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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//1233 $5.00
The Journal of Cell Biology, Volume 152, Number 6, , 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
Stanford University School of Medicine, Hematology Division, CCSR 1155, 269 Campus Dr., Stanford, CA 94305-5156.(650) 736-0974(650) 736-1992

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

© 2001 The Rockefeller University Press

The online version of this article contains supplemental material.

Abbreviations used in this paper: DDR, discoidin domain receptor; DN, dominant negative; ECM, extracellular matrix; EGS, ethylene glycol bis-succinimidyl succinate; EK, enterokinase; ERK, extracellular signal–regulated kinase; ES, endostatin; HGF, hepatocyte growth factor; HUVEC, human umbilical vein endothelial cell; MAP, mitogen-activated protein; MAPK, MAP kinase; MEK, MAPK kinase; MSP, macrophage stimulatory protein; NC, noncollagenous; VEGF, vascular endothelial growth factor.


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