Oligomerization-dependent regulation of motility and morphogenesis by the collagen XVIII NC1/endostatin domain.
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.
Department of Surgery, Children's Hospital, Harvard Medical School, Boston. Massachusetts 02115, USA. cjkuo@stanford.edu
C J
CJ
Kuo
K R
KR
LaMontagne
G
G
Garcia-Cardeña
B D
BD
Ackley
D
D
Kalman
S
S
Park
R
R
Christofferson
J
J
Kamihara
Y H
YH
Ding
K M
KM
Lo
S
S
Gillies
J
J
Folkman
R C
RC
Mulligan
K
K
Javaherian
D020533:Angiogenesis Inhibitors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001426:Bacterial Proteins; D001427:Bacterial Toxins / Q000494:pharmacology; D015153:Blotting, Western; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D003094:Collagen / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D043170:Collagen Type XVIII; D003603:Cytotoxins / Q000494:pharmacology; D019281:Dimerization; D043169:Endostatins; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects / Q000254:growth & development; D005109:Extracellular Matrix / Q000502:physiology*; D006801:Humans; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009024:Morphogenesis; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D020764:cdc42 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D001426:Bacterial Proteins; D001427:Bacterial Toxins; D043170:Collagen Type XVIII; D003603:Cytotoxins; D043169:Endostatins; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; C031815:toxB protein, Clostridium difficile; D003094:Collagen; D020928:Mitogen-Activated Protein Kinases; D020764:cdc42 GTP-Binding Protein; D020744:rac GTP-Binding Proteins; D020741:rho GTP-Binding Proteins