Stretchy proteins on stretchy substrates: the important elements of integrin-mediated rigidity sensing

Abstract

Matrix and tissue rigidity guides many cellular processes, including the differentiation of stem cells and the migration of cells in health and disease. Cells actively and transiently test rigidity using mechanisms limited by inherent physical parameters that include the strength of extracellular attachments, the pulling capacity on these attachments, and the sensitivity of the mechanotransduction system. Here, we focus on rigidity sensing mediated through the integrin family of extracellular matrix receptors and linked proteins and discuss the evidence supporting these proteins as mechanosensors.

Figure 1. Rigidity Moduli and the Energy Landscapes of a Slip bond

(A) Stress is the amount of force applied per area (F/A) and strain is the displacement in the direction of applied force relative to initial length (Δx/L or ΔL/L). While both elastic and shear moduli are the ratio of stress over strain, there is a difference in the direction of the applied force. (B) The energy landscapes of a slip bond with and without applied force.

Figure 2. Important Parameters of Rigidity Sensing

Reported values of the strength (A), rates (B), forces (C) and elasticity (D) of components involved in the coupling of the ECM to the cytoskeleton through integrins. References: (1) (Kishino and Yanagida, 1988), (2) (Jiang et al., 2003), (3) table 2, (4) see text, (5) table 1, (6) (Kovar and Pollard, 2004; Mogilner and Oster, 1996; Peskin et al., 1993), (7) (Tseng et al., 2005).

Figure 3. Mechanosensory Proteins in Integrin Mediated Rigidity Sensing

Proteins that bind directly to the depicted domains are highlighted in yellow boxes. (A) FAK does not bind integrins or actin directly but its kinase activity is regulated by mechanical force and it has been hypothesized that removal of the FERM domain from the kinase could play a role (Cooper et al., 2003). (B) The substrate domain of p130Cas contains fifteen tyrosine residues that become exposed upon stretching (Sawada et al., 2006). (C) Stretching of talin’s rod domain exposes vinculin binding sites (del Rio et al., 2009). (D) Extension of filamin immunoglobulin repeats (labeled 1-24) has been shown by AFM (Furuike et al., 2001) and could regulate the binding of proteins. (E) α-actinin forms antiparallel dimers; mechanical force could regulate this dimerization or its association with other proteins.

Figure 4. The Rigidity Sensing Cycle and Models for Uniform Displacements

(A) A possible rigidity sensing cycle involves three mechanosensory events: (1) integrin/ECM catch bond formation, (2) stretching of talin that reinforces the adhesion by recruiting vinculin and (3) stretching of FAK that activates its kinase domain leading to the disassembly and recycling of the adhesion. (B,C) Two models to explain the uniform displacements of approximately 100nm, one where the reference structure is the polymerization complex (B) and the other where a stable actin network provides the reference structure (C). In both models the key decision is based on whether the extension of the link to retrograde flowing actin (e.g. talin) occurs before the link to the reference structure is broken.