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Oligomerization-dependent regulation of motility and morphogenesis by the collagen XVIII NC1/endostatin domain.

Kuo CJ, LaMontagne KR, Garcia-Cardeña G, Ackley BD, Kalman D, Park S, Christofferson R, Kamihara J, Ding YH, Lo KM, Gillies S, Folkman J, Mulligan RC, Javaherian K - J. Cell Biol. (2001)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Children's Hospital, Harvard Medical School, Boston. Massachusetts 02115, USA. cjkuo@stanford.edu

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.

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Comparison of c18 and HGF motogenic activities. HUVEC tubules on Matrigel for 18 h (top) or MDCK cells on plastic (bottom) were treated with HGF (50 ng/ml), hES monomer (3,500 nM), hES dimer (50 nM), or c18 NC1/hES trimer (50 nM) for 24 h and photographed. Top, magnification ×200; bottom, ×100. Note complete absence of HGF response in HUVECs on Matrigel and complete absence of c18 responses in MDCK cells on plastic.
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Figure 6: Comparison of c18 and HGF motogenic activities. HUVEC tubules on Matrigel for 18 h (top) or MDCK cells on plastic (bottom) were treated with HGF (50 ng/ml), hES monomer (3,500 nM), hES dimer (50 nM), or c18 NC1/hES trimer (50 nM) for 24 h and photographed. Top, magnification ×200; bottom, ×100. Note complete absence of HGF response in HUVECs on Matrigel and complete absence of c18 responses in MDCK cells on plastic.

Mentions: Given the ability of HGF and c18 NC1 to induce motility and disaggregation of cells, effects on HUVEC tube formation were compared. In contrast to c18 NC1 and ES dimers, HGF did not promote motility of HUVECs (Fig. 6, top), despite abundant expression of the HGF receptor c-met on HUVECs (Bussolino et al. 1992). On the other hand, HGF potently disaggregated and scattered MDCK (Fig. 6, bottom) and HepG2 cells (data not shown) on plastic, whereas NC1 and ES dimers were inactive under these conditions (Fig. 6, bottom). MSP was also unable to disaggregate HUVEC tubules on Matrigel (data not shown). Notably, HGF stimulates tube formation in collagen matrices (Bussolino et al. 1992; Grant et al. 1993; Tamagnone and Comoglio 1997), as opposed to the antitubulogenic effects of c18 NC1 described here for endothelial cells. The collagen XVIII NC1 domain therefore defines a novel class of motogenic factor which strictly requires the presence of ECM and is both structurally and functionally distinct from HGF/MSP.


Oligomerization-dependent regulation of motility and morphogenesis by the collagen XVIII NC1/endostatin domain.

Kuo CJ, LaMontagne KR, Garcia-Cardeña G, Ackley BD, Kalman D, Park S, Christofferson R, Kamihara J, Ding YH, Lo KM, Gillies S, Folkman J, Mulligan RC, Javaherian K - J. Cell Biol. (2001)

Comparison of c18 and HGF motogenic activities. HUVEC tubules on Matrigel for 18 h (top) or MDCK cells on plastic (bottom) were treated with HGF (50 ng/ml), hES monomer (3,500 nM), hES dimer (50 nM), or c18 NC1/hES trimer (50 nM) for 24 h and photographed. Top, magnification ×200; bottom, ×100. Note complete absence of HGF response in HUVECs on Matrigel and complete absence of c18 responses in MDCK cells on plastic.
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Related In: Results  -  Collection

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Figure 6: Comparison of c18 and HGF motogenic activities. HUVEC tubules on Matrigel for 18 h (top) or MDCK cells on plastic (bottom) were treated with HGF (50 ng/ml), hES monomer (3,500 nM), hES dimer (50 nM), or c18 NC1/hES trimer (50 nM) for 24 h and photographed. Top, magnification ×200; bottom, ×100. Note complete absence of HGF response in HUVECs on Matrigel and complete absence of c18 responses in MDCK cells on plastic.
Mentions: Given the ability of HGF and c18 NC1 to induce motility and disaggregation of cells, effects on HUVEC tube formation were compared. In contrast to c18 NC1 and ES dimers, HGF did not promote motility of HUVECs (Fig. 6, top), despite abundant expression of the HGF receptor c-met on HUVECs (Bussolino et al. 1992). On the other hand, HGF potently disaggregated and scattered MDCK (Fig. 6, bottom) and HepG2 cells (data not shown) on plastic, whereas NC1 and ES dimers were inactive under these conditions (Fig. 6, bottom). MSP was also unable to disaggregate HUVEC tubules on Matrigel (data not shown). Notably, HGF stimulates tube formation in collagen matrices (Bussolino et al. 1992; Grant et al. 1993; Tamagnone and Comoglio 1997), as opposed to the antitubulogenic effects of c18 NC1 described here for endothelial cells. The collagen XVIII NC1 domain therefore defines a novel class of motogenic factor which strictly requires the presence of ECM and is both structurally and functionally distinct from HGF/MSP.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Children's Hospital, Harvard Medical School, Boston. Massachusetts 02115, USA. cjkuo@stanford.edu

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.

Show MeSH
Related in: MedlinePlus