Akt Promotes Cell Survival by Phosphorylating and Inhibiting a Forkhead Transcription Factor

Anne Brunet, Azad Bonni, Michael J Zigmond, Michael Z Lin, Peter Juo, Linda S Hu, Michael J Anderson, Karen C Arden, John Blenis, Michael E Greenberg
1999 Cell  
Recently, a signaling pathway by which extracellular * Division of Neuroscience stimuli suppress apoptosis has been characterized. Sur-Children's Hospital and Department of Neurobiology vival factors, such as insulin-like growth factor 1 (IGF1) Harvard Medical School and neurotrophins, bind to their cell surface receptors Boston, Massachusetts 02115 and trigger the activation of several kinases, including † Department of Cell Biology the phosphatidylinositol 3-kinase (PI3K) (Fruman et al.,
more » ... rd Medical School 1998) and the Ca 2ϩ /calmodulin-dependent kinase ki-Boston, Massachusetts 02115 nase (Yano et al., 1998). These kinases in turn lead to ‡ Ludwig Institute for Cancer Research the activation of a serine/threonine kinase termed Akt University of California at San Diego or PKB (for reviews, Datta and Greenberg, 1998; Down-San Diego, California 92093 ward, 1998). Akt plays a central role in promoting the survival of a wide range of cell types (Dudek et al., 1997; Kauffmann-Zeh et al., 1997; Kennedy et al., 1997; Summary Songyang et al., 1997). Recently, two Akt substrates that are components of the intrinsic cell death machinery Survival factors can suppress apoptosis in a transcriphave been identified: the Bcl2 family member BAD (Datta tion-independent manner by activating the serine/ et al., 1997; del Peso et al., 1997) and the protease threonine kinase Akt, which then phosphorylates and Caspase 9 (Cardone et al., 1998; Y. Gotoh et al., unpubinactivates components of the apoptotic machinery, lished data). In both cases, phosphorylation of these including BAD and Caspase 9. In this study, we demonproteins by Akt suppresses their proapoptotic function, strate that Akt also regulates the activity of FKHRL1, thereby accounting at least in part for the potent survival a member of the Forkhead family of transcription faceffects of Akt. tors. In the presence of survival factors, Akt phosphor-If Akt is a general mediator of cell survival, it is possible ylates FKHRL1, leading to FKHRL1's association with that this kinase catalyzes the phosphorylation of other 14-3-3 proteins and FKHRL1's retention in the cytosubstrates in addition to BAD and Caspase 9. One possiplasm. Survival factor withdrawal leads to FKHRL1 bility that remained to be examined was that Akt might dephosphorylation, nuclear translocation, and target phosphorylate and regulate the activity of transcription gene activation. Within the nucleus, FKHRL1 triggers factors that control cell death genes. This hypothesis is apoptosis most likely by inducing the expression of supported by the observation that Akt translocates into genes that are critical for cell death, such as the Fas the nucleus upon exposure of cells to survival factors ligand gene. (Andjelkovic et al., 1997). Although Akt targets within the nucleus remained to be identified, genetic studies of the PI3K/Akt signaling pathway in the nematode
doi:10.1016/s0092-8674(00)80595-4 pmid:10102273 fatcat:lisyektaqnfrzgnonbecvriqgi