Characterization of the molecular mechanisms of Akt activation

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Serine threonine kinase Akt, also called PKB (Protein Kinase B), plays a central role in the regulation of intracellular survival. Deregulation of this Akt signaling pathway underlies various human neoplastic diseases. Recently, the protooncogene TCL1 (T cell leukemia 1), with a previously unknown physiological function, was shown to interact with the Akt pleckstrin homology domain, enhancing Akt kinase activity; hence, it functions as an Akt kinase co-activator. In contrast to pathological conditions in which the TCL1 gene is highly activated in various human neoplasmic diseases, the physiological expression of TCL1 is tightly limited to early developmental cells as well as various developmental stages of immune cells. The NBRE (Nerve Growth Factor Responsive Element) of the proximal TCL1 promoter sequences can regulate the restricted physiological expression of TCL1 in a negative feedback mechanism. Further, based on the NMR structural studies of Akt-TCL1 protein complexes, an inhibitory peptide, "Akt-in," consisting of the βA strand of TCL1, has been identified and has therapeutic potential. Our study together promote substantial understanding of TCL1-Akt functional interaction and the biological action of the protooncogene TCL1 family and the new suppressive drug specific for Akt, a core intracellular survival regulator.