| Little information is currently available regarding the biochemical and molecular mechanisms by which the functional activity of specific proteins in angiogenesis is regulated. Integrins are one class of cell surface receptors that have been implicated in the regulation of a diverse set of angiogenic cellular processes including cell adhesion, migration and invasion. However, these processes also require the proteolytic properties of matrix-degrading enzymes, such as the metalloproteinases (MMPs), the activity of growth factors and their receptors, extracellular matrix components, as well as cytoplasmic cytoskeletal and signaling proteins.; Previous studies have shown that integrin αvβ3 is a receptor for MMP-2, localizing its proteinase activity to the cell surface, leading to site-specific ECM degradation. Here we investigate the possibility of a inter-play between MMP-9, and integrin α5β1. In fact, our study shows a co-localization of MMP-9 and α5β1 in tumor tissue and a direct protein-protein interaction in solid-phase binding assays. To further investigate our hypothesis, we consider a tetrapeptide, LRSG, which is a dimerizing sequence common to the extracellular domain of β1 integrin as well as the C-terminal hemopexin domain of MMP-9. Importantly, we used the LRSG sequence as an antigen to generate a monoclonal antibody, FM155, in an effort to identify its physiological relevance.; Our study provides evidence that LRSG is a cryptic motif, activated upon receptor's activation. In the context of cancer, integrins activation translates into induced angiogenesis and tumor progression. Interestingly, targeting this cryptic motif by MabFM155 inhibits endothelial cell migration in vitro, as well as abrogates tumor growth and angiogenesis in vivo. Our studies further potentiate the possible role MMP-9 and α5β1 play in cancer as well as ameliorate our prospects in developing effective cancer therapy. |
