RADIATION SIGNALING THROUGH THE ALPHA6 BETA 4 INTEGRIN

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DESCRIPTION (Provided by applicant): Integrins are cell adhesion and signaling receptors responsive to alterations in the extracellular environment. In the previous three year grant, our objective was to determine whether ionizing radiation activates the A6 integrin resulting in a phosphotyrosine signal and to determine whether this can be influenced by the natural or synthetic ligands. Our results show that the A6 integrin is activated in response to irradiation and that ionizing radiation will activate A6 integrin containing adhesion sites. The integrin linked kinase (ILK) is implicated as a downstream signaling event since a corresponding Akt/PKB phosphorylation is detected. The extracellular matrix ligands influence the response. In addition, a phosphotyrosine signal within the adhesion site located on paxillin is detected. We propose to extend these studies with the following aims: 1. Determine if the mechanism of IR signaling involves integrin linked kinase (ILK) activation. 2. Determine if focal adhesion site proteins are essential to the IR generated signal. 3. Determine if the extracellular domain of the A6 integrin (containing the beta barrel domain) or a specific splice variant of the B1 integrin is essential to the phosphorylation signals. 4. Determine if anti-adhesion peptides or natural ligands will alter the IR signal. The proposed work will add to our current knowledge of cellular signaling of a radiation damage response, basic integrin biology and suggest ways to increase the efficacy of the radiation treatment of A6 integrin expressing epithelial cancers.