Distinct Phosphatidylinositol 3-Kinase Lipid Products Accumulate upon Oxidative and Osmotic Stress and Lead to Different Cellular Responses

Signaling by phosphatidylinositol (PI) 3-kinases is mediated by 3-phosphoinositides, which bind to Pleckstrin homology (PH) domains that are present in a wide spectrum of proteins. PH domains can be classified into three groups based on their different lipid binding specificities. Distinct 3-phosphoinositides can accumulate upon PI 3-kinase activation in cells in response to different stimuli and mediate specific cellular responses. In Swiss 3T3 mouse fibroblasts, oxidative stress induced by 1 m m H 2 O 2 caused almost exclusive accumulation of phosphatidylinositol 3,4-bisphosphate (PtdIns(3,4)P 2 ), whereas osmotic stress increased both phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P 3 ) and PtdIns(3,4)P 2 levels. The increase in PtdIns(3,4)P 2 levels, caused by oxidative stress, correlated with the activation of protein kinase B, which has a promiscuous PH domain that binds both PtdIns(3,4,5)P 3 and PtdIns(3,4)P 2 . p70 S6 kinase, another signaling component downstream of PI 3-kinase, however, was not activated by this oxidative stress-induced increase in PtdIns(3,4)P 2 levels. Increased PtdIns(3,4,5)P 3 and PtdIns(3,4)P 2 levels in response to osmotic stress did not correlate with protein kinase B activation, because of concomitant activation of an inhibitory pathway, but p70 S6 kinase was activated by osmotic stress. These results demonstrate that PtdIns(3,4)P 2 can accumulate independently of PtdIns(3,4,5)P 3 and exerts a pattern of cellular responses that is distinct from that induced by accumulation of PtdIns(3,4,5)P 3 .