ADAMTS-2 functions as anti-angiogenic and anti-tumoral molecule independently of its catalytic activity.
ADAMTS-2 is a metalloproteinase that plays a key role in the processing of fibrillar procollagen precursors into mature collagen molecules by excising the amino-propeptide. We demonstrate that recombinant ADAMTS-2 is also able to reduce proliferation of endothelial cells, and to induce their retraction and detachment from the substrate resulting in apoptosis. Dephosphorylation of Erk1/2 and MLC largely precedes the ADAMTS-2 induced morphological alterations. In 3-D culture models, ADAMTS-2 strongly reduced branching of capillary-like structures formed by endothelial cells and their long-term maintenance and inhibited vessels formation in embryoid bodies (EB). Growth and vascularization of tumors formed in nude mice by HEK 293-EBNA cells expressing ADAMTS-2 were drastically reduced. A similar anti-tumoral activity was observed when using cells expressing recombinant deleted forms of ADAMTS-2, including catalytically inactive enzyme. Nucleolin, a nuclear protein also found to be associated with the cell membrane, was identified as a potential receptor mediating the antiangiogenic properties of ADAMTS-2.
Dubail
J
J
Laboratory of Connective Tissues Biology, GIGA-R, Tour de Pathologie, B23/3, 4000, Sart Tilman, Belgium.
Kesteloot
F
F
Deroanne
C
C
Motte
P
P
Lambert
V
V
Rakic
J-M
JM
Lapière
C
C
Nusgens
B
B
Colige
A
A
D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism*; D000071096:ADAMTS Proteins; D000071121:ADAMTS4 Protein; D020533:Angiogenesis Inhibitors / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002417:Cattle; D002460:Cell Line; D049109:Cell Proliferation; D058732:Embryoid Bodies / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D009374:Neoplasms, Experimental; D009389:Neovascularization, Pathologic; D011348:Procollagen N-Endopeptidase / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
D020533:Angiogenesis Inhibitors; D011994:Recombinant Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D051722:ADAM Proteins; D000071096:ADAMTS Proteins; C000609307:ADAMTS2 protein, human; C000609308:Adamts2 protein, mouse; D011348:Procollagen N-Endopeptidase; D000071121:ADAMTS4 Protein