Oligomerization-Dependent Regulation of Motility and Morphogenesis by the Collagen XVIII NC1/Endostatin Domain

• Published in: The Journal of cell biology Vol. 152; no. 6; pp. 1233 - 1246
• Main Authors: Kuo, Calvin J., LaMontagne, Kenneth R., Garcia-Cardeña, Guillermo, Ackley, Brian D., Kalman, Daniel, Park, Susan, Christofferson, Rolf, Kamihara, Junne, Ding, Yuan-Hua, Lo, Kin-Ming, Gillies, Stephen, Folkman, Judah, Mulligan, Richard C., Javaherian, Kashi
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 19.03.2001; The Rockefeller University Press
• Subjects: Angiogenesis Inhibitors - genetics; Angiogenesis Inhibitors - metabolism; Animals; Bacterial Proteins; Bacterial Toxins - pharmacology; Blotting, Western; cdc42 GTP-Binding Protein - genetics; cdc42 GTP-Binding Protein - metabolism; Cell Movement - drug effects; Cell Movement - physiology; Cells; Cells, Cultured; Collagen - chemistry; Collagen - genetics; Collagen - metabolism; Collagen Type XVIII; Collagens; Cytotoxins - pharmacology; Dimerization; Dimers; Endostatins; Endothelial cells; Endothelium, Vascular - cytology; Endothelium, Vascular - drug effects; Endothelium, Vascular - growth & development; Enzymes; Extracellular Matrix - physiology; Hepatocytes; Human umbilical vein endothelial cells; Humans; Membranes; Mice; Mitogen-Activated Protein Kinases - metabolism; Monomers; Morphogenesis; Original; Peptide Fragments - chemistry; Peptide Fragments - genetics; Peptide Fragments - metabolism; Physiological regulation; Protein Structure, Tertiary; Proteins; rac GTP-Binding Proteins - genetics; rac GTP-Binding Proteins - metabolism; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism; rho GTP-Binding Proteins - metabolism; Trimers
• ISSN: 0021-9525; 1540-8140
• DOI: 10.1083/jcb.152.6.1233

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