Shrewd AKT regulation to survive

Metabolic stress, such as an insufficient supply of nutrients or oxygen owing to inadequate tumor neovascularization, metastasis, or therapy, is a microenvironmental condition frequently encountered by cancer cells [1]. The ability to survive metabolic stress is thus a necessity for tumor initiation and progression. The serine/threonine kinase AKT (also known as protein kinase B) is a primary mediator of survival of both normal and malignant cells [2]. Our recent studies revealed that AKT could be differentially activated by site-specific phosphorylation according to the severity and duration of metabolic stress, enabling cells to shift gears to survive [3]. During canonical AKT activation, growth factors or other stimuli activate transmembrane receptor tyrosine kinases, which in turn activate phosphoinositide 3-kinase to phosphorylate phosphatidylinositol 4, 5-bisphosphate to form phosphatidylinositol 3, 4, 5-trisphosphate on the inner cell membrane. AKT and its upstream kinase, phosphoinositide-dependent kinase-1 (PDK1), are recruited to the cell membrane, which initiates AKT phosphorylation at Thr308 by PDK1 [4]. Mammalian target of rapamycin complex 2 and other potential PDK2 kinases phosphorylate AKT at Ser473, resulting in optimal AKT activation [5]. The active phosphorylated AKT then translocates from the cell membrane to other cell compartments to phosphorylate multiple downstream substrates to fulfill its versatile functions. In contrast with canonical AKT activation with coordinate phosphorylation on both Thr308 and Ser473, we identified a novel AKT activation mechanism induced by glucose deprivation by which AKT is selectively phosphorylated on Thr308 but not Ser473, resulting in targeting AKT to a specific group of substrates [3]. In HeLa cells, short-term glucose deprivation (for up to 6 h) induced a modest increase in AKT phosphorylation at both Thr308 and Ser473. In contrast, prolonged glucose deprivation (16 h) induced a marked increase in AKT phosphorylation at Thr308 (up to 30-fold) but only a modest increase at Ser473 (twofold to threefold). Phosphorylation at Thr308 continued to increase over a 16-h glucose deprivation period, whereas Ser473 phosphorylation peaked at about 6 h and subsequently declined (Figure). Apparently, at least two independent processes are responsible for AKT phosphorylation during 16-h glucose deprivation, with a switch occurring between 6 and 8 h. Our data indicated that the first process takes place primarily via the release of feedback inhibition from p70S6K that results in coordinated phosphorylation of AKT at both Thr308 and Ser473. The second process likely occurs via the formation of a complex including GRP78, PDK1, and AKT that promotes selective AKT phosphorylation at Thr308. AKT is functionally activated by selective Thr308 phosphorylation during prolonged glucose deprivation Editorial Material