The details of these pathways in any given cell type are not yet known. (a) In the absence of a trophic factor. Bad, a soluble pro-apoptotic protein, binds to the anti-apoptotic proteins Bcl-2 and Bcl-xl, which are inserted into the mitochondrial membrane. Bad binding prevents the anti-apoptotic proteins from interacting with Bax, a membrane-bound pro-apoptotic protein. As a consequence, Bax forms homo-oligomeric channels in the membrane that mediate ion flux. Through an as-yet unknown mechanism, this leads to the release of cytochrome c from the space between the inner and outer mitochondrial membrane. Cytochrome c then binds to the adapter protein Apaf-1, which in turn promotes a caspase cascade leading to cell death. (b) In the presence of a trophic factor such as NGF. In some cells, binding of trophic factors stimulates PI-3 kinase activity, leading to activation of the downstream kinase Akt, which phosphorylates Bad. Phosphorylated Bad then forms a complex with the 14 - 3 - 3 protein. With Bad sequestered in the cytosol, the antiapoptotic Bcl-2/Bcl-xl proteins can inhibit the activity of Bax, thereby preventing the release of cytochrome c and activation of the caspase cascade. [Adapted from B. Pettman and C. E. Henderson, 1998, Neuron 20:633.]