Mechanosignaling

What is the role of the cytoskeleton in the regulation of cell-cell adhesions?

Given the function and stability of clustered cell-cell adhesions is tightly coupled to the formation and function of the actin cytoskeleton, it is not surprising that many of the components that regulate actin filament dynamics, also localize to adhesions sites, and have been implicated in their regulation. This has been highlighted for the Arp2/3 complex, formins and various nucleation promotion factors (NPFs), where, depending on the experimental conditions and cell types used, their presence was required for stability and function of the adhesion complex [1][2][3][4][5].

For example, down-regulation of Dia1 in human MCF7 cells by shRNA reportedly disrupted both E-cadherin localization to adhesion sites, and AJ integrity [2]. Likewise, it was found that knockdown of N-WASP diminished the integrity of zonula adherens [3]. This was manifested in the fragmentation of the apical actin ring structure and was attributed to the role of the WIP-family protein WIRE; which is normally recruited to the ZA by N-WASP where it interacts with E-cadherin, and regulates actin cytoskeleton formation at the junction via direct interactions with F-actin. Knocking-down, WIRE, as well as N-WASP, induced the same level of disruption to ZA integrity [3]. Similar results were found in MDCK cells where actin filament assembly at adhesion sites was diminished by inhibition of the Arp2/3 complex. In this case, the necessity for nucleators, and their associated NPFs, to localize to adhesion sites was attributed to a finding that indicated pre-existing filaments are unable to link to mature adhesion sites, and instead, new actin filaments must be polymerized [4]. As discussed in recent reviews, [5][1] the requirement for nucleators and regulators of the actin cytoskeleton to localize to sites of cell-cell adhesion may reflect a system of synergistic regulation where the function of the adhesion complex contributes to the regulation of the actin cytoskeleton, and vice versa in a form of feedback [5][1].

References

1. Zaidel-Bar R. Cadherin adhesome at a glance. J. Cell. Sci. 2013; 126(Pt 2):373-8. [PMID: 23547085]
2. Carramusa L, Ballestrem C, Zilberman Y, and Bershadsky AD. Mammalian diaphanous-related formin Dia1 controls the organization of E-cadherin-mediated cell-cell junctions. J. Cell. Sci. 2007; 120(Pt 21):3870-82. [PMID: 17940061]
3. Kovacs EM, Verma S, Ali RG, Ratheesh A, Hamilton NA, Akhmanova A, and Yap AS. N-WASP regulates the epithelial junctional actin cytoskeleton through a non-canonical post-nucleation pathway. Nat. Cell Biol. 2011; 13(8):934-43. [PMID: 21785420]
4. Tang VW, and Brieher WM. α-Actinin-4/FSGS1 is required for Arp2/3-dependent actin assembly at the adherens junction. J. Cell Biol. 2012; 196(1):115-30. [PMID: 22232703]
5. Ratheesh A, and Yap AS. A bigger picture: classical cadherins and the dynamic actin cytoskeleton. Nat. Rev. Mol. Cell Biol. 2012; 13(10):673-9. [PMID: 22931853]