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Cytoskeletal protein tyrosine phosphatase PTPH1 reduces T cell antigen receptor signaling
S Han1, S Williams, T Mustelin
1Laboratory of Signal Transduction, La Jolla Cancer Research Center, The Burnham Institute, La Jolla 92037, USA.
Abstract:
The subgroup of protein tyrosine phosphatases that contain an N-terminal ezrin-, radixin- and moesin homology (ERM) domain and a C-terminal catalytic domain is represented by three enzymes in Jurkat T cells, PTPH1, PTP-MEG1 and PTP36. These enzymes are located at the cytoplasmic face of the plasma membrane and may be involved in regulation of the membrane cytoskeleton, signal transduction, or both. Here we report that expression of PTPH1 in Jurkat T cells reduced the TCR-induced activation of reporter genes encompassing parts of the IL-2 gene promoter and driven by nuclear factor of activated T cells plus activator protein-1. PTP-MEG1 had a weaker inhibitory effect, while PTP36 had none. The catalytically inactive mutants PTPH1-CS and PTP-MEG1-CS lacked effects on gene transcription. Expression of active PTPH1 also reduced receptor-induced activation of Erk2 MAP kinase, its upstream activator, Mek, and the Jnk kinases. The effect of PTPH1 was reduced by deletion of its N-terminal ERM domain. We suggest that PTPH1 inhibits T cell activation by dephosphorylating membrane-associated targets involved in TCR signaling.
Insights
Protein tyrosine phosphatase PTPH1 inhibits T cell activation by dephosphorylating key signaling molecules. This phosphatase plays a crucial role in regulating T cell receptor signaling pathways.
Area of Science:
- Immunology
- Cell Biology
- Biochemistry
Background:
- Protein tyrosine phosphatases (PTPs) with ezrin-, radixin-, and moesin-homology (ERM) domains are involved in regulating the plasma membrane and signal transduction.
- Three such PTPs (PTPH1, PTP-MEG1, PTP36) are found at the cytoplasmic face of the plasma membrane in Jurkat T cells.
Purpose of the Study:
- To investigate the role of PTPH1, PTP-MEG1, and PTP36 in T cell activation.
- To determine the specific signaling pathways affected by these PTPs, particularly in response to T cell receptor (TCR) stimulation.
Main Methods:
- Expression of PTPH1, PTP-MEG1, PTP36, and their catalytically inactive mutants (PTPH1-CS, PTP-MEG1-CS) in Jurkat T cells.
- Assessing the impact on TCR-induced reporter gene activation (IL-2 promoter, NFAT, AP-1).
- Evaluating the effects on the activation of Erk2 MAP kinase, Mek, and Jnk kinases.
Main Results:
- PTPH1 significantly inhibited TCR-induced reporter gene activation, while PTP-MEG1 showed a weaker effect and PTP36 had no effect.
- Catalytically inactive mutants (PTPH1-CS, PTP-MEG1-CS) did not affect gene transcription, indicating the necessity of phosphatase activity.
- Active PTPH1 reduced the activation of Erk2, Mek, and Jnk kinases; this effect was diminished when the N-terminal ERM domain was deleted.
Conclusions:
- PTPH1 is a key inhibitor of T cell activation, acting through its phosphatase activity.
- PTPH1 likely dephosphorylates membrane-associated targets crucial for TCR signaling.
- The ERM domain of PTPH1 may play a role in its localization or function in TCR signaling inhibition.