Lck regulates the threshold of activation in primary T cells, while both Lck and Fyn contribute to the magnitude of the extracellular signal-related kinase response
Lck regulates the threshold of activation in primary T cells, while both Lck and Fyn contribute to the magnitude of the extracellular signal-related kinase response
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DOI：
10.1128/mcb.00168-06
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发表时间：
2006-11-01
影响因子：
5.3
通讯作者：
Zamoyska, Rose
中科院分区：
文献类型：
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作者：
Lovatt, Matthew;Filby, Andrew;Zamoyska, Rose
Src家族的p56(Lck)(Lck)和p59(Fyn)(Fyn)是T细胞受体下游被激活的最近端的信号分子。使用可诱导的转基因模型，我们可以调节原代T细胞中Lck的表达，并询问Lck的水平是否降低对信号级联和分化潜力有何影响。我们发现，在幼稚T细胞中，Lck通过激活磷脂酶C-γ和蛋白激酶C，以及激活细胞外信号调节激酶(ERK)/丝裂原活化蛋白激酶(MAPK)通路，优先调控多种信号通路，从而导致钙离子的动员。Fyn还能刺激原代T细胞的ERK/MAPK通路，但对钙离子的动员几乎没有影响。只有Lck有效地刺激二酰甘油的产生，从而使RASGRP1重新募集到质膜上，并使SHE磷酸化，这表明Fyn通过不同的上游信号途径激活ERK。最后，我们证明了通过Lck的信号对于T细胞效应潜能的发展是必不可少的，特别是对于有效的细胞因子转录。
The src family kinases p56(lck) (Lck) and p59(fyn) (Fyn) are the most proximal signaling molecules to be activated downstream of the T-cell receptor. Using an inducible transgenic model, we can regulate the expression of Lck in primary T cells and ask how the signaling cascade and differentiation potential are affected by the absence or the presence of reduced levels of Lck. We show that in naive T cells, Lck controls the threshold of activation by preferentially regulating multiple signaling pathways that result in the mobilization of Ca2+ through activation of phospholipase C-gamma and protein kinase C as well as activation of the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) pathway. Fyn is also able to stimulate the ERK/MAPK pathway in primary T cells but has little influence on the mobilization of Ca2+. Only Lck efficiently stimulates production of diacylglycerol and therefore RasGRP1 recruitment to the plasma membrane and phosphorylation of She, suggesting that Fyn activates ERK via a different upstream signaling route. Finally, we show that signals through Lck are essential for the development of T-cell-effector potential, particularly for effective cytokine transcription.