The AKT2 oncogene encodes a
protein-serine/threonine kinase that was recently shown to be activated by a variety of
growth factors. In addition, we previously showed that AKT2 is abundant in brown fat and skeletal muscle, tissues that are highly
insulin responsive and that play a role in
glucose metabolism. In this study, we demonstrate that AKT2 is activated in response to stimulation by
insulin in a dose- and time-dependent manner in human ovarian
carcinoma cells and that activation of AKT2 is abolished in cells pretreated with
wortmannin, an inhibitor of
phosphatidylinositol 3-kinase (PI 3-kinase). Activation of AKT2 is manifested by changes in its phosphorylation state. Immunofluorescence experiments demonstrate that AKT2 is translocated to the plasma membrane after
insulin stimulation, and this translocation is abolished by
wortmannin. Both wild-type AKT2 activated by
insulin and constitutively active AKT2, which has been targeted to the membrane by the addition of a myristoylation signal, were found to inactivate
glycogen synthase kinase-3 (GSK-3) in vitro.
GSK-3 was not inactivated by a catalytically inactive AKT2 mutant. Collectively, these data indicate that activation of AKT2 by
insulin is mediated by
PI 3-kinase and that
GSK-3 is a downstream target of AKT2, suggesting a potentially important role of AKT2 in
glycogen synthesis and other
GSK-3 signaling pathways.