Novel Phosphatase PHLPP-1 Regulates Mitochondrial Akt Activity and Cardiac Cell Survival

See related article, pages 476–484The serine-threonine kinase Akt/PKB regulates a variety of diverse cellular functions, including cardiac growth, glucose uptake, energy metabolism, gene expression, and, most recently, mitochondrial integrity and survival. In mammalian cells, 3 isoforms of Akt (Akt1, Akt2, and Akt3) have been identified, exhibiting similar structure and moderate overlap for substrate specificity.1 All 3 Akt isoforms are expressed in the myocardium, with the Akt1 and Akt2 isoforms most abundant.1 Following growth factor stimulation, Akt is phosphorylated at 2 critical regulatory phosphorylation sites, Ser473/Thr308 in Akt1, Ser474/Thr309 in Akt2, and Ser472/Thr305 in Akt3.1,2 Threonine phosphorylation is vital and sufficient for Akt activation, and Ser473 phosphorylation is required for maximal Akt activity.1 Based on Akt gene knockout studies, Akt1 and Akt2 seem to have partially redundant functions. Disruption of the Akt1 gene results in mild growth retardation and spontaneous apoptosis in restricted cell types.2,3 Notably, in the heart, Akt1-dependent signaling pathways have been implicated in myocyte survival and cardiac growth.2,4Arguably, among the best proven and well studied posttranslational events for regulating cellular Akt activity is phosphorylation. Akt contains an N-terminal PH domain, a central catalytic kinase domain, and a C-terminal regulatory domain. Cellular Akt is regulated differentially by phosphatidylinositol 3-kinase respectively via modulation of intracellular phosphatidylinositol (3,4,5)-triphosphate levels.5,6 In cells, Akt is activated following its recruitment to the cell membrane …