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 S-phosphoin ositides, which bind to Pleckstrin homology (PH) domains that are present i n a wide spectrum of proteins. PH domains can be classified into three grou ps based on their different lipid binding specificities. Distinct 3-phospho inositides 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 I mM H2O2 caused almost excl usive accumulation of phosphatidylinositol 3,4-bisphosphate (PtdIns(3,4)P-2 ), whereas osmotic stress increased both phosphatidylinositol 3,4,5-trispho sphate (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 Ptd Ins(3,4,5)P-3 and PtdIns(3,4)P-2. p70 S6 kinase, another signaling componen t downstream of PI 3-kinase, however, was not activated by this oxidative s tress-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 i nhibitory pathway, but p70 S6 kinase was activated by osmotic stress. These results demonstrate that PtdIns(3,4)P-2 can accumulate independently of Pt dIns(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.