Cellular Mechanotransduction

Force is ubiquitous in nature at all levels of organization. At the cellular scale, physical stimuli integrate with biochemical signals to orchestrate the precisely controlled pathways of proteins interaction that govern the fate of cells. A failure or modification of this subtle control mark the onset of numerous human disorders, particularly those that are highly sensitive to mechanical cues such as cardiovascular diseases and cancer.

Our research is focused on elucidating the mechanisms through which mechanical forces entwine with chemical signaling to regulate the behavior of cells and molecules in physiological conditions; and how these mechanisms are lost or altered in pathological scenarios. To this end, we use a combination of microscopy, nanotechnology, and cellular and molecular biology approaches.

Mechanosenstive molecules

One recent area of research in the field of mechanotransduction has been focused on mechanosensitive molecules: those molecules that undergo transformations to their structure when exposed to mechanical forces. These structural changes reveal previously-buried binding sites, which allows ligand binding and triggering of  downstream signalling cascades. One such mechanosensitive molecule/ligand pairing that has been studied is talin/vinculin.

Talin binds to both actin and trans-membrane integrins, providing a mechanical bridge between the cellular cytoskeleton and the extracellular environment. When force is applied to talin (e.g. by actomyosin contraction), talin stretches to reveal additional vinculin binding sites. Vinculin occurs normally in an inactive state and the binding of vinculin to talin triggers its activated state. Activated vinculin then interacts with signalling molecules such as paxillin and FAK, which in turn can activate other signalling pathways related to cell cycle and apoptosis.

We believe this process of force-induced conformational change leading to signalling cascades through the interaction of ligands forms a possible template by which a variety of mechanotransduction pathways are activated.