Cell adhesion, migration and tumor invasion are mediated by the interactions of cell surface adhesion receptors, such as integrins, with adhesion proteins in the extracellular matrix and at the surface of other cells. These interactions have profound influences on malignant cells. For example, fibronectin matrix, when formed around tumorigenic cells, can suppress tumorigenicity in such cells. Moreover, peptides containing the cell adhesion sequence RGD can inhibit tumor cell invasion and tumor dissemination in experimental metastasis models. Peptides that bind to the alpha5beta1 integrin appear to be particularly effective in this regard. In this proposal, phage libraries that display random cyclic peptides will be screened for sequences that bind to integrins that recognize the RGD cell attachment motif. The isolated phage and peptides synthesized according to the peptide motifs carried by these phage will be used to study the recognition specificity and ligand-binding site of the alpha5beta1 integrin. The search will also yield peptides with improved affinity and specificity toward the alpha5beta1 integrin. Comparison of the alpha5beta1 binding sequences to those that bind to another RGD- directed integrin, alpha/v/beta3, will be used to explore the relationships of the specificities of these integrins. These peptides will be tested in various in vitro assays for their ability to interfere with tumor cell attachment, proliferation and migration. These experiments will further the understanding of ligand recognition specificities by integrins and provide improved reagents for the study of integrin roles in tumor growth and metastasis.
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