Angiogenesis Inhibitors in Breast Cancer
Abstract
METH1/ADAMTS1 is a metalloprotease with a disintegrin motif and three thrombospondin anti-angiogenic domains in the carboxy. terminal. METH1 was previously shown to inhibit angiogenesis in a variety of in vitro and in vivo assays. In the present study, 1 demonstrate that METH1 significantly blocks VEGFR2 phosphorylation with consequent suppression of endothelial cell proliferation. The effect on VEGFR2 function was due to direct binding and sequestration of the VEGF165 by ADAMTS1. Binding was confirmed by co-immunoprecipitation and crosslinking 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, as VEGF(sub 121) failed to bind to ADAMTS1. Structure/function analysis with independent ADAMTS1 domains indicated that binding to VEGF(sub 165) was mediated by the carboxy terminal (CT) region. ADAMTS1 and VEGF(sub 165) 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.
Document Details
- Document Type
- Technical Report
- Publication Date
- Apr 01, 2003
- Accession Number
- ADA420135
Entities
People
- Alfonso Luque
- Luisa Iruela-arispe
Organizations
- University of California, Los Angeles