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Inhibition of PTPs by H(2)O(2) regulates the activation of distinct MAPK pathways
Kyoungmun Lee1, Walter J Esselman
1Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI 48824, USA.
Abstract:
It has been shown that endogenous production of reactive oxygen species (ROS) during T cell activation regulates signaling events including MAPK activation. Protein tyrosine phosphatases (PTPs) have been regarded as targets of ROS which modify the catalytic cysteine residues of the enzymes. We have analyzed the interplay between the inhibition of PTPs and the activation of MAPK by H(2)O(2). Stimulation of Jurkat T cells with H(2)O(2) induces the phosphorylation of ERK, p38, and JNK members of MAPK family. H(2)O(2) stimulation of T cells was found to inhibit the PTP activity of CD45, SHP-1, and HePTP. Transfection of cells with wtSHP-1 decreased H(2)O(2)-induced ERK and JNK phosphorylation without affecting p38 phosphorylation. Transfection with wtHePTP inhibited H(2)O(2)-induced ERK and p38 phosphorylation without inhibiting JNK phosphorylation. The Src-family kinase inhibitor, PP2, inhibited the H(2)O(2)-induced phosphorylation of ERK, p38, and JNK. The phospholipase C (PLC) inhibitor, U73122, or the protein kinase C (PKC) inhibitor, Ro-31-8425, blocked H(2)O(2)-induced ERK phosphorylation, whereas the same treatment did not inhibit p38 or JNK phosphorylation. Taken together, these results suggest that inhibition of PTPs by H(2)O(2) contributes to the induction of distinct MAPK activation profiles via differential signaling pathways.
Insights
Hydrogen peroxide (H2O2) inhibits protein tyrosine phosphatases (PTPs), leading to distinct mitogen-activated protein kinase (MAPK) pathway activation during T cell activation. This study explores the interplay between PTP inhibition and MAPK signaling.
Area of Science:
- Immunology
- Cell Signaling
- Biochemistry
Background:
- Endogenous reactive oxygen species (ROS) production during T cell activation regulates signaling pathways, including MAPK activation.
- Protein tyrosine phosphatases (PTPs) are known targets of ROS, with ROS modifying their catalytic cysteine residues.
Purpose of the Study:
- To analyze the interplay between PTP inhibition and MAPK activation induced by hydrogen peroxide (H2O2) in T cells.
- To elucidate the specific roles of PTPs (CD45, SHP-1, HePTP) in H2O2-mediated MAPK signaling.
Main Methods:
- Stimulation of Jurkat T cells with H2O2.
- Assessing MAPK phosphorylation (ERK, p38, JNK) and PTP activity.
- Utilizing gene transfection (wtSHP-1, wtHePTP) and specific inhibitors (PP2, U73122, Ro-31-8425).
Main Results:
- H2O2 induced phosphorylation of ERK, p38, and JNK, while inhibiting CD45, SHP-1, and HePTP activity.
- wtSHP-1 transfection reduced H2O2-induced ERK and JNK phosphorylation.
- wtHePTP transfection inhibited H2O2-induced ERK and p38 phosphorylation.
- Src-family kinase, PLC, and PKC inhibitors differentially affected MAPK phosphorylation.
Conclusions:
- H2O2-induced PTP inhibition contributes to distinct MAPK activation profiles.
- Differential signaling pathways are involved in H2O2-mediated MAPK activation via PTP inhibition.