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How do Focal Adhesions Facilitate Mechanosensing?

Focal adhesions are known to sense both chemical and physical properties of their matrix environment. Chemical sensing is mediated by the different types of receptors that may function additively, synergistically or antagonistically [1],[2],[3],[4]. However, even with the molecular repertoire of focal adhesions (FAs) having been unveiled substantially (reviewed in [5], [6]), the details of functional interplay between these proteins on sensing mechanical forces remain fairly elusive. From available data, it can only be suggested that FAs undergo regulated turnover at any given time governed by diverse environmental signals (reviewed in[7]).

Matrix density, spacing [8],[9], rigidity [10], orientation and geometry [11] are some of the physical parameters the focal adhesions and in turn, cells are known to be sensitive to. However, over years, the mechanisms that integrate such complex information have not been understood. Only recently, the key determinants of rigidity sensing by integrins have been described (reviewed in [12],[13]):

1. The strength of integrin-ECM bonds
2. Rates of cell protrusion/ retraction
3. Force produced during protrusion/ retraction and
4. Elasticity of associated mechanosensitive proteins

A remarkable feature of cell-matrix adhesions, which makes them more versatile than any individual surface receptor, is the large repertoire of mechanosensitive and signaling components in their cytoplasmic scaffold. Mechanotransduction most likely occurs through protein conformational changes in multi-modular proteins, that act as molecular switches [13] (reviewed in [14]) leading to subsequent phosphorylation signaling pathways or addition of components [15] (reviewed in [16]) under internal/external mechanical perturbation [17]. These ultimately affect prominent protein-protein interactions allowing self-assembly and/or remodeling of the adhesion unit [18]. These allow a multitude of possibilities that trigger force-induced signal transduction pathways involving the adhesion components and diverse targets, resulting in cascading events at a distance (reviewed in [14]).

A mature FA contains hundreds of proteins that are grouped based on their contribution to four basic processes: receptor/matrix binding, linkage to actin cytoskeleton, intracellular signal transduction, and actin polymerization. Both actin polymerization and actomyosin contractile machinery generate forces that affect mechanosensitive proteins in the actin linking module, the receptor module (e.g. integrins), the signaling module, and the actin polymerization module. The combined activity of the mechanosensitive components form the mechanoresponsive network. The theoretical organization and protein-protein interactions as shown are based upon references.

References

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