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Lack of SHPTP1 results in src-family kinase hyperactivation and thymocyte hyperresponsiveness
U Lorenz1, K S Ravichandran, S J Burakoff
1Molecular Medicine Unit, Beth Israel Hospital, Boston, MA 02215, USA.
Abstract:
Protein tyrosine phosphorylation and dephosphorylation are key regulatory events in T-cell receptor (TCR) signaling. We investigated the role of the tyrosine phosphatase SHPTP1 in TCR signaling by analysis of TCR signal transduction in motheaten (me/me) mice, which lack SHPTP1 expression. As revealed by flow cytometric analysis, thymocyte development was normal in me/me mice. However, me/me thymocytes hyperproliferated (3-to 5-fold) in response to TCR stimulation, whereas their response to interleukin 2 stimulation was unchanged compared with normal thymocytes. TCR-induced hyperproliferation of me/me thymocytes was reproduced in purified single-positive thymocytes. Moreover, me/me thymocytes produced increased amounts of interleukin 2 production upon TCR stimulation. Biochemical analysis revealed that, in response to TCR or TCR/CD4 stimulation, thymocytes lacking SHPTP1 showed increased tyrosyl phosphorylation of several cellular substrates, which correlated with increased activation of the src-family kinases Lck and Fyn. Taken together, our data suggest that SHPTP1 is an important negative regulator of TCR signaling, acting at least in part to inactivate Lck and Fyn.
Insights
The tyrosine phosphatase SHPTP1 normally limits T-cell receptor (TCR) signaling. Mice lacking SHPTP1 exhibit hyperproliferation and increased interleukin-2 production upon TCR stimulation, indicating SHPTP1
Area of Science:
- Immunology
- Cellular Signaling
- Molecular Biology
Background:
- T-cell receptor (TCR) signaling is crucial for adaptive immunity.
- Protein tyrosine phosphorylation and dephosphorylation are key regulatory events in TCR signaling.
- SHPTP1 is a tyrosine phosphatase implicated in immune cell regulation.
Purpose of the Study:
- To investigate the role of the tyrosine phosphatase SHPTP1 in T-cell receptor (TCR) signaling.
- To analyze TCR signal transduction in motheaten (me/me) mice, which lack SHPTP1 expression.
Main Methods:
- Flow cytometric analysis of thymocyte development and proliferation.
- Analysis of interleukin-2 production upon stimulation.
- Biochemical analysis of protein tyrosyl phosphorylation.
- Investigation of src-family kinases (Lck and Fyn) activation.
Main Results:
- Thymocyte development was normal in SHPTP1-deficient (me/me) mice.
- me/me thymocytes showed 3-to 5-fold hyperproliferation in response to TCR stimulation.
- Interleukin-2 stimulation response was unchanged in me/me thymocytes.
- Increased tyrosyl phosphorylation of substrates and activation of Lck and Fyn were observed in me/me thymocytes upon TCR stimulation.
Conclusions:
- SHPTP1 acts as a negative regulator of TCR signaling.
- SHPTP1 likely inactivates Lck and Fyn kinases, thereby controlling TCR signal strength.
- Dysregulation of SHPTP1 function may contribute to aberrant T-cell responses.