Control of integrin-mediated mechanoresponse by binding partners and force loading rates
Víctor González Tarragó, Cellular and Molecular Mechanobiology group
This thesis is a study on the integrin-mediated mechanoresponse by binding partners and force loading rates. Regarding the binding partners, here we demonstrate an alternative and counter-intuitive mechanism, by which another adaptor protein (ZO-1) promotes activation but decreases mechanical resistance. Because such mechanical regulation is bound to impact in downstream mechanosensing processes, this provides an interesting and novel way to regulate cell adhesion, mechanoresponse, and function in general. Regarding the force loading rates, our results show that force loading rates drive mechanosensing by increasing reinforcement and adhesion growth at the local adhesion level, in a talin-dependent way. However, if mechanically induced deformations are too high or too fast, the cytoskeleton fluidizes, thereby decreasing force loading rates and mechanosensing. This provides a unifying mechanism to understand how cells respond not only to directly applied forces, but also to passive mechanical stimuli such as tissue rigidity or ECM ligand distribution. Further, it also provides a framework to understand how the seemingly opposed concepts of reinforcement and fluidization are coupled to drive mechanosensing.