Integrin-mediated adhesion to extracellular matrix proteins confers resistance to radiation-or drug-induced genotoxic injury. To analyse the underlying mechanisms specific for b1-integrins, wild-type b1A-integrin-expressing GD25b1A cells were compared to GD25b1B cells, which express signaling-incompetent b1B variants. Cells grown on fibronectin, collagen-III, b1-integrin-IgG or poly-l-lysine were exposed to 0-6 Gy X-rays in presence or depletion of growth factors and phosphatidylinositol-3 kinase (PI3K) inhibitors (LY294002, wortmannin). In order to test the relevance of these findings in tumor cells, human A-172 glioma cells were examined under the same conditions after siRNA-mediated silencing of b1-integrins. We found that b1A-integrin-mediated adhesion to fibronectin, collagen-III or b1-IgG was essential for cell survival after radiation-induced genotoxic injury. Mediated by PI3K, pro-survival b1A-integrin/Akt signaling was critically involved in this process. Additionally, the b1-integrin downstream targets p130Cas and paxillinimpaired survival-regulating PI3K-dependent JNK. In A-172 glioma cells, b1-integrin knockdown and PI3K inhibition confirmed the central role of b1-integrins in Akt-and p130Cas/paxillin-mediated prosurvival signaling. These findings suggest b1-integrins as critical regulators of cell survival after radiation-induced genotoxic injury. Elucidation of the molecular circuitry of prosurvival b1-integrin-mediated signaling in tumor cells may promote the development of innovative moleculartargeted therapeutic antitumor strategies.