Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Feb 15;121(4):596-606.
doi: 10.1016/j.bpj.2022.01.006. Epub 2022 Jan 11.

Cortical tension initiates the positive feedback loop between cadherin and F-actin

Qilin Yu  1 , William R Holmes  2 , Jean P Thiery  3 , Rodney B Luwor  4 , Vijay Rajagopal  5
Affiliations

Cortical tension initiates the positive feedback loop between cadherin and F-actin

Qilin Yu et al. Biophys J. .

Abstract

Adherens junctions physically link two cells at their contact interface via extracellular binding between cadherin molecules and intracellular interactions between cadherins and the actin cytoskeleton. Cadherin and actomyosin cytoskeletal dynamics are regulated reciprocally by mechanical and chemical signals, which subsequently determine the strength of cell-cell adhesions and the emergent organization and stiffness of the tissues they form. However, an understanding of the integrated system is lacking. We present a new mechanistic computational model of intercellular junction maturation in a cell doublet to investigate the mechanochemical cross talk that regulates adherens junction formation and homeostasis. The model couples a two-dimensional lattice-based simulation of cadherin dynamics with a reaction-diffusion representation of the reorganising actomyosin network through its regulation by Rho signalling at the intracellular junction. We demonstrate that local immobilization of cadherin induces cluster formation in a cis-less-dependent manner. We then recapitulate the process of cell-cell contact formation. Our model suggests that cortical tension applied on the contact rim can explain the ring distribution of cadherin and actin filaments (F-actin) on the cell-cell contact of the cell doublet. Furthermore, we propose and test the hypothesis that cadherin and F-actin interact like a positive feedback loop, which is necessary for formation of the ring structure. Different patterns of cadherin distribution were observed as an emergent property of disturbances of this positive feedback loop. We discuss these findings in light of available experimental observations on underlying mechanisms related to cadherin/F-actin binding and the mechanical environment.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Lattice-based model of cadherin dynamics. (A) Schematic of cadherin trans and cis interactions on the lattice-based model. (B) The 2D field is composed of square lattices, representing the contact area of a cell doublet. Each lattice can only be occupied by one monomer from each cell. Simultaneous occupancy by a monomer A from the upper membrane (red arrow) and a monomer B from the bottom membrane (green arrow) is necessary for formation of a trans dimer (blue dot). Monomers from the same surface can interact with each other through cis interaction.
Figure 2
Figure 2
Biochemical signaling pathway and mechanical tension in cell adhesion of a cell doublet. (A) Upon cell-cell contact, cadherin trans dimers upregulate Rac, which works as an upstream regulator of actin polymerization. Rac also inhibits RhoA, myosin, and contact contractility βcont via p190B-RhoGAP. (B) Cadherin trans-dimerization and clustering lead to an increase in adhesion tension Γ. Assuming a contact cortical tension β, as the actin cortex disassembles on the contact, βcont decreases, whereas the contact angle θ and the linking tension λ sustained in the cadherin-catenin-actin complex increase. The cell membrane is shown in black and the actin cortex in blue. Cadherin trans dimers are represented by orange bars between membranes.
Figure 3
Figure 3
Cadherin dynamics were simulated on a region composed of 50 × 50 lattice sites. (A–D) With the periodic boundaries, cadherin can diffuse across the boundaries. The monomer concentration is 0.04 on each side. The snapshots in (A) and (C) were taken when the maximum cluster appears in the simulation with Δgtrans0=6kBT and Δgcis0=2kBT. The maximum cluster size from these simulations are labeled by black stars in (B and D). Blue dots represent trans dimers, and red and green dots represent cadherin monomers located on the two opposite surfaces. Heatmaps in (B) and (D) show the maximum cluster size in each simulation with a wide range of Δgtrans0 and Δgcis0, from 0–10 kBT. The cluster size is calculated by counting the number of cadherin molecules in each cluster. Each data point represents the mean value of the maximum cluster size of five simulations. In (A) and (B), trans dimers can be formed everywhere. All cadherin monomers and trans dimers can diffuse freely on all lattices. In (C) and (D), trans dimers can be formed everywhere but will be immobilized when they are in the central 10 × 10 lattice “immobilization trap” (black square) and can only leave after the trans dimer dissembles.
Figure 4
Figure 4
The process of cell-cell contact formation. (A) Serial snapshots of the lattice-based model of cadherin and RD model of actin (sum of G-actin (actin) and F-actin (actin∗)). The model replicates the maturation process of the cell-cell contact when two cells are brought to each other. Photos on the two sides show the experiment where two cells were brought into contact using micropipettes (41). Two cells were gently held in contact using micropippettes for 4 min. The left image shows the cells at the start of the experiment and the right image shows the adhered cells after 4 min.. (B) Development of the contact in the first 100 s. trans dimers translocate and form on the contact edge to resist the challenge from cortical tension as the contact angle increases. Force sustained in each cad trans dimer decreases as more cadherins locate on the contact edge. (C) Ratios of monomers on the contact area that are involved in trans and cis interactions in the first 100 s. (D) The concentration of cadherin on the contact center, contact edge, and free contact area in the first 100 s. Cadherin/F-actin binding rate, 10−3 μm2 s−1; Rac activation rate by cadherin trans dimer, 10−5 μm2 s−1corticaltensionβ=4000pN/μm; [cad]=0.04; Δgtrans0=6kBT; Δgcis0=2kBT.
Figure 5
Figure 5
The positive feedback loop between cadherin and F-actin is essential for ring formation. (A) Snapshots of the cadherin lattice-based model at 300 s. (B) Cadherin concentration on the whole contact. (C) Cadherin concentration on the contact edge. (D and E) Ratios of monomers on the contact area that are involved in trans and cis interactions, respectively. (B–E) Average of data in 200–300 s. For all simulations, cortical tension λ = 4,000 pN/μm, [cad]=0.04, Δgtrans0=6kBT,Δgcis0=2kBT.
Figure 6
Figure 6
The positive feedback loop between F-actin and cadherin. Cadherin trans-dimerization leads to actin polymerization in a Rac-dependent manner. F-actin immobilizes cadherin locally through cadherin/F-actin linkers, such as α-catenin and vinculin, leading to cadherin local accumulation. trans and cis interactions happen more frequently because of local cadherin accumulation, resulting in cadherin clustering.
Figure 7
Figure 7
Disturbance of the cadherin F-actin positive feedback loop results in cadherin redistribution. (A) Serial snapshots of the lattice-based model of cadherin (contact area) and RD model of actin (sum of G-actin (actin) and F-actin (actin∗)). The model replicates the process of cadherin and F-actin redistribution on a mature cell-cell contact. The trans dimer affinity Δgtrans0 was brought up to 8 kBT cyclically with a frequency of 1 Hz after 100 s on the right contact edge and kept at 6 kBT at all other places. (B) Schematic of the cell-cell doublet experiment (38). Cyclical water flow introduces external stresses that challenge the cell adhesion with a higher linking tension λ. (C) The mean ratios between cadherin concentration change on the right side and left side of the contact rim (ΔI, relative concentration increase). Each column represents the mean value from five simulations. Error bars show the std. Δgtrans0 on the right side of the contact rim is increased cyclically to 6.5, 7.0, 7.5, and 8.0 kBT, respectively. Cadherin/F-actin binding rate, 0.5 × 10−3 μm2 s−1; Rac activation rate by cadherin trans dimer, 0.5 × 10−5 μm2 s−1; corticaltensionλ=4000pN/μm,[cad]=0.04; Δgtrans0=6kBT; Δgcis0=2kBT.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Song Y., Ye M., et al. Zhu X. Targeting E-cadherin expression with small molecules for digestive cancer treatment. Am. J. Transl. Res. 2019;11:3932–3944. - PMC - PubMed
    1. Yu W., Yang L., et al. Zhang Y. Cadherin signaling in cancer: its functions and role as a therapeutic target. Front. Oncol. 2019;9:989. doi: 10.3389/fonc.2019.00989. - DOI - PMC - PubMed
    1. Hong S., Troyanovsky R.B., Troyanovsky S.M. Binding to F-actin guides cadherin cluster assembly, stability, and movement. J. Cell Biol. 2013;201:131–143. doi: 10.1083/jcb.201211054. - DOI - PMC - PubMed
    1. Baumgartner W., Hinterdorfer P., et al. Drenckhahn D. Cadherin interaction probed by atomic force microscopy. Proc. Natl. Acad. Sci. U S A. 2000;97:4005–4010. doi: 10.1073/pnas.070052697. - DOI - PMC - PubMed
    1. Sako Y., Nagafuchi A., et al. Kusumi A. Cytoplasmic regulation of the movement of E-cadherin on the free cell surface as studied by optical tweezers and single particle tracking: corralling and tethering by the membrane skeleton. J. Cell Biol. 1998;140:1227–1240. doi: 10.1083/jcb.140.5.1227. - DOI - PMC - PubMed

LinkOut - more resources