IMPACT OF OXIDATIVE STRESS ON SIGNAL-TRANSDUCTION CONTROL BY PHOSPHOTYROSINE PHOSPHATASES

Phosphotyrosine phosphatases (PTPs) serve as important regulators of c ellular signal transduction pathways. PTPs are sensitive targets of ox idative stress and may be inhibited by treatments that induce intracel lular oxidation. The effects of PTP inactivation under oxidizing condi tions are amplified by the redox-linked activation of key protein tyro sine kinases (PTKs), thus leading to the initiation of phosphotyrosine -signaling cascades that are no longer under normal receptor control. These ligand-independent signals result in the accumulation of protein phosphotyrosine, the generation of second messengers, the activation of downstream kinases, and the nuclear translocation of nuclear factor kappa B (NF-kappa B). In this review we consider the relative contrib ution of oxidative stress to the effects of PTP inhibition by vanadium -based compounds in lymphocytes. Although the inactivation of PTPs can lead to NF-kappa B mobilization in the presence of antioxidants, the other effects noted appear to require a threshold of intracellular oxi dation. The combined effects of oxidative stress on signal transductio n cascades reflect a synergy between the initiation of signals by PTKs and the loss of control by PTPs. This suggests a mechanism by which e nvironmental agents that cause oxidative stress may alter the course o f cellular responses through induction or enhancement of signaling cas cades leading to functional changes or cell death.