▲ FIGURE 22-32 Proposed intracellular pathways leading to cell death by apoptosis or to trophic factor-mediated cell survival in mammalian cells. (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 (1). 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 (2). Through an as-yet-unknown mechanism, this leads to the release of cytochrome c into the cytosol, where it binds to the adapter protein Apaf-1 (3), promoting a caspase cascade that leads to cell death (4). (b) In some cells, binding of a trophic factor (e.g., NGF) stimulates PI-3 kinase activity, leading to activation of the downstream kinase Akt, which phosphorylates Bad (1). Phosphorylated Bad then forms a complex with the 14-3-3 protein ( 2|). With Bad sequestered in the cytosol, the anti-apoptotic Bcl-2/Bcl-xl proteins can inhibit the activity of Bax ( 3), 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.]

cell death. Phosphorylated Bad, however, cannot bind to Bcl-2/Bcl-xl and is found in the cytosol complexed to the phosphoserine-binding protein 14-3-3. Hence, signaling pathways leading to Bad phosphorylation would be particularly attractive candidates for transmitting survival signals.

A number of trophic factors including NGF have been shown to trigger the PI-3 kinase signaling pathway, leading to activation of a downstream kinase called PKB (see Figure 14-27). Activated PKB phosphorylates Bad at sites known to inhibit its pro-apoptotic activity. Moreover, a constitutively active form of PKB can rescue cultured neurotrophin-deprived neurons, which otherwise would undergo apoptosis and die. These findings support the mechanism for the survival action of trophic factors depicted in Figure 22-32b. In other cell types, different trophic factors may promote cell survival through post-translational modification of other components of the cell-death machinery.

Tumor Necrosis Factor and Related Death Signals Promote Cell Murder by Activating Caspases

Although cell death can arise as a default in the absence of survival factors, apoptosis can also be stimulated by positively acting "death" signals. For instance, tumor necrosis factor (TNF), which is released by macrophages, triggers the cell death and tissue destruction seen in certain chronic inflammatory diseases. Another important death-inducing signal, the Fas ligand, is a cell-surface protein expressed by activated natural killer cells and cytotoxic T lymphocytes. This signal can trigger death of virus-infected cells, some tumor cells, and foreign graft cells.

Both TNF and Fas ligand act through cell-surface "death" receptors that have a single transmembrane domain and are activated when ligand binding brings three receptor molecules into close proximity. The trimeric receptor complex attracts a protein called FADD (Fas-associated death domain), which serves as an adapter to recruit and in some way activate caspase-8, an initiator caspase, in cells receiving a death signal. The death domain found in FADD is a sequence that is present in a number of proteins involved in apoptosis. Once activated, caspase-8 activates other caspases and the amplification cascade begins. To test the ability of the Fas receptor to induce cell death, researchers incubated cells with antibodies against the receptor. These antibodies, which bind and cross-link Fas receptors, were found to stimulate cell death, indicating that activation of the Fas receptor is sufficient to trigger apoptosis.

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