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Impact of oxidative stress on signal transduction control by phosphotyrosine phosphatases
1Department of Environmental Health, University of Washington, Seattle, USA.
Abstract:
Phosphotyrosine phosphatases (PTPs) serve as important regulators of cellular signal transduction pathways. PTPs are sensitive targets of oxidative stress and may be inhibited by treatments that induce intracellular oxidation. The effects of PTP inactivation under oxidizing conditions are amplified by the redox-linked activation of key protein tyrosine 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 contribution 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 oxidation. The combined effects of oxidative stress on signal transduction cascades reflect a synergy between the initiation of signals by PTKs and the loss of control by PTPs. This suggests a mechanism by which environmental agents that cause oxidative stress may alter the course of cellular responses through induction or enhancement of signaling cascades leading to functional changes or cell death.
Insights
Oxidative stress inhibits phosphotyrosine phosphatases (PTPs), amplifying signals from protein tyrosine kinases (PTKs). This leads to uncontrolled signaling, potentially causing cell death, especially with vanadium compounds in lymphocytes.
Area of Science:
- Cellular Biology
- Signal Transduction
- Oxidative Stress Research
Background:
- Phosphotyrosine phosphatases (PTPs) regulate cellular signaling pathways.
- PTPs are vulnerable to oxidative stress, leading to inhibition.
- Oxidative stress amplifies PTP inactivation effects by activating protein tyrosine kinases (PTKs).
Purpose of the Study:
- To review the role of oxidative stress in PTP inhibition by vanadium compounds in lymphocytes.
- To elucidate the synergistic effects of oxidative stress and PTP inactivation on cellular signaling.
- To understand how environmental oxidative stress impacts cellular responses and cell fate.
Main Methods:
- Review of existing literature on PTPs, PTKs, oxidative stress, and vanadium compounds.
- Analysis of signaling cascades initiated by PTP inactivation and PTK activation.
- Examination of NF-kappa B mobilization under varying oxidative conditions.
Main Results:
- PTP inactivation under oxidizing conditions leads to uncontrolled phosphotyrosine signaling.
- Ligand-independent signals result in protein phosphotyrosine accumulation and downstream kinase activation.
- Oxidative stress synergizes with PTP inactivation, impacting signaling cascades and potentially leading to cell death.
Conclusions:
- Oxidative stress plays a critical role in modulating PTP inhibition effects.
- A threshold of intracellular oxidation is required for most observed signaling effects.
- Environmental oxidative stress can alter cellular responses, promoting signaling cascades that lead to functional changes or cell death.