The insulin-like growth factor I receptor (IGF-IR) activated by its ligands controls the proliferation of animal cells in at least 3 different ways: it is mitogenic, it is required for the establishment and maintenance of the transformed phenotype in several types of cells, and it protects from apoptosis, both in vivo and in vitro. The present application focuses on this third aspect, apoptosis, and it is intended to explore the mechanisms(s) by which the IGF-IR exerts its protective effect. In the first project, we wish to determine the domains in the IGF- IR that are necessary for its protective function, in analogy with the previously defined domains for growth and transformation. In the second project, we wish to dissect the signal transducing pathways of the IGF-IR that are involved in the protection from apoptosis. The third project explores the relationship between the IGF-IR and another major player in the apoptotic process: p53. In the fourth project, we wish to determine the relationship between the IGF-IR and other gene products, known to be important in apoptosis, such as tumor necrosis factor, and integrins. Finally, in the last project, a chance discovery that an Aderro vector caused an increase in the number of IGF-IRs, will allow us to ask whether certain Adeno proteins may have an effect on the expression of the receptor. We hope that these studies will yield insights on the mechanism of apoptosis at the basic level, and, at the same time, open the possibility of therapeutic applications.