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首页> 外文期刊>Molecular and Cellular Biology >Genetic Evidence of a Role for Lck in T-Cell Receptor Function Independent or Downstream of ZAP-70/Syk Protein Tyrosine Kinases
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Genetic Evidence of a Role for Lck in T-Cell Receptor Function Independent or Downstream of ZAP-70/Syk Protein Tyrosine Kinases

机译：Lck在独立的或ZAP-70 / Syk蛋白酪氨酸激酶下游的T细胞受体功能中的作用的遗传证据。

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T-cell antigen receptor (TCR) engagement results in sequential activation of the Src protein tyrosine kinases (PTKs) Lck and Fyn and the Syk PTKs, ZAP-70 and Syk. While the Src PTKs mediate the phosphorylation of TCR-associated signaling subunits and the phosphorylation and activation of the Syk PTKs, the lack of a constitutively active Syk PTK has prohibited the analysis of Lck function downstream of these initiating signaling events. We describe here the generation of an activated Syk family PTK by substituting the kinase domain of Syk for the homologous region in ZAP-70 (designated as KS for kinase swap). Expression of the KS chimera resulted in its autophosphorylation, the phosphorylation of cellular proteins, the upregulation of T-cell activation markers, and the induction of interleukin-2 gene synthesis in a TCR-independent fashion. The KS chimera and downstream ZAP-70 or Syk substrates, such as SLP-76, were still phosphorylated when expressed in Lck-deficient JCaM1.6 T cells. However, expression of the KS chimera in JCaM1.6 cells failed to rescue downstream signaling events, demonstrating a functional role for Lck beyond the activation of the ZAP-70 and Syk PTKs. These results indicate that downstream TCR signaling pathways may be differentially regulated by ZAP-70 and Lck PTKs and provide a mechanism by which effector functions may be selectively activated in response to TCR stimulation.
机译：T细胞抗原受体（TCR）的参与导致Src蛋白酪氨酸激酶（PTK）Lck和Fyn以及Syk PTK，ZAP-70和Syk的顺序激活。尽管Src PTK介导TCR相关信号亚基的磷酸化以及Syk PTK的磷酸化和激活，但缺乏组成型活性Syk PTK阻止了在这些起始信号事件下游进行Lck功能的分析。我们在这里描述了通过将Syk的激酶域替换为ZAP-70中的同源区域（称为KS进行激酶交换）而激活的Syk家族PTK的产生。 KS嵌合体的表达导致其自身磷酸化，细胞蛋白磷酸化，T细胞活化标志物的上调以及以TCR独立的方式诱导白介素2基因合成。当在Lck缺失的JCaM1.6 T细胞中表达时，KS嵌合体和下游ZAP-70或Syk底物（如SLP-76）仍被磷酸化。然而，KS嵌合体在JCaM1.6细胞中的表达未能挽救下游信号转导事件，表明Lck的功能作用超出ZAP-70和Syk PTK的激活。这些结果表明，下游TCR信号传导途径可能受到ZAP-70和Lck PTK的差异调节，并提供了一种机制，通过该机制可以响应TCR刺激选择性激活效应子功能。

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