AKT, also known as protein kinase B (PKB) or RAS-alpha, is a ubiquitous serine/threonine kinase that plays an important role in diverse biological responses such as regulation of metabolism, cell survival, and growth. This protein kinase is activated by insulin, PI3K, IGF1, and other growth and survival factors. AKT promotes cell survival by inhibiting apoptosis through phosphorylation and inactivation of several targets, including forkhead transcription factors and caspase-9. The AKT pathway is a major target for cancer drug discovery research.
The AKT pathway and key targets
Citations for Akt pathway targets
Akt is expressed as three isoforms: AKT1/ PKBα, AKT2/ PKBβ and AKT3/ PKBγ, respectively1. An amino terminal pleckstrin homology (PH) domain, a central serine–threonine catalytic domain, and a small carboxy‑terminal regulatory domain characterize all the three isoforms. The PH domain binds to phosphatidylinositol-3,4-bisphosphate (PIP2) and phosphatidylinositol-3,4,5-trisphosphate (PIP3), products of Phosphatidylinositol-4,5-bisphosphate 3-kinase ( PI3K. This binding causes Akt to locate to the plasma membrane, where it becomes phosphorylated by phosphoinositide-dependent kinase 1 (PDK1) on Thr308 in the activation loop of the catalytic domain. This phosphorylation leads to activation. Full activation requires phosphorylation at a second site (Ser473). Current evidence leads to the mTOR–rictor complex (mTORC2) as the primary kinase for the second phosphorylation event, although other kinases like Ilk (integrin linked kinase)2, PDK13. DNA-dependent protein kinase (DNA-PK)4, ATM (ataxia telangiectasia mutated) have also been identified5.
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