ECM and Cell Surface Proteolysis: Regulating Cellular Ecology

Zena Werb mechanism could explain how the shedding of L-selec-tin and syndecan can occur within minutes upon cell Department of Anatomy University of California, San Francisco stimulation. Through these diverse mechanisms, adhesion , deadhesion, and ECM proteolysis are all brought San Francisco, California 94143-0750 to bear at the leading edge of migrating and invading cells where dynamic changes take place. However, the ECM, per se, is not the only target of Cell–cell and cell–extracellular matrix (ECM) interactions pericellular proteolysis (Table 1). During the cellular provide cells with information essential for controlling response to developmental and pathologic cues, cell morphogenesis, cell fate specification, gain or loss of surface proteins, receptors, and transmembrane ECM tissue-specific functions, cell migration, tissue repair, proteins are altered by proteolysis. The nature of the and cell death. Degradation or activation of cell surface proteinases mediating these events has been elusive, and ECM proteins by proteolysis can mediate rapid and but there are now emerging concepts supporting a role irreversible responses to changes in the cellular micro-for integral membrane proteinases. The ADAMs (Wolfs-environment. By concentrating proteolytic events at or berg and White, 1996; Blobel, 1997) are particularly in-near the cell surface, these processes can be effective even in the presence of high concentrations of inhibitors. triguing because they contain both cell adhesion and proteolytic domains. Kuz, the Drosophila homolog of This minireview considers the cellular and organismal functions of ECM proteinases. Their biochemical and ADAM 10, activates the signaling receptor Notch during development and TNF␣ converting enzyme (TACE) re-structural properties are reviewed elsewhere (Stocker et al., 1995; Wolfsberg and White, 1996; Andreasen et leases membrane-bound TNF␣ by proteolysis. Genetic modification of proteinase and inhibitor gene expression in vivo is necessary to elucidate their real Proteolysis regulates ECM assembly, editing of excess ECM components, remodeling of ECM structure, and The initial studies of null mutants release of bioactive fragments and growth factors during growth, morphogenesis, tissue repair, and pathological of uPA, tPA, MMPs, and their inhibitors PAI-1 and TIMP-1 were disappointing because of their mild pheno-processes. The major enzymes that degrade ECM and cell surface proteins (Table 1) are the matrix metallo-types. In contrast, their ectopic expression produces pathologic remodeling. This suggests that requirements proteinase (MMP) family of secreted and membrane proteinases, the adamalysin-related membrane protein-for pericellular proteolysis become evident only under conditions of acute perturbation. What is less obvious ases that contain disintegrin and metalloproteinase domains (ADAMs or …