The extracellular matrix remodeled: Interdependency of matrix proteolysis, cell adhesion, and force sensing

Membrane Type-1 Matrix Metalloproteinase (MT1-MMP, MMP-14) is regarded as the prototype of a membrane- tethered protease. It drives fundamental biological processes ranging from embryogenesis to cancer metastasis. The proteolytic cleavage of proteins by MT1-MMP can rapidly alter the biophysical properties of a cell's microenvironment. Cell's must thus be able to sense and react to these alterations and transduce these effectively in biochemical signals and cell responses. Although many cells react as acutely to such physical stimuli as they do to chemical ones, the regulatory effects of these have been less extensively explored. In order to investigate a possible interdependency of proteolytic matrix cleavage by MT1-MMP and the generation and sensing of force by cells, a model system was established which exploits the properties of a matrix array of parallel collagen-I fibers. The resulting an-isotropy of the matrix with high tensile strength along the fibers and high mobility perpendicular to it allows the convenient detection of bundling and cleavage of the collagen fibers, as well as spreading and durotaxis of the cells. In summary, we have demonstrated that cell adhesion, force generation, and force sensing are vital for the regulation of MT1-MMP for efficient cleavage of collagen-I.