Once fully activated, PKB can dissociate from the plasma membrane and phosphorylate its many target proteins throughout the cell, which have a wide range of effects on cell behavior. In many cells, activated PKB directly phosphorylates and inactivates pro-apoptotic proteins such as Bad, a short-term effect that prevents activation of an apoptotic pathway leading to cell death (see Figure 21-40). Activated PKB also promotes survival of many cultured cells by phosphorylating the Forkhead transcription factor FOXO3a on multiple serine/threonine residues, thereby reducing its ability to induce expression of several pro-apoptotic genes. In the absence of growth factors, FOXO3a is nonphosphorylated and mainly localizes to the nucleus, where it activates transcription of several genes encoding pro-apoptotic proteins. When growth factors are added to the cells, PKB becomes active and phosphorylates FOXO3a. This allows the cytosolic phosphoserine-binding protein 14-3-3 to bind FOXO3a and thus sequester it in the cytosol. (Recall that 14-3-3 also retains many other phosphorylated proteins, including Raf, in an inactive state in the cytosol; see Figure 16-24.) A FOXO3a mutant in which the three serine residues that are targets for PKB are mutated to alanines is constitutively active and initiates apoptosis even in the presence of activated PKB. This finding demonstrates the importance of FOXO3a and PKB in controlling apoptosis of cultured cells. Deregulation of PKB is implicated in the pathogenesis of both cancer and diabetes, and in Section 16.8 we will see how PKB, activated downstream of the insulin RTK, promotes glucose uptake and storage in muscle and liver. This is another example of one signaling pathway controlling different cellular functions in different cells.