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Survival signaling pathways in neurons. Schematic representation of pathways that promote neuronal survival. In this model, a major factor contributing to the survival of CNS neurons is the stimulation of the PI3K-Akt kinase pathway following trophic factor receptor activation. Akt is a central player as it phosphorylates a number of critical substrates. For example, phosphorylation of the forkhead transcription factor inhibits its ability to transcribe death-promoting genes, while the phosphorylation of Bad promotes its separation from Bcl2/Bcl-X_L and its sequestration by the 14-3-3 protein. The sequestration of Bad allows Bcl2/Bcl-X_L to suppress the death-promoting action of Bax and Bak at the mitochondria. Akt has also been shown to antagonize the apoptotic action of p53 in hippocampal neurons, as well as caspase-9 activity, although the latter action has only been demonstrated for human caspase-9. Akt phosphorylates hexokinase, which in turn maintains the voltage-dependent anion channel in an active state, preventing the opening of the permeability transition pore. Akt has also been shown to enhance the degradation of IκB, thus helping to promote NF-κB-mediated transcriptional activation. NF-κB induces the caspase inhibitors IAP1 and IAP2 and pro-survival Bcl-2 family members Bcl-X_L and Bfl-1/A1 (not shown). The extracellular signal-regulated kinase, ERK, is also activated in response to trophic factor signaling. ERK phosphorylates multiple substrates and its phosphorylation of Bad, acting in concert with Akt, promotes the sequestration of Bad by 14-3-3. Heat shock proteins (HSP) are induced by a wide array of insults and act at multiple levels to mitigate stress signals by inhibiting caspase activation or through interactions with JNK-1.