Mechanical Force-Driven Adherens Junction Remodeling and Epithelial Dynamics

During epithelial tissue development, repair, and homeostasis, adherens junctions (AJs) ensure intercellular adhesion and tissue integrity while allowing for cell and tissue dynamics. Mechanical forces play critical roles in AJs’ composition and dynamics. Recent findings highlight that beyond a well-established role in reinforcing cell-cell adhesion, AJ mechanosensitivity promotes junctional remodeling and polarization, thereby regulating critical processes such as cell intercalation, division, and collective migration. Here, we provide an integrated view of mechanosensing mechanisms that regulate cell-cell contact composition, geometry, and integrity under tension and highlight pivotal roles for mechanosensitive AJ remodeling in preserving epithelial integrity and sustaining tissue dynamics. During epithelial tissue development, repair, and homeostasis, adherens junctions (AJs) ensure intercellular adhesion and tissue integrity while allowing for cell and tissue dynamics. Mechanical forces play critical roles in AJs’ composition and dynamics. Recent findings highlight that beyond a well-established role in reinforcing cell-cell adhesion, AJ mechanosensitivity promotes junctional remodeling and polarization, thereby regulating critical processes such as cell intercalation, division, and collective migration. Here, we provide an integrated view of mechanosensing mechanisms that regulate cell-cell contact composition, geometry, and integrity under tension and highlight pivotal roles for mechanosensitive AJ remodeling in preserving epithelial integrity and sustaining tissue dynamics. During development, epithelia undergo extensive two- and three-dimensional remodeling to shape the organism, a process termed morphogenesis (Box 1). Morphogenetic processes result from temporal and spatial integration of a relatively small range of cellular behaviors, in particular cell shape and size changes, collective migration, cell-cell intercalation, cell division, and delamination events (Etournay et al., 2015Etournay R. Popović M. Merkel M. Nandi A. Blasse C. Aigouy B. Brandl H. Myers G. Salbreux G. Jülicher F. et al.Interplay of cell dynamics and epithelial tension during morphogenesis of the Drosophila pupal wing.Elife. 2015; 4: e07090Crossref PubMed Google Scholar, Gilmour et al., 2017Gilmour D. Rembold M. Leptin M. From morphogen to morphogenesis and back.Nature. 2017; 541: 311-320Crossref PubMed Scopus (26) Google Scholar, Guirao et al., 2015Guirao B. Rigaud S.U. Bosveld F. Bailles A. López-Gay J. Ishihara S. Sugimura K. Graner F. Bellaïche Y. Unified quantitative characterization of epithelial tissue development.Elife. 2015; 4 (pii: e08519)Crossref PubMed Scopus (49) Google Scholar, Heisenberg and Bellaïche, 2013Heisenberg C.P. Bellaïche Y. Forces in tissue morphogenesis and patterning.Cell. 2013; 153: 948-962Abstract Full Text Full Text PDF PubMed Scopus (332) Google Scholar, Miller and Davidson, 2013Miller C.J. Davidson L.A. The interplay between cell signalling and mechanics in developmental processes.Nat. Rev. Genet. 2013; 14: 733-744Crossref PubMed Scopus (74) Google Scholar). In agreement with D’Arcy Thompson’s original proposal that biological form results from the integration of physical processes and mechanical forces (Thompson, 1942Thompson D.W. On Growth and Form.Second Edition. Cambridge University Press, 1942Google Scholar), work over the last decades emphasized the critical role of mechanical forces and tissue mechanics in regulating epithelial cell dynamics and tissue morphogenesis (Gilmour et al., 2017Gilmour D. Rembold M. Leptin M. From morphogen to morphogenesis and back.Nature. 2017; 541: 311-320Crossref PubMed Scopus (26) Google Scholar, Heisenberg and Bellaïche, 2013Heisenberg C.P. Bellaïche Y. Forces in tissue morphogenesis and patterning.Cell. 2013; 153: 948-962Abstract Full Text Full Text PDF PubMed Scopus (332) Google Scholar, Miller and Davidson, 2013Miller C.J. Davidson L.A. The interplay between cell signalling and mechanics in developmental processes.Nat. Rev. Genet. 2013; 14: 733-744Crossref PubMed Scopus (74) Google Scholar, Petridou et al., 2017Petridou N.I. Spiró Z. Heisenberg C.P. Multiscale force sensing in development.Nat. Cell Biol. 2017; 19: 581-588Crossref PubMed Scopus (13) Google Scholar) (Box 1). Although Thompson’s pioneer work dates back to the turn of the 20th century, only recently have we attained the right technological toolkit to fully explore the role of mechanical forces in tissue development. The combined power of high-resolution live imaging in a variety of tissues and organisms along with the development of an array of biophysical tools permitted major advances in our understanding of how cells produce mechanical forces at the molecular, cellular, and tissue scales (reviewed in Campàs, 2016Campàs O. A toolbox to explore the mechanics of living embryonic tissues.Semin. Cell Dev. Biol. 2016; 55: 119-130Crossref PubMed Scopus (21) Google Scholar and Roca-Cusachs et al., 2017Roca-Cusachs P. Conte V. Trepat X. Quantifying forces in cell biology.Nat. Cell Biol. 2017; 19: 742-751Crossref PubMed Scopus (31) Google Scholar) (Figure 1). Furthermore, an increasing body of evidence now supports that remodeling epithelial architecture requires cells to sense and respond to mechanical forces. Accordingly, the cell-cell contacts not only resist deformation and integrate subcellular forces but also transduce and respond to tension, thereby modulating cell behavior and ensuring coherent force transmission across neighboring cells (Heisenberg and Bellaïche, 2013Heisenberg C.P. Bellaïche Y. Forces in tissue morphogenesis and patterning.Cell. 2013; 153: 948-962Abstract Full Text Full Text PDF PubMed Scopus (332) Google Scholar, Hoffman and Yap, 2015Hoffman B.D. Yap A.S. Towards a dynamic understanding of cadherin- based mechanobiology.Trends Cell Biol. 2015; 25: 803-814Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, Leckband and de Rooij, 2014Leckband D.E. de Rooij J. cadherin adhesion and mechanotransduction.Annu. Rev. Cell Dev. Biol. 2014; 30: 291-315Crossref PubMed Google Scholar, Lecuit and Yap, 2015Lecuit T. Yap A.S. E-cadherin junctions as active mechanical integrators in tissue dynamics.Nat. Cell Biol. 2015; 17: 533-539Crossref PubMed Scopus (143) Google Scholar). While both tight junctions and desmosomes can affect force transmission (Bazellières et al., 2015Bazellières E. Conte V. Elosegui-Artola A. Serra-Picamal X. Bintanel-Morcillo M. Roca-Cusachs P. Muñoz J.J. Sales-Pardo M. Guimerà R. Trepat X. Control of cell-cell forces and collective cell dynamics by the intercellular adhesome.Nat. Cell Biol. 2015; 17: 409-420Crossref PubMed Google Scholar, Tornavaca et al., 2015Tornavaca O. Chia M. Dufton N. Almagro L.O. Conway D.E. Randi A.M. Schwartz M.A. Matter K. Balda M.S. ZO-1 controls endothelial adherens junctions, cell-cell tension, angiogenesis, and barrier formation.J. Cell Biol. 2015; 208: 821-838Crossref PubMed Scopus (84) Google Scholar), in this review we focus primarily on the adherens junctions (AJs), which have emerged as central regulators of both mechanosensing and epithelial morphogenesis.Box 1Glossary of TermsMorphogenesis:describes the processes by which an organism acquires its shape during development.Tension:considering the actomyosin network, one can define tension as the pulling force exerted by myosin motors on actin filaments.Stress:describes the internal force an object is experiencing, per unit cross sectional area. For example, MyoII motors generate stress by pulling on actin filaments in the network.Strain:describes the extent to which an object is deformed by stress.Tissue mechanics:refers to the study of mechanical forces and the material properties of a tissue (e.g., stiffness, viscosity, elasticity).•Stiffness: defined as the rigidity of an object or its ability to resist deformation (amount of force required to impose a given deformation).•Elasticity: refers to the ability of a material to return to its original configuration upon the removal of a load.•Viscosity: describes the resistance of a fluid to flow.Mechanosensing:describes the ability of cells to sense a mechanical stimulus.Mechanotransduction:implies the conversion of a mechanical signal into a biochemical response.Catch Bonds:implies bond reinforcement under tension, either due to an increase in binding affinity and/or a more long-lived bond. Catch bonds contrast with both slip and ideal bonds, which describe, respectively, bond detachment and/or a shorter-lived bond upon application of mechanical forces and bonds insensitive to mechanical stimulation.Durotaxis:describes a form of cell migration during which cells are guided by a rigidity gradient in the extracellular matrix. Recent findings support that durotaxis is an emerging property of migrating cell collectives (Sunyer et al., 2016Sunyer R. Conte V. Escribano J. Elosegui-Artola A. Labernadie A. Valon L. Navajas D. García-Aznar J.M. Muñoz J.J. Roca-Cusachs P. et al.Collective cell durotaxis emerges from long-range intercellular force transmission.Science. 2016; 353: 1157-1161Crossref PubMed Scopus (73) Google Scholar). Morphogenesis:describes the processes by which an organism acquires its shape during development.Tension:considering the actomyosin network, one can define tension as the pulling force exerted by myosin motors on actin filaments.Stress:describes the internal force an object is experiencing, per unit cross sectional area. For example, MyoII motors generate stress by pulling on actin filaments in the network.Strain:describes the extent to which an object is deformed by stress.Tissue mechanics:refers to the study of mechanical forces and the material properties of a tissue (e.g., stiffness, viscosity, elasticity).•Stiffness: defined as the rigidity of an object or its ability to resist deformation (amount of force required to impose a given deformation).•Elasticity: refers to the ability of a material to return to its original configuration upon the removal of a load.•Viscosity: describes the resistance of a fluid to flow.Mechanosensing:describes the ability of cells to sense a mechanical stimulus.Mechanotransduction:implies the conversion of a mechanical signal into a biochemical response.Catch Bonds:implies bond reinforcement under tension, either due to an increase in binding affinity and/or a more long-lived bond. Catch bonds contrast with both slip and ideal bonds, which describe, respectively, bond detachment and/or a shorter-lived bond upon application of mechanical forces and bonds insensitive to mechanical stimulation.Durotaxis:describes a form of cell migration during which cells are guided by a rigidity gradient in the extracellular matrix. Recent findings support that durotaxis is an emerging property of migrating cell collectives (Sunyer et al., 2016Sunyer R. Conte V. Escribano J. Elosegui-Artola A. Labernadie A. Valon L. Navajas D. García-Aznar J.M. Muñoz J.J. Roca-Cusachs P. et al.Collective cell durotaxis emerges from long-range intercellular force transmission.Science. 2016; 353: 1157-1161Crossref PubMed Scopus (73) Google Scholar). In epithelia, the core molecular components of the AJs are cadherin transmembrane receptors and their binding partners β-, α-, and p120-catenin. Cadherin receptors from neighboring cells engage in homophilic adhesive complexes, which are connected to the actomyosin cytoskeleton primarily via α-catenin (α-cat; reviewed in Takeichi, 2014Takeichi M. Dynamic contacts: rearranging adherens junctions to drive epithelial remodelling.Nat. Rev. Mol. Cell Biol. 2014; 15: 397-410Crossref PubMed Scopus (186) Google Scholar) (Figure 2A). The seminal observations that cadherin bonds stiffen upon application of an external force and that junctional composition changes in a tension-dependent manner (Hoffman and Yap, 2015Hoffman B.D. Yap A.S. Towards a dynamic understanding of cadherin- based mechanobiology.Trends Cell Biol. 2015; 25: 803-814Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, Leckband and de Rooij, 2014Leckband D.E. de Rooij J. cadherin adhesion and mechanotransduction.Annu. Rev. Cell Dev. Biol. 2014; 30: 291-315Crossref PubMed Google Scholar) suggested that the ability of cell-cell contacts to resist mechanical stimulation results from an active process. Since then, cadherin molecules themselves, a number of junctional components, and actomyosin binding proteins were reported to be mechanosensitive and shown to contribute to adhesion reinforcement under tension, thereby defining the AJs as critical mechanosensing and transduction platforms (Hoffman and Yap, 2015Hoffman B.D. Yap A.S. Towards a dynamic understanding of cadherin- based mechanobiology.Trends Cell Biol. 2015; 25: 803-814Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, Leckband and de Rooij, 2014Leckband D.E. de Rooij J. cadherin adhesion and mechanotransduction.Annu. Rev. Cell Dev. Biol. 2014; 30: 291-315Crossref PubMed Google Scholar) (Box 1). Although force transduction has been extensively studied in the context of adhesion reinforcement, recent studies now highlight that mechanical cues can also induce cell-cell contact remodeling and polarization. Examples can be found during collective cell migration (e.g., mesendoderm migration in the Xenopus embryo [Weber et al., 2012Weber G.F. Bjerke M.A. DeSimone D.W. A mechanoresponsive cadherin-keratin complex directs polarized protrusive behavior and collective cell migration.Dev. Cell. 2012; 22: 104-115Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar]), border cell migration in Drosophila (Cai et al., 2014Cai D. Chen S.C. Prasad M. He L. Wang X. Choesmel-Cadamuro V. Sawyer J.K. Danuser G. Montell D.J. Mechanical feedback through E-cadherin promotes direction sensing during collective cell migration.Cell. 2014; 157: 1146-1159Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar), cell-cell intercalation (e.g., germband extension [Collinet et al., 2015Collinet C. Rauzi M. Lenne P.F. Lecuit T. Local and tissue-scale forces drive oriented junction growth during tissue extension.Nat. Cell Biol. 2015; 17: 1247-1258Crossref PubMed Scopus (80) Google Scholar, Fernandez-Gonzalez et al., 2009Fernandez-Gonzalez R. Simoes Sde M. Röper J.C. Eaton S. Zallen J.A. Myosin II dynamics are regulated by tension in intercalating cells.Dev. Cell. 2009; 17: 736-743Abstract Full Text Full Text PDF PubMed Scopus (319) Google Scholar, Yu and Fernandez-Gonzalez, 2016Yu J.C. Fernandez-Gonzalez R. Local mechanical forces promote polarized junctional assembly and axis elongation in Drosophila.Elife. 2016; 5: e10757Crossref PubMed Scopus (23) Google Scholar, Butler et al., 2009Butler L.C. Blanchard G.B. Kabla A.J. Lawrence N.J. Welchman D.P. Mahadevan L. Adams R.J. Sanson B. Cell shape changes indicate a role for extrinsic tensile forces in Drosophila germ-band extension.Nat. Cell Biol. 2009; 11: 859-864Crossref PubMed Scopus (120) Google Scholar]), and cell division (e.g., Drosophila pupal epithelia [Founounou et al., 2013Founounou N. Loyer N. Le Borgne R. Septins regulate the contractility of the actomyosin ring to enable adherens junction remodeling during cytokinesis of epithelial cells.Dev. Cell. 2013; 24: 242-255Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar, Guillot and Lecuit, 2013aGuillot C. Lecuit T. Adhesion disengagement uncouples intrinsic and extrinsic forces to drive cytokinesis in epithelial tissues.Dev. Cell. 2013; 24: 227-241Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar, Herszterg et al., 2013Herszterg S. Leibfried A. Bosveld F. Martin C. Bellaïche Y. Interplay between the dividing cell and its neighbors regulates adherens junction formation during cytokinesis in epithelial tissue.Dev. Cell. 2013; 24: 256-270Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar, Morais-de-Sá and Sunkel, 2013Morais-de-Sá E. Sunkel C.E. Adherens junctions determine the apical position of the midbody during follicular epithelial cell division.EMBO Rep. 2013; 14: 696-703Crossref PubMed Scopus (43) Google Scholar, Pinheiro et al., 2017Pinheiro D. Hannezo E. Herszterg S. Bosveld F. Gaugue I. Balakireva M. Wang Z. Cristo I. Rigaud S.U. Markova O. et al.Transmission of cytokinesis forces via E-cadherin dilution and actomyosin flows.Nature. 2017; 545: 103-107Crossref PubMed Scopus (11) Google Scholar] and chick [Firmino et al., 2016Firmino J. Rocancourt D. Saadaoui M. Moreau C. Gros J. Cell division drives epithelial cell rearrangements during gastrulation in chick.Dev. Cell. 2016; 36: 249-261Abstract Full Text Full Text PDF PubMed Google Scholar] and mouse embryos [Lau et al., 2015Lau K. Tao H. Liu H. Wen J. Sturgeon K. Sorfazlian N. Lazic S. Burrows J.T.A. Wong M.D. Li D. et al.Anisotropic stress orients remodelling of mammalian limb bud ectoderm.Nat. Cell Biol. 2015; 17: 569-579Crossref PubMed Google Scholar]), indicating that AJs’ remodeling under tension is not only a common theme during epithelial morphogenesis but also a critical process to regulate tissue size and architecture in vivo. Importantly, force sensitivity at the AJs is not restricted to short-term effects on junction architecture. On longer timescales, mechanical forces can also affect the transcriptional landscape and modulate key regulatory gene networks controlling cell proliferation, apoptosis, stemness, and differentiation, thus establishing a feedback loop between tissue mechanics and the regulatory signaling pathways controlling long-term tissue patterning and morphogenesis (Gilmour et al., 2017Gilmour D. Rembold M. Leptin M. From morphogen to morphogenesis and back.Nature. 2017; 541: 311-320Crossref PubMed Scopus (26) Google Scholar, Heisenberg and Bellaïche, 2013Heisenberg C.P. Bellaïche Y. Forces in tissue morphogenesis and patterning.Cell. 2013; 153: 948-962Abstract Full Text Full Text PDF PubMed Scopus (332) Google Scholar, Petridou et al., 2017Petridou N.I. Spiró Z. Heisenberg C.P. Multiscale force sensing in development.Nat. Cell Biol. 2017; 19: 581-588Crossref PubMed Scopus (13) Google Scholar). Here, we outline the molecular and biophysical mechanisms underlying force sensitivity at cadherin-based junctions to provide an integrated view of the mechanosensing mechanisms regulating cell-cell contact composition, geometry, and integrity under tension. We first briefly discuss mechanosensing in the context of cell-cell adhesion reinforcement, the most-studied junctional response to mechanical stimulation, and then focus on the role of mechanical forces in cell-cell contact remodeling and polarization, which in turn contributes to regulate both short- and long-term epithelial dynamics and sustain tissue and organ morphogenesis. The cell-cell contacts bear mechanical forces in vivo, as evidenced mesoscopically by their recoil upon laser ablation (Cavey et al., 2008Cavey M. Rauzi M. Lenne P.F. Lecuit T. A two-tiered mechanism for stabilization and immobilization of E-cadherin.Nature. 2008; 453: 751-756Crossref PubMed Scopus (263) Google Scholar, Farhadifar et al., 2007Farhadifar R. Röper J.C. Aigouy B. Eaton S. Jülicher F. The influence of cell mechanics, cell-cell interactions, and proliferation on epithelial packing.Curr. Biol. 2007; 17: 2095-2104Abstract Full Text Full Text PDF PubMed Scopus (430) Google Scholar, Fernandez-Gonzalez et al., 2009Fernandez-Gonzalez R. Simoes Sde M. Röper J.C. Eaton S. Zallen J.A. Myosin II dynamics are regulated by tension in intercalating cells.Dev. Cell. 2009; 17: 736-743Abstract Full Text Full Text PDF PubMed Scopus (319) Google Scholar, Mayer et al., 2010Mayer M. Depken M. Bois J.S. Jülicher F. Grill S.W. Anisotropies in cortical tension reveal the physical basis of polarizing cortical flows.Nature. 2010; 467: 617-621Crossref PubMed Scopus (224) Google Scholar, Rauzi et al., 2008Rauzi M. Verant P. Lecuit T. Lenne P.F. Nature and anisotropy of cortical forces orienting Drosophila tissue morphogenesis.Nat. Cell Biol. 2008; 10: 1401-1410Crossref PubMed Scopus (321) Google Scholar) (Figure 1). Work in a variety of in vitro systems, from single molecule setups to cell droplets and epithelial monolayers collectively established that mechanical stimulation of the AJs produces a positive feedback loop able to reinforce cell-cell adhesion and promote subsequent junction growth (le Duc et al., 2010le Duc Q. Shi Q. Blonk I. Sonnenberg A. Wang N. Leckband D.E. de Rooij J. Vinculin potentiates E-cadherin mechanosensing and is recruited to actin-anchored sites within adherens junctions in a myosin II-dependent manner.J. Cell Biol. 2010; 189: 1107-1115Crossref PubMed Scopus (307) Google Scholar, Liu et al., 2010Liu Z. Tan J.L. Cohen D.M. Yang M.T. Sniadecki N.J. Ruiz S.A. Nelson C.M. Chen C.S. Mechanical tugging force regulates the size of cell-cell junctions.Proc. Natl. Acad. Sci. USA. 2010; 107: 9944-9949Crossref PubMed Scopus (374) Google Scholar, Maître et al., 2012Maître J.L. Berthoumieux H. Krens S.F.G. Salbreux G. Jülicher F. Paluch E.K. Heisenberg C.P. Adhesion functions in cell sorting by mechanically coupling the cortices of adhering cells.Science. 2012; 338: 253-256Crossref PubMed Scopus (207) Google Scholar, Thomas et al., 2013Thomas W.A. Boscher C. Chu Y.S. Cuvelier D. Martinez-Rico C. Seddiki R. Heysch J. Ladoux B. Thiery J.P. Mège R.M. et al.α-catenin and vinculin cooperate to promote high E-cadherin-based adhesion strength.J. Biol. Chem. 2013; 288: 4957-4969Crossref PubMed Scopus (68) Google Scholar). Tension-dependent reinforcement of cadherin-based cell-cell contacts results from multiple mechanisms acting directly on cadherin receptors, as well as their interaction with the actomyosin cytoskeleton. Upon application of an external force, both E-cadherin homophilic bonds and α-cat-F-actin bonds behave as catch bonds (Buckley et al., 2014Buckley C.D. Tan J. Anderson K.L. Hanein D. Volkmann N. Weis W.I. Nelson W.J. Dunn A.R. Cell adhesion. The minimal cadherin-catenin complex binds to actin filaments under force.Science. 2014; 346: 1254211Crossref PubMed Scopus (158) Google Scholar, Perret et al., 2004Perret E. Leung A. Feracci H. Evans E. Trans-bonded pairs of E-cadherin exhibit a remarkable hierarchy of mechanical strengths.Proc. Natl. Acad. Sci. USA. 2004; 101: 16472-16477Crossref PubMed Scopus (102) Google Scholar, Rakshit et al., 2012Rakshit S. Zhang Y. Manibog K. Shafraz O. Sivasankar S. Ideal, catch, and slip bonds in cadherin adhesion.Proc. Natl. Acad. Sci. USA. 2012; 109: 18815-18820Crossref PubMed Scopus (80) Google Scholar) (Box 1). Catch bond behavior relies on load-dependent conformational changes in the interacting proteins, thereby increasing their binding affinity and/or bond lifetime (Hoffman and Yap, 2015Hoffman B.D. Yap A.S. Towards a dynamic understanding of cadherin- based mechanobiology.Trends Cell Biol. 2015; 25: 803-814Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, Thomas, 2008Thomas W. Catch bonds in adhesion.Annu. Rev. Biomed. Eng. 2008; 10: 39-57Crossref PubMed Scopus (101) Google Scholar). These bonds are particularly relevant for force transmission in many contexts and were already described for other members of mechanotransduction cascades, such as Integrin receptors (Chen et al., 2010Chen W. Lou J. Zhu C. Forcing switch from short- to intermediate- and long-lived states of the alphaA domain generates LFA-1/ICAM-1 catch bonds.J. Biol. Chem. 2010; 285: 35967-35978Crossref PubMed Scopus (76) Google Scholar, Kong et al., 2009Kong F. García A.J. Mould A.P. Humphries M.J. Zhu C. Demonstration of catch bonds between an integrin and its ligand.J. Cell Biol. 2009; 185: 1275-1284Crossref PubMed Scopus (310) Google Scholar). For E-cadherin, tension-sensitive bond stabilization relies on a conformational change of its extracellular domains, while α-cat catch bonds require both its β-catenin (β-cat) and F-actin-binding domains (Buckley et al., 2014Buckley C.D. Tan J. Anderson K.L. Hanein D. Volkmann N. Weis W.I. Nelson W.J. Dunn A.R. Cell adhesion. The minimal cadherin-catenin complex binds to actin filaments under force.Science. 2014; 346: 1254211Crossref PubMed Scopus (158) Google Scholar, Chien et al., 2008Chien Y.H. Jiang N. Li F. Zhang F. Zhu C. Leckband D. Two stage cadherin kinetics require multiple extracellular domains but not the cytoplasmic region.J. Biol. Chem. 2008; 283: 1848-1856Crossref PubMed Scopus (36) Google Scholar, Manibog et al., 2014Manibog K. Li H. Rakshit S. Sivasankar S. Resolving the molecular mechanism of cadherin catch bond formation.Nat. Commun. 2014; 5: 3941Crossref PubMed Scopus (40) Google Scholar, Rakshit et al., 2012Rakshit S. Zhang Y. Manibog K. Shafraz O. Sivasankar S. Ideal, catch, and slip bonds in cadherin adhesion.Proc. Natl. Acad. Sci. USA. 2012; 109: 18815-18820Crossref PubMed Scopus (80) Google Scholar) (Figure 2B). Unfolded α-cat not only stabilizes F-actin binding but also recruits additional actin-binding proteins to the cell-cell contacts, such as Vinculin, α-Actinin, Formin 1, and Afadin (Leckband and de Rooij, 2014Leckband D.E. de Rooij J. cadherin adhesion and mechanotransduction.Annu. Rev. Cell Dev. Biol. 2014; 30: 291-315Crossref PubMed Google Scholar). In particular, Vinculin binding was shown to stabilize “open” α-cat, thereby prolonging tension-dependent AJ reinforcement (Yao et al., 2014Yao M. Qiu W. Liu R. Efremov A.K. Cong P. Seddiki R. Payre M. Lim C.T. Ladoux B. Mège R.M. et al.Force-dependent conformational switch of α-catenin controls vinculin binding.Nat. Commun. 2014; 5: 4525Crossref PubMed Scopus (136) Google Scholar). In several cultured cell lines, Vinculin is essential for force-dependent stiffening of cadherin junctions, both by establishing additional bonds with the actin cytoskeleton and by promoting additional F-actin nucleation, via the Arp2/3 complex and Ena/VASP (le Duc et al., 2010le Duc Q. Shi Q. Blonk I. Sonnenberg A. Wang N. Leckband D.E. de Rooij J. Vinculin potentiates E-cadherin mechanosensing and is recruited to actin-anchored sites within adherens junctions in a myosin II-dependent manner.J. Cell Biol. 2010; 189: 1107-1115Crossref PubMed Scopus (307) Google Scholar, Huveneers et al., 2012Huveneers S. Oldenburg J. Spanjaard E. van der Krogt G. Grigoriev I. Akhmanova A. Rehmann H. de Rooij J. Vinculin associates with endothelial VE-cadherin junctions to control force-dependent remodeling.J. Cell Biol. 2012; 196: 641-652Crossref PubMed Scopus (204) Google Scholar, Kris et al., 2008Kris A.S. Kamm R.D. Sieminski A.L. VASP involvement in force-mediated adherens junction strengthening.Biochem. Biophys. Res. Commun. 2008; 375: 134-138Crossref PubMed Scopus (31) Google Scholar, Leerberg et al., 2014Leerberg J.M. Gomez G.A. Verma S. Moussa E.J. Wu S.K. Priya R. Hoffman B.D. Grashoff C. Schwartz M.A. Yap A.S. Tension-sensitive actin assembly supports contractility at the epithelial zonula adherens.Curr. Biol. 2014; 24: 1689-1699Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar, Maddugoda et al., 2007Maddugoda M.P. Crampton M.S. Shewan A.M. Yap A.S. Myosin VI and vinculin cooperate during the morphogenesis of cadherin cell cell contacts in mammalian epithelial cells.J. Cell Biol. 2007; 178: 529-540Crossref PubMed Scopus (0) Google Scholar, Thomas et al., 2013Thomas W.A. Boscher C. Chu Y.S. Cuvelier D. Martinez-Rico C. Seddiki R. Heysch J. Ladoux B. Thiery J.P. Mège R.M. et al.α-catenin and vinculin cooperate to promote high E-cadherin-based adhesion strength.J. Biol. Chem. 2013; 288: 4957-4969Crossref PubMed Scopus (68) Google Scholar, Twiss et al., 2012Twiss F. le Duc Q. Van Der Horst S. Tabdili H. Van Der Krogt G. Wang N. Rehmann H. Huveneers S. Leckband D.E. de Rooij J. Vinculin-dependent cadherin mechanosensing regulates efficient epithelial barrier formation.Biol. Open. 2012; 1: 1128-1140Crossref PubMed Scopus (57) Google Scholar, Watabe-Uchida et al., 1998Watabe-Uchida M. Uchida N. Imamura Y. Nagafuchi A. Fujimoto K. Uemura T. Vermeulen S. Van Roy F. Adamson E.D. Takeichi M. α-catenin-vinculin interaction functions to organize the apical junctional complex in epithelial cells.J. Cell Biol. 1998; 142: 847-857Crossref PubMed Scopus (234) Google Scholar) (Figure 2B). Since Vinculin is itself an auto-inhibited molecule, F-actin was proposed to initially unfurl Vinculin and allow its subsequent binding to α-cat (Bakolitsa et al., 2004Bakolitsa C. Cohen D.M. Bankston L.A. Bobkov A.A. Cadwell G.W. Jennings L. Critchley D.R. Craig S.W. Liddington R.C. Structural basis for vinculin activation at sites of cell adhesion.Nature. 2004; 430: 583-586Crossref PubMed Scopus (234) Google Scholar, Borgon et al., 2004Borgon R.A. Vonrhein C. Bricogne G. Bois P.R.J. Izard T. Crystal structure of human vinculin.Structure. 2004; 12: 1189-1197Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar, Choi et al., 2012Choi H.J. Pokutta S. Cadwell G.W. Bobkov A.A. Bankston L.A. Liddington R.C. Weis W.I. αE-catenin is an autoinhibited molecule that coactivates vinculin.Proc. Natl. Acad. Sci. USA. 2012; 109: 8576-8581Crossref PubMed Scopus (66) Google Scholar, Rangarajan and Izard, 2012Rangarajan E.S. Izard T. The cytoskeletal protein α-catenin unfurls upon binding to vinculin.J. Biol. Chem. 2012; 287: 18492-18499Crossref PubMed Scopus (44) Google Scholar) (Figure 2B). Importantly, α-cat-independent mechanisms promoting AJs’ reinforcement under tension are also starting to emerge. In line with this, a recent study reported tension-sensitive recruitment of VASP, Zyxin (Zyx), and Testin, a Zyx-related protein, to nascent forming AJs in an α-cat- and Vinculin-independent manner (Oldenburg et al., 2015Oldenburg J. van der Krogt G. Twiss F. Bongaarts A. Habani Y. Slotman J.A. Houtsmuller A. Huveneers S. de Rooij J. VASP, zyxin and TES are tension-dependent members of Focal adherens Junctions independent of the α-catenin-vinculin modul