Pratt J C, van den Brink M R, Igras V E, Walk S F, Ravichandran K S, Burakoff S J
Division of Pediatric Oncology, Dana-Farber Cancer Institute, Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
J Immunol. 1999 Sep 1;163(5):2586-91.
Engagement of the TCR determines the fate of T cells to activate their functional programs, proliferate, or undergo apoptosis. The intracellular signal transduction pathways that dictate the specific outcome of receptor engagement have only been partially elucidated. The adapter protein, Shc, is involved in cytokine production, mitogenesis, transformation, and apoptosis in different cell systems. We found that Shc becomes phosphorylated on tyrosine residues upon stimulation of the TCR in DO11.10 hybridoma T cells; therefore, we investigated the role of Shc in activation-induced cell death in these cells by creating a series of stably transfected cell lines. Expression of Shc-SH2 (the SH2 domain of Shc) or Shc-Y239/240F (full-length Shc in which tyrosines 239 and 240 have been mutated to phenylalanine) resulted in the inhibition of activation-induced cell death and Fas ligand up-regulation after TCR cross-linking. Expression of wild-type Shc or Shc-Y317F had no significant effect. In addition, we found that Shc-SH2 and Shc-Y239/240F, but not Shc-Y317F, inhibited phosphorylation of extracellular signal-regulated protein kinase and production of IL-2 after TCR cross-linking. These results indicate an important role for Shc in the early signaling events that lead to activation-induced cell death and IL-2 production after TCR activation.
TCR的激活决定了T细胞的命运，使其启动功能程序、增殖或发生凋亡。决定受体激活特定结果的细胞内信号转导途径仅得到了部分阐明。衔接蛋白Shc参与不同细胞系统中的细胞因子产生、有丝分裂、转化和凋亡。我们发现，在DO11.10杂交瘤T细胞中，TCR受到刺激后，Shc的酪氨酸残基会发生磷酸化；因此，我们通过创建一系列稳定转染的细胞系，研究了Shc在这些细胞激活诱导的细胞死亡中的作用。Shc-SH2（Shc的SH2结构域）或Shc-Y239/240F（酪氨酸239和240已突变为苯丙氨酸的全长Shc）的表达导致TCR交联后激活诱导的细胞死亡和Fas配体上调受到抑制。野生型Shc或Shc-Y317F的表达没有显著影响。此外，我们发现，Shc-SH2和Shc-Y239/240F，而非Shc-Y317F，在TCR交联后抑制细胞外信号调节蛋白激酶的磷酸化和IL-2的产生。这些结果表明，Shc在TCR激活后导致激活诱导的细胞死亡和IL-2产生的早期信号事件中发挥重要作用。
