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ADAMTS1/METH1 inhibits endothelial cell proliferation by direct binding and sequestration of VEGF165
Alfonso Luque1, Darren R Carpizo, M Luisa Iruela-Arispe
1Department of Molecular, University of California, Los Angeles, California 90095, USA.
Abstract:
ADAMTS1 is a metalloprotease previously shown to inhibit angiogenesis in a variety of in vitro and in vivo assays. In the present study, we demonstrate that ADAMTS1 significantly blocks VEGFR2 phosphorylation with consequent suppression of endothelial cell proliferation. The effect on VEGFR2 function was due to direct binding and sequestration of VEGF165 by ADAMTS1. Binding was confirmed by co-immunoprecipitation and cross-linking analysis. Inhibition of VEGF function was reversible, as active VEGF could be recovered from the complex. The interaction required the heparin-binding domain of the growth factor, because VEGF121 failed to bind to ADAMTS1. Structure/function analysis with independent ADAMTS1 domains indicated that binding to VEGF165 was mediated by the carboxyl-terminal (CT) region. ADAMTS1 and VEGF165 were also found in association in tumor extracts. These findings provide a mechanism for the anti-angiogenic activity of ADAMTS1 and describe a novel modulator of VEGF bioavailability.
Insights
ADAMTS1 metalloprotease inhibits angiogenesis by binding VEGF165, blocking VEGFR2 phosphorylation and endothelial cell proliferation. This interaction, mediated by ADAMTS1's C-terminal region, offers a new mechanism for controlling blood vessel growth.
Area of Science:
- Biochemistry
- Molecular Biology
- Cell Biology
Background:
- ADAMTS1 is a metalloprotease known to inhibit angiogenesis.
- Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) signaling is crucial for angiogenesis.
Purpose of the Study:
- To elucidate the mechanism by which ADAMTS1 inhibits angiogenesis.
- To investigate the interaction between ADAMTS1 and Vascular Endothelial Growth Factor (VEGF).
Main Methods:
- Co-immunoprecipitation and cross-linking analysis to confirm binding.
- In vitro and in vivo angiogenesis assays.
- Structure/function analysis of ADAMTS1 domains.
Main Results:
- ADAMTS1 significantly blocks VEGFR2 phosphorylation, suppressing endothelial cell proliferation.
- ADAMTS1 directly binds and sequesters VEGF165, requiring the heparin-binding domain of VEGF165.
- Binding is mediated by the carboxyl-terminal region of ADAMTS1.
- ADAMTS1 and VEGF165 associate in tumor extracts.
Conclusions:
- ADAMTS1 exerts anti-angiogenic activity by directly inhibiting VEGF165 function.
- ADAMTS1 acts as a novel modulator of VEGF bioavailability.
- This interaction provides a potential therapeutic target for angiogenesis-related diseases.