Lack of SHPTP1 results in src-family kinase hyperactivation and thymocyte hyperresponsiveness

Ulrike Lorenz, Kodimangalam S. Ravichandran, Steven J. Burakoff, Benjamin G. Neel

Research output: Contribution to journalArticlepeer-review

157 Scopus citations

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.

Original languageEnglish
Pages (from-to)9624-9629
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume93
Issue number18
DOIs
StatePublished - Sep 3 1996

Keywords

  • Fyn
  • Lck
  • T lymphocytes
  • motheaten mice
  • protein tyrosine phosphatase

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