Proteolytic interstitial cell migration: A five-step process

Cell migration is a multi-step process that leads to the actin-driven translocation of cells on or through tissue substrate. Basic steps involved in cell migration have been defined for two-dimensional haptokinetic migration which, however, does not provide physical constraints imposed by three-dimensional interstitial tissues. We here describe the process of pericellular proteolysis that leads to extracellular matrix (ECM) degradation and realignment during cell movement and integrate it into established steps of cell migration. After actin-driven leading edge protrusion (step I) and anterior formation of integrin-mediated focal interactions to the substrate (step II), ECM breakdown is focalized towards physical ECM barriers several micrometer rearward of the leading edge (step III). Actomyosin-mediated cell contraction (step IV) then leads to rear-end retraction and forward sliding of cell body and nucleus so that a small tube-like matrix defect bordered by realigned ECM fibers becomes apparent (step V). Pericellular proteolysis is thus integral to the migration cycle and serves to widen ECM gaps and thereby lowers physical stress upon the cell body, which ultimately leads to aligned higher-oder ECM patterns.