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Protein tyrosine phosphorylation and protein tyrosine nitration in redox signaling
Hugo P Monteiro1, Roberto J Arai, Luiz R Travassos
1Department of Biochemistry/Molecular Biology and CINTERGEN, Universidade Federal de São Paulo, São Paulo, Brazil. hpmonte@uol.com.br
Abstract:
Reversible phosphorylation of protein tyrosine residues by polypeptide growth factor-receptor protein tyrosine kinases is implicated in the control of fundamental cellular processes including the cell cycle, cell adhesion, and cell survival, as well as cell proliferation and differentiation. During the last decade, it has become apparent that receptor protein tyrosine kinases and the signaling pathways they activate belong to a large signaling network. Such a network can be regulated by various extracellular cues, which include cell adhesion, agonists of G protein-coupled receptors, and oxidants. It is well documented that signaling initiated by receptor protein tyrosine kinases is directly dependent on the intracellular production of oxidants, including reactive oxygen and nitrogen species. Accumulated evidence indicates that the intracellular redox environment plays a major role in the mechanisms underlying the actions of growth factors. Oxidation of cysteine thiols and nitration of tyrosine residues on signaling proteins are described as posttranslational modifications that regulate, positively or negatively, protein tyrosine phosphorylation (PTP). Early observations described the inhibition of PTP activities by oxidants, resulting in increased levels of proteins phosphorylated on tyrosine. Therefore, a redox circuitry involving the increasing production of intracellular oxidants associated with growth-factor stimulation/cell adhesion, oxidative reversible inhibition of protein tyrosine phosphatases, and the activation of protein tyrosine kinases can be delineated.
Insights
Growth factors regulate cell functions through protein tyrosine kinases. Intracellular oxidants, including reactive oxygen and nitrogen species, reversibly inhibit protein tyrosine phosphatases, creating a redox circuitry that influences cell signaling.
Area of Science:
- Cell Biology
- Biochemistry
- Signal Transduction
Background:
- Receptor protein tyrosine kinases (RPTKs) control fundamental cellular processes like cell cycle, adhesion, proliferation, and survival.
- RPTKs are part of a complex signaling network influenced by extracellular cues such as cell adhesion and oxidants.
- RPTK signaling is intrinsically linked to intracellular oxidant production, including reactive oxygen and nitrogen species.
Purpose of the Study:
- To elucidate the role of the intracellular redox environment in growth factor signaling.
- To investigate the regulatory mechanisms of protein tyrosine phosphorylation (PTP) by oxidative posttranslational modifications.
- To delineate the redox circuitry involving oxidants, protein tyrosine phosphatases (PTPs), and protein tyrosine kinases (PTKs).
Main Methods:
- Analysis of existing literature on RPTK signaling and redox regulation.
- Review of studies on posttranslational modifications, including cysteine thiol oxidation and tyrosine nitration.
- Examination of the impact of oxidants on PTP activity and tyrosine phosphorylation levels.
Main Results:
- Intracellular oxidants, such as reactive oxygen and nitrogen species, are crucial for RPTK-mediated signaling.
- Oxidation of cysteine thiols and nitration of tyrosine residues are key posttranslational modifications regulating PTP.
- Oxidants can reversibly inhibit PTP activity, leading to increased levels of tyrosine-phosphorylated proteins.
Conclusions:
- A redox circuitry exists where growth factor stimulation and cell adhesion increase intracellular oxidants.
- This oxidant production leads to the reversible inhibition of PTPs, thereby promoting the activation of PTKs.
- The intracellular redox environment plays a critical role in modulating growth factor signaling pathways.
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