AKT

Abstract

AKT is a serine/threonine kinase member of the AGC family of protein kinases. The three isoforms of AKT (AKT1/2/3) play a central role in growth, proliferation, glucose uptake, metabolism, protein translation and cell survival. Given the importance of the AKT pathway in all these processes it is not surprising that its deregulation is associated with a variety of human diseases including cardiac hypertrophy, diabetes, neuronal degeneration, vascular disorders and cancer. Therefore, AKT-dependent pathways are considered an attractive target for therapeutic intervention AKT contains an N-terminal pleckstrin homology domain which interacts with PIP2 and PIP3, a central kinase domain and a C-terminal domain that contains an hydrophobic motif with homology to other AGC kinases. When bound to cognate ligands, receptor tyrosine kinases such as the insulin-like growth factor-I receptor undergo autophosphorylation, resulting in the recruitment of adaptor molecules. PI3K regulatory subunits complexed to p110 catalytic subunits in turn convert plasma membrane associated PIP2 to PIP3. PIP3 recruits AKT to the plasma membrane where AKT gets phosphorylated and therefore activated. Dephosphorylation of AKT leads to the termination of AKT activation. Activated AKT acts on multiple targets located in the cytoplasm and nucleus. A number of known and putative AKT targets have been identified thus far by virtue of their containing the essential AKT consensus motif (RXRXXS/TB) where X is any amino acid and B represents a bulky hydrophobic residue. Deregulation of the AKT pathway is associated with a variety of human diseases including cardiac hypertrophy, diabetes, neuronal degeneration, vascular disorders and cancer and therefore this pathway is considered an attractive target for therapeutic intervention.