Marti Francesc, Garcia Gonzalo G, Lapinski Philip E, MacGregor Jennifer N, King Philip D
Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
J Exp Med. 2006 Feb 20;203(2):281-7. doi: 10.1084/jem.20051637. Epub 2006 Jan 30.
T cell-specific adapter protein (TSAd) is a SRC-homology-2 (SH2) domain-containing intracellular signaling molecule that is required for T cell antigen receptor (TCR)-induced cytokine synthesis in T cells. How TSAd functions in TCR signal transduction is not clear. Previous work has suggested a nuclear role for this adapter. However, other evidence suggests that TSAd also functions in the cytoplasm. Using T cells from TSAd-deficient mice, we now show that the major role of TSAd in the cytoplasm is in activation of the LCK protein tyrosine kinase at the outset of TCR signal transduction. Consequently, TSAd regulates several downstream signaling events, including intracellular calcium mobilization and activation of the Ras-extracellular signal-regulated kinase signaling pathway. TSAd regulates LCK activity directly through physical interaction with LCK SH3 and SH2 domains. These studies reveal TSAd as a positive regulator of proximal TCR signal transduction and provide important new information on the mechanism of TCR-induced LCK activation.
T细胞特异性衔接蛋白（TSAd）是一种含有Src同源2（SH2）结构域的细胞内信号分子，T细胞抗原受体（TCR）诱导T细胞合成细胞因子时需要该分子。TSAd在TCR信号转导中如何发挥作用尚不清楚。先前的研究表明该衔接蛋白具有核内作用。然而，其他证据表明TSAd也在细胞质中发挥作用。利用来自TSAd基因缺陷小鼠的T细胞，我们现在表明TSAd在细胞质中的主要作用是在TCR信号转导开始时激活LCK蛋白酪氨酸激酶。因此，TSAd调节多个下游信号事件，包括细胞内钙动员和Ras-细胞外信号调节激酶信号通路的激活。TSAd通过与LCK的SH3和SH2结构域直接物理相互作用来调节LCK活性。这些研究揭示TSAd是近端TCR信号转导的正调节因子，并为TCR诱导的LCK激活机制提供了重要的新信息。
