Signal transduction via PI 3-kinases plays an important role in regulating the cellular processes of cell growth, survival, proliferation, and motility. The stimulated generation of
reactive oxygen species is a necessary component of the signal transduction mechanisms by which many
growth factors and
cytokines activate this signaling pathway and elicit their cellular responses. Evidence now supports the oxidative inactivation of both
tyrosine phosphatases acting upstream of
PI 3-kinase, and of the
lipid phosphatase PTEN as components of the normal stimulated regulation of
PI 3-kinase signaling. However, the effects of chronic oxidative stress appear rather different, particularly a proposed role for nitrosylation of Akt and other targets leading to inhibition of
PI 3-kinase signaling during diabetic
insulin resistance in muscle. Recently, evidence has also begun to emerge, indicating that physiological redox signaling may display the same tight spatial and temporal specificity as seen with many other signal transduction systems in terms of targeting individual
proteins for modification, and of enzymatic reversal mechanisms. This review will focus upon the details of these and other roles for reactive
oxygen and
nitrogen species in the regulation of
PI 3-kinase signaling, both during acute stimulation and chronic oxidative stress, and the evidence for their significance.