Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Angiogenesis Inhibitors / genetics
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Angiogenesis Inhibitors / metabolism
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Animals
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Bacterial Proteins*
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Bacterial Toxins / pharmacology
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Blotting, Western
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Cell Movement / drug effects
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Cell Movement / physiology*
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Cells, Cultured
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Collagen / chemistry
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Collagen / genetics
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Collagen / metabolism*
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Collagen Type XVIII
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Cytotoxins / pharmacology
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Dimerization
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Endostatins
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Endothelium, Vascular / cytology*
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Endothelium, Vascular / drug effects
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Endothelium, Vascular / growth & development
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Extracellular Matrix / physiology*
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Humans
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Mice
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Mitogen-Activated Protein Kinases / metabolism
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Morphogenesis
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Peptide Fragments / chemistry
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Peptide Fragments / genetics
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Peptide Fragments / metabolism*
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Protein Structure, Tertiary*
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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cdc42 GTP-Binding Protein / genetics
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cdc42 GTP-Binding Protein / metabolism
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rac GTP-Binding Proteins / genetics
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rac GTP-Binding Proteins / metabolism
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rho GTP-Binding Proteins / metabolism
Substances
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Angiogenesis Inhibitors
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Bacterial Proteins
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Bacterial Toxins
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Collagen Type XVIII
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Cytotoxins
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Endostatins
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Peptide Fragments
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Recombinant Fusion Proteins
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toxB protein, Clostridium difficile
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Collagen
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Mitogen-Activated Protein Kinases
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cdc42 GTP-Binding Protein
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rac GTP-Binding Proteins
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rho GTP-Binding Proteins