Aktion in the Nucleus

Akt is a serine-threonine kinase first identified in miceas the cellular homologue of the v-akt oncogene andidentified independently as a kinase related to pro-tein kinases A and C.1 As a consequence of the latter discoveries, Akt is also referred to as protein kinase B (PKB). There are three closely related mammalian Akts (Akt1/ PKB, Akt 2/PKB, and Akt 3/PKB) with similar substrate specificities but distinctive tissue distributions. They all share a common structure that consists of an N-terminal regulatory domain with pleckstrin homology (PH), a hinge region connecting the PH domain to the kinase domain, and a C-terminal region required for the induction and maintenance of the kinase activity. Akt sits strategically at the hub of insulin and insulin-like growth factor-1 (IGF-1) signaling, communicating directly with phosphatidylinositol 3-kinase (PI3-kinase) through the membrane lipids phosphatidylinosi-tol 4,5 bisphosphate (PIP2) and phosphatidylinositol 3,4,5 triphosphate (PIP3). The pathway is also activated by growth factors including PDGF, cytokines (leukemia inhibitory factor [LIF-1], and cardiotropin), and by adrenergic stimula-tion.2,3 The src homology-2 (SH-2) domain-containing inosi-tol phosphatase SHIP-1/2 and the PTEN phosphatase dephos-phorylate Akt are critical mediators of the activity of the pathway. Studies on the pro-oncogenic activities of Akt kinase first established its pivotal role in cell growth and survival. Akt was shown to promote transformation by suppressing apo-ptosis and differentiation and increasing cell cycle progres-sion.1 These activities were subsequently extended to nontu-mor cells including hematopoietic cells, neuronal cells, and cardiac myocytes, and Akt regulation is now being explored as a possible therapeutic strategy for degenerative diseases to prevent cell loss. Stimulation of the PI3-kinase pathway by IGF-1 or overexpression of constitutively active Akt in the heart protects against ischemia and multiple other apoptotic stimuli. Unfortunately, chronic activation of this pathway can also lead to hypertrophic and dilated cardiomyopathy, heart failure, and sudden death.4,5 Therefore if the prosurvival therapeutic potential of Akt is to be realized, it will be necessary to tease apart the different functions and targets of the pathway