The PI 3-kinase/Akt signaling pathway delivers an anti-apoptotic signal.

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 Ratla fibroblasts, activated Akt did not alter Bcl-2 or Bcl-X^ 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.

Tuberous sclerosis complex is required for tumor maintenance in MYC‐driven Burkitt's lymphoma

“…Hyperactivation of mTORC1 in certain cell types results in suppression of AKT kinase activity through negative feedback, which is reflected by the hypophosphorylation of Thr308 and Ser493 (Harrington et al , 2004; Manning, 2004; Rozengurt et al , 2014). Since AKT has a known anti‐apoptotic activity (Ahmed et al , 1997; Dudek et al , 1997; Kauffmann‐Zeh et al , 1997; Kennedy et al , 1997), a potential inhibition of AKT could be involved in the observed cell death. However, in a panel of BL cell lines, TSC1 knockdown either resulted in an increase in Ser493 phosphorylation or did not change Ser493 phosphorylation of AKT, while we were unable to detect any Thr308 phosphorylation in our assay (Fig EV4A).…”

Inhibition of Myc-dependent apoptosis by eukaryotic translation initiation factor 4E requires cyclin D1

“…Rescue of cycling cells by growth factors, at least in part, occurs through the PI3/Akt kinase pathway, which can operate independently of translational control (Datta et al, 1997;del Peso et al, 1997;Franke et al, 1997;Gonzalez-Garcia et al, 1997;Kennedy et al, 1997). We have reported a growth factor activated anti-apoptotic mechanism which operates through translation initiation factor 4E (eIF4E) (Polunovsky et al, 1996).…”

Concomitant activation of MEK-1 and Rac-1 increases the proliferative potential of thyroid epithelial cells, without affecting their differentiation

“…In contrast, Ras transformed thyroid cells proliferate faster, and such an high rate of proliferation could be essential for tumor formation in vivo. In addition Ras is known to protect cells from apoptosis through an AKT/PKB-dependent mechanism (Kennedy et al, 1997). Since neither MEK-1 or Rac-1 are able to activate this pathway, it is conceivable that cells carrying MEK-1 and Rac-1 might be more susceptible to apoptosis during tumor formation, even if their rate of apoptosis in thyroid cell cultures is very low and comparable to wild type controls (GC and CM, unpublished observations).…”