Protein kinase B (PKB)/Akt is a growth-factor-regulated Ser/Thr kinase that is central to the insulin signaling pathway and induction of glycogen synthesis. Study of PKB has expedited the elucidation of a complete pathway that accounts for the insulin-induced biological effects. Ligation of the insulin receptor and activation of the insulin-receptor Tyr kinase results in the rapid recruitment of phosphoinositide 3-kinase (PI3K) into receptor-associated signaling complexes that include the insulin receptor tyrosine kinase substrate, IRS-1. Activation of PI3K results in the production of phosphatidylinositide (3,4,5) trisphosphate (PIP3), which functions as an insulin-induced second. Another enzyme in this pathway, 3-phosphoinositide-dependent protein kinase (PDK1), activates PKB in the presence of PIP3. PKBs have a C-terminal catalytic domain and an N-terminal non-catalytic pleckstrin homology (PH) domain. Binding of phosphatidylinositol (3,4) bisphosphate (PIP2) and PIP3 products to the PH domain of PKB induces its translocation to the plasma membrane where phosphorylation by PDK1 and other kinases results in PKB activation.
PKB, in turn, inactivates glycogen synthase kinase (GSK3). This leads to the dephosphorylation (activation) of glycogen synthase and subsequent glycogen production. PDK1, PKB, and GSK3 regulate various physiological events via the phosphorylation of multiple intracellular targets. Other
Ser/Thr kinases regulated downstream of PI 3-kinases include PKC isoforms (PKC λ/ι and ξ), p70 S6 kinase, and PKA. Thus, PKB and a number of other kinases and signaling factors are essential for intracellular transduction of insulin-induced signals and the anti-apoptotic effects of multiple survival
factors.
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