Abstract
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 mM 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).
Highlights
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
These cellular stresses were subsequently tested for their ability to activate PKB, which, both in vitro and in vivo, requires binding of either PtdIns(3,4,5)P3 or PtdIns(3,4)P2 to its PH domain (22, 23)
An inhibitory pathway triggered by H2O2 cannot be ruled out, the results suggest that different patterns of 3-phosphoinositides can elicit distinct downstream responses
Summary
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. P70 S6 kinase, another signaling component downstream of PI 3-kinase, was not activated by this oxidative stress-induced increase in PtdIns(3,4)P2 levels. Increased PtdIns(3,4,5)P3 and PtdIns(3,4)P2 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)P2 can accumulate independently of PtdIns(3,4,5)P3 and exerts a pattern of cellular responses that is distinct from that induced by accumulation of PtdIns(3,4,5)P3. Cells respond to different extracellular inputs from their environment by activation of protein kinase cascades These complex networks allow amplification of the signal and can mediate the required diversity of cellular responses. Because oxidative stress induced by direct exposure of cells to H2O2 results in a complex array of signaling events and osmotic shock activates many different components of several kinase cascades (16 –18), the role of PI 3-kinase in these events has been analyzed in more detail
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