Death and survival signals converge to activate components of the posttranscriptional apoptotic machinery, such as the caspases or the Bcl-2 family of proteins.
7 It has been suggested that the balance of pro- and antiapoptotic members of the Bcl-2 family determines life or death in a cell (for review, see Ref.
8 ). Indeed, the regulation of mitochondrial cytochrome
c release and mitochondrial function by several Bcl-2 family members plays a large part in controlling cell death.
9 10 11 BAD, one of the proapoptotic family members, is the first target of Akt, a major inhibitor of apoptosis (for review, see Ref.
12 ). By phosphorylating BAD, Akt precludes its binding to the Bcl-x
L and Bcl-2 antiapoptotic family members leading to increased cell survival.
13 Akt, a serine-threonine protein kinase, is a key component of cell survival pathways and is a major downstream target of phosphoinositide 3-kinase (PI3K), which has been shown to mediate growth factor-induced neuronal survival in a wide variety of circumstances (for review, see Ref.
14 ). Activation of PI3K leads to Akt activation by both phosphoinositide-dependent protein kinase-1 (PDK1), which phosphorylates Akt at Thr-308, and PDK1-independent mechanisms, which result in Akt phosphorylation at Ser-473.
12 14 Akt is also phosphorylated at Ser-473 by the p38 MAPK-activated protein kinase-2 (MAPKAPK-2) pathway.
15 16 MAPKAPK-2 activates both Akt and the small heat shock protein 27 (HSP27).
16 17 18 Moreover, there is evidence that the three components p38 MAPK, MAPKAPK-2, and HSP27 form a signaling complex with Akt.
15 As a general mediator of cell survival, activated Akt catalyzes the phosphorylation of the Forkhead-related family of mammalian transcription factors (FKHRs; for review, see Ref.
12 ,
14 ). FKHRs are inhibited when phosphorylated, which prevents them from stimulating the transcription of cell death genes, resulting in the inhibition of transcription-dependent apoptosis (for review, see Ref.
19 ). Further, the PI3K/Akt signaling pathway is negatively regulated by the tumor-suppressor phosphatase PTEN through the latter’s ability to dephosphorylate the lipid second messenger phosphatidylinositol.
20 21 PTEN is thought to promote apoptosis by facilitating caspase-8 activation and Bid cleavage through a Fas-associated death domain (FADD)-dependent pathway.
22 Its function has been shown to be inhibited by the Src protein-tyrosine kinases that efficiently induce PTEN tyrosine phosphorylation, leading to the activation of the PI3K/Akt signaling pathway.
23