Abstract/Summary

Focal adhesions are plasma membrane-associated protein complexes that connect the cellular cytoskeleton to the extracellular matrix via discrete "focal" points on the plasma membrane. As such they are critical to the movement of cells and therefore of great interest in the study of organismal development, immunity and inflammation, and in cancer metastasis. Therefore it is critical to better understand the structure of focal adhesions and the underlying processes behind their assembly and disassembly, as well as how assembly and disassembly are regulated. Modelling these processes mathematically, using computers, can offer insights not available to other approaches. Here differential equations (both ordinary and partial) are used to model various aspects of focal adhesion dynamics to produce compartmental and spatial models, respectively. By these methods new insights have been derived, unveiling the huge complexity of focal adhesion dynamics, but also pointing to the key factors that principally determine overall rates of focal adhesion assembly and disassembly, as well as levels of individual isoforms. Overall, the key finding of this project is that, for focal adhesion dynamics to occur over a physiologically realistic timescale (typically 5-20 minutes), numbers of focal adhesion-associated proteins must be highly enriched in the immediate vicinity of where such dynamics are taking place. This implies a higher level of organisation in both the plasma membrane and cytosol than is usually assumed in reaction-diffusion models such as this. Only by assuming that concentrations of such proteins are much higher locally than they would be if uniformly distributed throughout these and other relevant cellular compartments, can the required interactions between them occur at a rate consistent with what is observed physiologically. This finding is likely to extend to many other cell-critical behaviours.