2.2 Identification of the Molecules That Mediate Gardel 2012; Wehrle-Haller 2012). Adhesions serve as sig- the Linkage between Actin and the ECM naling hubs; they trigger downstream pathways through a In the late 1970s and early 1980s, a number of proteins were plethora of effectors, including kinases and the Rho family identified that localized in regions of close contact between of GTPases, which regulate the organization and dynamics cells and the ECM. These included a-actinin (Lazarides of the actin cytoskeleton (Hynes 2002; Burridge and Wen- and Burridge 1975), which also decorated actin filaments, nerberg 2004). In addition, these signaling pathways con- vinculin (Geiger 1979), talin (Burridge and Connell 1983), trol cellular processes such as proliferation, survival, and and integrin, a receptor for fibronectin (Chen et al. 1985; gene expression, although these pathways will not be cov- Damsky et al. 1985; Hynes 2002). These proteins interacted ered in this review (Schwartz and Assoian 2001). with each other and with actin, suggesting that they func- Here, we discuss the interplay between the organization tioned as a protein complex mediating the fibronectin– of the actin cytoskeleton and adhesions at cell–ECM and actin linkage (Horwitz et al. 1986). Thus, these discrete cell–cell contacts. We first present an overview of how cell regions of cell adhesion to the ECM, often termed focal adhesions were identified as sites of protein accumulation contacts or focal adhesions (FAs), acquired a distinct mo- and physical linkage to the actin cytoskeleton, and then we lecular identity. discuss the distinct actin architectures that underlie these different adhesions. Furthermore, we highlight the impor- tant roles of actomyosin activity in force transmission 2.3 E-Cadherin Mediates Cell–Cell Attachment through adhesions and in sensing and translating the prop- and Localizes with Actin erties of the ECM and forces from neighboring cells During the same period, electron microscopy studies of through specific cellular responses. Finally, we discuss the polarized epithelia revealed the presence of three types of significance of cross talk between cell–ECM and cell–cell intercellular junctions among adhering cells. They com- adhesions in cell behavior. prised the tight junction (TJ), adherens junction (AJ), and desmosomes (Farquhar and Palade 1963); the TJ and 2 CELL ADHESIONS LINK ACTIN TO THE CELLULAR AJ localized at the juxta-lumenal region and are collectively MICROENVIRONMENT: A HISTORICAL called the apical junction complex. The TJ regulates the PERSPECTIVE passage of ions and small solutes among epithelial cells, whereas desmosomes provide mechanical strength to epi- 2.1 A Molecular Link between Actin Filaments thelial sheets and connect with intermediate filaments. and the ECM Here, we focus on the AJ as it mediates cell–cell adhesion The first imaging studies of fibroblasts on planar substrates through a linkage with actin and is the best characterized of in culture revealed discrete regions of close substratum the intracellular junctions (Takeichi 1995; Takeichi 2014). contact and physical linkage between the ECM and actin E-cadherin was identified as a key transmembrane + filament bundles across the plasma membrane (Curtis adhesion receptor involved in Ca2 -dependent cell–cell 1964). Subsequent electron microscope (EM) images adhesion (Takeichi 1977; Yoshida-Noro et al. 1984). Sub- showed dense cytoplasmic fibrillar structures (actin fila- sequent immunocytochemical studies revealed that cad- ment bundles) that terminated in discrete areas of electron herin family proteins concentrate in the apical region of 2 Cite this article as Cold Spring Harb Perspect Biol 2017;9:a023234 Downloaded from http://cshperspectives.cshlp.org/ on October 3, 2021 - Published by Cold Spring Harbor Laboratory Press Actin-Based Adhesion epithelial tissues where the AJ is primarily located. Today, actin cytoskeleton; second, they modulate actin organiza- the term “cadherin” refers to a large family of related trans- tion and dynamics; and, third, they trigger intracellular membrane receptors involved in cell–cell adhesion in var- signaling pathways. Together they form an intricate net- ious types of cell junctions (reviewed in detail elsewhere work that facilitates the dynamic association of the actin [Takeichi 2014]). In addition to cadherins, members of the cytoskeleton to either the ECM or adjacent cells. + Ca2 -independent IgG superfamily termed nectins were also found at the AJ and are involved in the initial forma- tion of cell–cell contacts (Rikitake et al. 2012). Cadherins 3.1 The Actin Linkage Module colocalized with cortical actin bundles, which suggested At cell–ECM adhesions, linkages between the integrin ad- that AJ linkage to the actin cytoskeleton is required for hesion receptors and actin are mediated by talin (Critchley cell–cell adhesion (Hirano et al. 1987; Geiger and Ginsberg 2009) and/or a-actinin (Otey et al. 1990), both of which 1991). Thus, E-cadherin, and other classical cadherins can bind to vinculin (Ziegler et al. 2008), which itself also (such as N-, P- and R-cadherin), emerged as the AJ trans- binds to actin (Humphries et al. 2007). The actin-binding membrane molecule that connected the actin cytoskeleton and -cross-linking protein filamin can also link integrins to between neighboring cells, an idea that was further sup- the actin cytoskeleton (Loo et al. 1998), either directly ported by the finding that deletion
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