Holding it together: when cadherin meets cadherin

Abstract

Intercellular adhesion is the key to multicellularity, and its malfunction plays an important role in various developmental and disease-related processes. Although it has been intensively studied by both biologists and physicists, a commonly accepted definition of cell-cell adhesion is still being debated. Cell-cell adhesion has been described at the molecular scale as a function of adhesion receptors controlling binding affinity, at the cellular scale as resistance to detachment forces or modulation of surface tension, and at the tissue scale as a regulator of cellular rearrangements and morphogenesis. In this review, we aim to summarize and discuss recent advances in the molecular, cellular, and theoretical description of cell-cell adhesion, ranging from biomimetic models to the complexity of cells and tissues in an organismal context. In particular, we will focus on cadherin-mediated cell-cell adhesion and the role of adhesion signaling and mechanosensation therein, two processes central for understanding the biological and physical basis of cell-cell adhesion.

Figure 1

Cells can undergo adhesions with other cells and the extracellular matrix (ECM) via junctions. Cadherins mediate specific cell-cell adhesions via trans interactions in the extracellular space, where glycocalices act as a repulsive barrier. Cadherins indirectly bind to the underlying actomyosin cortex via β- and ɑ-catenins. Mechanosensitive cadherin adhesion complexes can change their binding strength to the actin cortex by cis clustering and by recruiting adaptor proteins such as vinculin. These complexes can also lead to local changes in actomyosin contractility by regulating the architecture of the cortex.

Figure 2

(A) A schematic representation of dual pipette aspiration (DPA) is shown. Applied detachment forces, F₁ + F₂, on suspended cells with a given viscoelasticity (viscosity, η, and Young’s modulus, E) forming a contact, where E-cadherin and actin accumulate at the contact rim. (B) Radius, R, and the cortex thickness, t_C, define the cortical tensions, γ₁ and γ₂, of the connected cells. For γ₁ = γ₂ = γ, cortical tensions at the contact-free area are counteracted by the interfacial tension, γ_IT = 2 × γ × cos(θ), at the cell-cell adhesion area, A_CC. The interfacial tension, γ_IT, is determined by the difference in magnitude between the cortical tension of both cells at the cell-cell interface, 2^∗γ_CC, and the adhesion tension, γ_A, acting in antiparallel directions. The cortical tension is in balance with the internal cellular pressure, P.

Figure 3

The tissue surface tension, σ, at the tissue edge results from the difference between the interfacial tension, γ_IT, at the cell-cell contact and the cortical tension, γ, at the contact-free surface. It minimizes the contact-free surface area by smoothing the tissue edge. Interfacial tension also contributes to determining the cell shape index, an indicator of tissue fluidity: cells within the cluster typically display more regular hexagonal shapes, are densely packed by surrounding neighbors, and thus behave more solid-like. Cells at the tissue edge, in contrast, are more elongated and mobile, and thus show a fluid-like behavior.