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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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Motile response of nonendothelial cell types to c18 derivatives. PC12 and 293T cells were cultured with hES monomer (3,000 nM), hES dimer (25 nM), or hNC1 (50 nM) on Matrigel for 16 h and photographed under phase–contrast (magnification ×200 [bottom]).
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Figure 5: Motile response of nonendothelial cell types to c18 derivatives. PC12 and 293T cells were cultured with hES monomer (3,000 nM), hES dimer (25 nM), or hNC1 (50 nM) on Matrigel for 16 h and photographed under phase–contrast (magnification ×200 [bottom]).

Mentions: The ability of c18 NC1 or ES dimer to induce motility of nonendothelial cell types was evaluated using PC12 pheochromocytoma cells or 293T embryonic kidney cells plated on Matrigel. Under these plating conditions, these cell lines aggregated into multicellular collections (Fig. 5). However, culture with ES dimer or c18 NC1 produced a dispersed phenotype resembling plastic-plated cells rather than forming multicellular aggregates, with ES monomer completely inactive (Fig. 5). We have also observed similar results with NIH 3T3 fibroblasts and Lewis lung carcinoma (data not shown). The trimeric c18 NC1 domain can thus modulate the matrix-regulated motility and morphogenesis of numerous cell types and possesses considerably broader tissue tropism than described for monomeric c18 ES domains (O'Reilly et al. 1997; Dhanabal et al. 1999a,Dhanabal et al. 1999b; Yamaguchi et al. 1999).


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)

Motile response of nonendothelial cell types to c18 derivatives. PC12 and 293T cells were cultured with hES monomer (3,000 nM), hES dimer (25 nM), or hNC1 (50 nM) on Matrigel for 16 h and photographed under phase–contrast (magnification ×200 [bottom]).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2199214&req=5

Figure 5: Motile response of nonendothelial cell types to c18 derivatives. PC12 and 293T cells were cultured with hES monomer (3,000 nM), hES dimer (25 nM), or hNC1 (50 nM) on Matrigel for 16 h and photographed under phase–contrast (magnification ×200 [bottom]).
Mentions: The ability of c18 NC1 or ES dimer to induce motility of nonendothelial cell types was evaluated using PC12 pheochromocytoma cells or 293T embryonic kidney cells plated on Matrigel. Under these plating conditions, these cell lines aggregated into multicellular collections (Fig. 5). However, culture with ES dimer or c18 NC1 produced a dispersed phenotype resembling plastic-plated cells rather than forming multicellular aggregates, with ES monomer completely inactive (Fig. 5). We have also observed similar results with NIH 3T3 fibroblasts and Lewis lung carcinoma (data not shown). The trimeric c18 NC1 domain can thus modulate the matrix-regulated motility and morphogenesis of numerous cell types and possesses considerably broader tissue tropism than described for monomeric c18 ES domains (O'Reilly et al. 1997; Dhanabal et al. 1999a,Dhanabal et al. 1999b; Yamaguchi et al. 1999).

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