Distinct Combinatorial Cascade of Events Generated by ECM Proteolysis Dictates Cell Behavior

It is well established that the expression profiles of multiple and possibly redundant matrix remodeling proteases (e.g. collagenases) strongly differentiates in disease and development. Although enzymatic redundancy might be inferred from their close similarity in structure, their in-vivo activity can lead to extremely diverse tissue-remodeling outcomes. We observed that proteolysis of collagen, generated uniquely by individual homologous proteases, leads to a specific cascade of combinatorial events, which eventually affects overall extracellular matrix (ECM) topography, visco-elastic properties and composition. We reveal striking differences in the migratory and signaling patterns, morphology, and gene expression profiles of cells interacting with native collagen-rich ECM matrix degraded by different collagenases. Thus unlike envisioned before degradative matrix remodeling systems are not redundant and give rise to precise ECM-cell crosstalk. As ECM proteolysis is an abundant biochemical process critical to tissue homeostasis these results improve our fundamental understanding of systemic factors dictating cell behavior.