Fig. 2. Integrin-mediated resistance to stress-induced apoptosis via the Ras-PI-3-kinase-Akt pathway. Cell stresses such as serum withdrawal result in the localization of proapoptotic Bcl-2 family proteins, such as Bad (or Bod or Bax), at the mitochondria, which results in cytochrome C leakage and Apaf-1-mediated assembly of the caspase-9-containing apoptosome complex. Ras-mediated activation of PI 3-kinase triggers the phosphorylation of Akt through the functions of phosphoinositide-dependent kinases (PDKs), such as PDK1, PDK2 and ILK. Akt then acts as a central regulator of cell survival, phosphorylating mTOR (and E4BP, allowing iEF-4E activation of CAP-dependent translation; not shown), while also phosphorylating the proapoptotic protein Bad, leading to displacement from the mitochondria and sequestration by chaperones of the 14-3-3 family. Akt also potentiates the transactivating potential of NFkB, leading to the increased expression of NFkB target genes, including Bcl-2 and Bcl-_xl., Akt signaling is attenuated by the action of phosphatases such as PTEN.