Roles of kringle domain-containing serine proteases in epithelial-mesenchymal transitions during embryonic development.

Transformation of an epithelial sheet into a migrating mesenchymal cell population implies the destruction of the basal lamina underlying the epithelium, and the subsequent localized digestion of the extracellular matrix by the migrating cells. Proteases are involved in these processes. Among them, molecules containing both a serine protease domain and at least one kringle domain have been identified as possible important effectors. Interestingly, related proteins containing an inactive serine protease domain also seem to play a role, suggesting that the function of these molecules in epithelial-mesenchymal transformation is not confined to proteolytic digestion of cell attachments. Instead, these molecules act through specific tyrosine kinase receptors in the membrane of the responding cells. In this review, we summarize data implicating this family of molecules in various epithelial-mesenchymal transitions during embryonic development. Our major focus of attention are: hepatocyte growth factor/scatter factor (HGF/SF), its tyrosine kinase receptor proto-oncogene c-met, and the related peptide factor HGF-like/macrophage-stimulating protein (HGF1/MSP), whose receptor is the Ron tyrosine kinase. c-met and Ron also have another close homolog in the chick, called Sea, whose ligand remains unknown. Interestingly, HGF/SF is activated by other plasminogen-related molecules which, apart from a specific activator, include the protease urokinase. HGF/SF, c-met and HGF/MSP are expressed in dynamic ways during early embryonic development, correlating with regions undergoing epithelial/mesenchymal transformations. Moreover, several assays are now starting to reveal great pleiotropism of function during development, including both the loss and the acquisition of epithelial morphology according to the cell type and assay used, as well as angiogenesis, kidney tubule morphogenesis, cell motility, the maintenance of competence for neural induction and some aspects of the later development of the musculoskeletal and nervous systems.