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The PI 3-kinase/Akt signaling pathway delivers an anti-apoptotic signal
S G Kennedy1, A J Wagner, S D Conzen
1The Ben May Institute for Cancer Research and Department of Pharmacological and Physiological Sciences, The University of Chicago, Illinois 60637, USA.
Abstract:
Serum and certain growth factors have the ability to inhibit programmed cell death (apoptosis) and promote survival. The mechanism by which growth factors deliver an anti-apoptotic signal and the mechanism by which this survival signal is uncoupled from mitogenesis are not clear. We studied five downstream effectors of growth factor receptors--Ras, Raf, Src, phosphoinositide 3-kinase (PI 3-kinase), and Akt (PKB)--for their abilities to block apoptosis. Activated forms of Ras, Raf, and Src, although transforming, were not sufficient to deliver a survival signal upon serum withdrawal. In contrast, inhibition of PI 3-kinase accelerated apoptosis, and an activated form of the serine/threonine kinase Akt, a downstream effector of PI 3-kinase, blocked apoptosis. The ability of Akt to promote survival was dependent on and proportional to its kinase activity. In Rat1a fibroblasts, activated Akt did not alter Bcl-2 or Bcl-X(L) expression but inhibited Ced3/ICE-like activity. Thus, the PI 3-kinase/Akt (PKB) signaling pathway transduces a survival signal that ultimately blocks Ced3/ICE-like activity. These results suggest that uncoupling of survival and mitogenesis can be explained by differing abilities of distinct mitogens to efficiently induce the PI 3-kinase/Akt signaling pathway.
Insights
Growth factors inhibit apoptosis via the PI 3-kinase/Akt pathway, blocking cell death signals. This pathway
Area of Science:
- Cellular Biology
- Molecular Signaling
- Apoptosis Research
Background:
- Growth factors and serum inhibit programmed cell death (apoptosis) and promote cell survival.
- The precise mechanisms by which growth factors signal anti-apoptosis and how this signal is separated from mitogenesis remain unclear.
Purpose of the Study:
- To investigate the roles of five key downstream effectors of growth factor receptors—Ras, Raf, Src, phosphoinositide 3-kinase (PI 3-kinase), and Akt (also known as protein kinase B or PKB)—in blocking apoptosis.
- To elucidate the signaling pathway responsible for transducing survival signals and its relationship with mitogenesis.
Main Methods:
- Studied the effects of activated forms of Ras, Raf, Src, and Akt on apoptosis.
- Investigated the impact of PI 3-kinase inhibition on apoptosis.
- Assessed the kinase activity of Akt and its effect on apoptosis and gene expression (Bcl-2, Bcl-X(L)).
- Examined the inhibition of Ced3/ICE-like activity by activated Akt in Rat1a fibroblasts.
Main Results:
- Activated Ras, Raf, and Src were insufficient to prevent apoptosis upon serum withdrawal.
- Inhibition of PI 3-kinase accelerated apoptosis, while activated Akt blocked apoptosis.
- Akt's survival-promoting ability correlated directly with its kinase activity.
- Activated Akt inhibited Ced3/ICE-like activity without altering Bcl-2 or Bcl-X(L) expression.
Conclusions:
- The phosphoinositide 3-kinase (PI 3-kinase)/Akt signaling pathway transmits a survival signal that ultimately inhibits Ced3/ICE-like activity, thereby blocking apoptosis.
- The uncoupling of cell survival from mitogenesis can be attributed to the varying efficiencies of different mitogens in inducing the PI 3-kinase/Akt pathway.