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Published online 19 March 2001. doi:10.1083/jcb.152.6.1233
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© The Rockefeller University Press, 0021-9525/2001/3/1233/ $5.00
The Journal of Cell Biology, Volume 152, Number 6, March 19, 2001 1233-1246

Original Article

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

Calvin J. Kuoa,b, Kenneth R. LaMontagne, Jr.a, Guillermo Garcia-Cardeñac, Brian D. Ackleyd, Daniel Kalmane, Susan Parka, Rolf Christoffersona, Junne Kamiharaa, Yuan-Hua Dingf, Kin-Ming Log, Stephen Gilliesg, Judah Folkmana, Richard C. Mulliganb, and Kashi Javaheriana
a Department of Surgery, Children's Hospital
b Department of Genetics and Howard Hughes Medical Institute, Children's Hospital
c Vascular Research Division, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115
d Department of Cell and Molecular Biology, Northwestern University Medical School, Chicago, Illinois 60611
e Department of Microbiology and Immunology, G.W. Hooper Foundation Laboratories, University of California at San Francisco, San Francisco, California 94143
f Department of Cellular and Molecular Biology and Howard Hughes Medical Institute, Harvard University, Cambridge, Massachussetts 02138
g Lexigen Pharmaceuticals Corporation, Lexington, Massachusetts 02421

Correspondence to: Calvin J. Kuo, Stanford University School of Medicine, Hematology Division, CCSR 1155, 269 Campus Dr., Stanford, CA 94305-5156. Tel:(650) 736-1992 Fax:(650) 736-0974 E-mail:cjkuo{at}stanford.edu.

Collagen XVIII (c18) is a triple helical endothelial/epithelial basement membrane protein whose noncollagenous (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.

Key Words: collagen XVIII, endostatin, motility, morphogenesis, extracellular matrix


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