Lorenz U, Ravichandran K S, Burakoff S J, Neel B G
Molecular Medicine Unit, Beth Israel Hospital, Boston, MA 02215, USA.
Proc Natl Acad Sci U S A. 1996 Sep 3;93(18):9624-9. doi: 10.1073/pnas.93.18.9624.
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.
蛋白质酪氨酸磷酸化和去磷酸化是T细胞受体（TCR）信号传导中的关键调节事件。我们通过分析缺乏SHPTP1表达的动性吞噬细胞（me/me）小鼠的TCR信号转导，研究了酪氨酸磷酸酶SHPTP1在TCR信号传导中的作用。流式细胞术分析显示，me/me小鼠的胸腺细胞发育正常。然而，me/me胸腺细胞在TCR刺激下过度增殖（3至5倍），而与正常胸腺细胞相比，它们对白介素2刺激的反应未发生变化。在纯化的单阳性胸腺细胞中重现了TCR诱导的me/me胸腺细胞过度增殖。此外，me/me胸腺细胞在TCR刺激后产生的白介素2量增加。生化分析表明，响应TCR或TCR/CD4刺激时，缺乏SHPTP1的胸腺细胞显示几种细胞底物的酪氨酰磷酸化增加，这与src家族激酶Lck和Fyn的激活增加相关。综上所述，我们的数据表明SHPTP1是TCR信号传导的重要负调节因子，至少部分作用是使Lck和Fyn失活。
