We saw earlier that neurotrophins such as NGF protect neurons from cell death; this effect is mediated by inactivation of a pro-apoptotic BH3-only protein called Bad. In the absence of trophic factors, Bad is nonphosphorylated and binds to Bcl-2, or to the closely related anti-apoptotic protein Bcl-xL, at the outer mitochondrial membrane (see Figure 21-40). This binding inhibits the ability of Bcl-2 and Bcl-xL to bind Bax and Bak, thereby allowing Bak and Bax to oligomerize and form pores and holes in the outer mitochondrial membrane.
A number of trophic factors, including NGF, induce the PI-3 kinase signaling pathway, leading to the activation of protein kinase B (see Figure 16-29). Activated protein kinase B phosphorylates Bad; phosphorylated Bad cannot bind to Bcl-2 or Bcl-xL and is found in the cytosol complexed to the phosphoserine-binding protein 14-3-3 (see Figure 16-24). As evidence for this pathway, a constitutively active form of protein kinase B can rescue cultured neurotrophin-deprived neurons, which would otherwise undergo apoptosis and die. These findings support the mechanism for the survival action of trophic factors depicted in Figure 21-40. In other cell types, different trophic factors may promote cell survival through post-translational modification of other components of the cell-death machinery.