For example, the lifetime of the notoriously strong avidin-biotin bond is reduced from more than a day to ∼1 minute under a force of 5 pN ( Merkel et al., 1999). The mechanism of cell-derived tension that drives this mechanical cycle is described in Box 1.įorce-dependent strengthening of adhesion sites is remarkable, because all receptor-ligand bonds eventually break under high forces. S1, a single integrin is highlighted during each step of this mechanical cycle. These centripetally polarized supramolecular structures have been termed `focal adhesions'. When forces are sufficiently high – that is, when the substrate is sufficiently rigid – sites of integrin-mediated adhesion undergo further maturation, extending anisotropically several μm in length as additional proteins are recruited. Following this matrix movement or, in the case of cell migration, following this cell movement, the integrins then release from the matrix. On a larger scale, the pulling force also acts to either pull the matrix over the cell or pull the cell over the matrix. 1C) ( Galbraith et al., 2002 von Wichert et al., 2003b). Within seconds, these initial sites of integrin-ECM linkage begin to strengthen as additional components are recruited under force ( Fig. Thus, a pulling force is quickly generated across nascent integrin-matrix linkages ( Fig. The binding of integrin to the ECM is rapidly followed by integrin binding to the actin cytoskeleton, which is typically moving inwards from the site of assembly at the leading edge towards the cell center. This implies a rapid feedback mechanism at sites of integrin-mediated attachment, between the rigidity-sensing system and the force-producing machinery.Ī cell, probing its environment, initiates matrix adhesion through actin-dependent protrusions that bring integrins at the leading edge in contact with the matrix where they can bind ( Fig. Similarly, to produce a uniform displacement on substrates of increasing rigidity, epithelial cells recruit additional motor proteins to generate higher forces ( Saez et al., 2005).
MACDOWN INTEGRING FIGURE SERIES
When that process is analyzed in detail, it appears to be controlled by a series of mechanical steps that result in periodic rows of αVβ3-integrin aggregates together with early adhesion components ( Giannone et al., 2007). For example, fibroblasts and endothelial cells periodically contract fibronectin to test its rigidity ( Giannone et al., 2004). Yet, despite differences in tissue and cell types, force and position are crucial aspects of many, if not most, cell-matrix interactions. Across different tissue types, rigidities are in the range of 1-100 kPa, from the softness in which fat cells or neurons thrive, to the relative stiffness that is home for chrondrocytes ( Discher et al., 2005). As rigidity is defined by the force per unit displacement, rigidity-sensing cells must measure both force and displacement. In turn, cells are finely attuned to the forces and rigidity of their surroundings. Here, we focus on the steps in the integrin mechanical cycle that are sensitive to force and closely linked to integrin function, such as the lateral alignment of integrin aggregates and related adhesion components.Ĭells shape tissues by pulling on neighboring cells and extracellular matrices (ECMs), creating specific levels of tension. How the cell integrates these dynamic elements into a rigidity response is not clear.
Within this mechanical cycle, integrins themselves exhibit intramolecular conformational change that regulates their binding affinity and may also be dependent upon force. This mechanical cycle enables the transition from early complexes to larger, more stable adhesions that can then rapidly release. Recent studies have shown that a key aspect of mechanotransduction is the cycle by which integrins bind to the matrix at the leading cell edge, attach to the cytoskeleton, transduce mechanical force, aggregate in the plasma membrane as part of increasingly strengthened adhesion complexes, unbind and, ultimately, are recycled.
As the major force-bearing adhesion-receptor protein, integrins have a central role in how cells sense and respond to the mechanics of their surroundings. Cells govern tissue shape by exerting highly regulated forces at sites of matrix adhesion.
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