Oligomerization-dependent regulation of motility and morphogenesis by the collagen XVIII NC1/endostatin domain

Collagen XVIII (c18) is a triple helical endothelial/epithelial basement me mbrane protein whose noncollagenous (NC)1 region trimerizes a COOH-terminal endostatin (ES) domain conserved in vertebrates, Caenorhabditis elegans an d Drosophila. Here, the c18 NC1 domain functioned as a motility-inducing fa ctor regulating the extracellular matrix (ECM)-dependent morphogenesis of e ndothelial and other cell types. This motogenic activity required ES domain oligomerization, was dependent on rac, cdc42, and mitogen-activated protei n kinase, and exhibited functional distinction from the archetypal motogeni c scatter factors hepatocyte growth factor and macrophage stimulatory prote in. The motility-inducing and mitogen-activated protein kinase-stimulating activities of c18 NC1 were blocked by its physiologic cleavage product ES m onomer, consistent with a proteolysis-dependent negative feedback mechanism . These data indicate that the collagen XVIII NCI region encodes a motogen strictly requiring ES domain oligomerization and suggest a previously unsus pected mechanism for ECM regulation of motility and morphogenesis.