Akt Like a Woman

he oncogenic murine AKT8 retrovirus was identified almost 25 years ago, and the presence of the causative oncogenic agent v-akt was subsequently demonstrated in transformed cells or tumors from both mice and humans. 1,2he cellular homolog of v-akt was cloned in the early 1990s and was termed c-Akt (or simply Akt).Largely on the basis of its sequence similarity to both protein kinases A and C, it was concluded that Akt (alternatively known as protein kinase B [PKB]) represented a Ser-/Thr-protein kinase.Three mammalian genes have been identified, with transcripts of akt1 and akt2 being highly expressed in heart.The explosion of interest in Akt was the direct consequence of the realization that it is an effector of the lipid signaling molecule phosphatidylinositol 3,4,5trisphosphate [PtdIns(3,4,5)P 3 ] (Figure ).By binding to their transmembrane receptor protein tyrosine kinases, a variety of growth factors, including insulin and insulin-like growth factor 1 (IGF1), activate the lipid kinase phosphatidylinositol 3-kinase (PI3K) to phosphorylate the membrane phospholipid PtdIns(4,5)P 2 , producing PtdIns(3,4,5)P 3 .PtdIns(3,4,5)P 3 remains in the plane of the membrane and may serve to recruit Akt to this compartment from its normal cytoplasmic location by binding to the Akt pleckstrin-homology domain. 1,2In addition, PtdIns(3,4,5)P 3 activates PtdIns(3,4,5)P 3 -dependent protein kinase, which phosphorylates Akt on a Thr-residue (Thr 308 in Akt1/PKB␣, Thr 309 in Akt2/PKB␤, and Thr 305 in PKB␥). 2 Activation of Akt1/PKB␣ and Akt2/PKB␤ also requires phosphorylation of Ser 473 and Ser 474 , respectively, although the kinase involved is not clear and the site is absent from PKB␥.After activation of Akt, the signaling pathway diverges, with Akt stimulating a variety of anabolic processes, including glucose uptake and glycogen synthesis, translational protein synthesis, and, by increasing resistance to or delaying apoptosis, cell survival.Although many of the processes modulated by Akt are cytoplasmic, activated Akt also translocates to the nucleus, 2 where it is presumably involved in the regulation of gene expression.