The Lck SH3 domain is required for activation of the mitogen-activated protein kinase pathway but not the initiation of T-cell antigen receptor signaling
The Lck SH3 domain is required for activation of the mitogen-activated protein kinase pathway but not the initiation of T-cell antigen receptor signaling
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DOI：
10.1074/jbc.274.8.5146
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发表时间：
1999-02-19
影响因子：
4.8
通讯作者：
Straus, DB
中科院分区：
文献类型：
--
作者：
Denny, MF;Kaufman, HC;Straus, DB
T 细胞抗原受体 (TCR) 信号传导的启动取决于蛋白酪氨酸激酶的活性，Src 家族激酶 Lck 是 TCR 信号传导初始事件所必需的，例如 TCR 复合物的磷酸化和 ZAP-70 的激活，但对其在下游信号传导中的作用知之甚少。 Lck 缺陷 T 细胞系 JCaM1 中缺乏 SH3 结构域功能的 Lck 突变形式 (LckW97A) 的表达揭示了除了 TCR 信号传导启动之外还需要 Lck。在表达 LckW97A 的细胞中，尽管 TCR z 链磷酸化、ZAP-70 募集和 ZAP-70 激活正常，但刺激 TCR 未能激活丝裂原激活蛋白激酶 (MAPK) 途径。 JCaM1/LckW97A 细胞中细胞外信号调节激酶 (ERK) 和 MAPK 激酶 (MEK) 的激活以及 CD69 表达的诱导受到极大损害。相比之下，磷脂酶 C gamma 1 (PLC gamma 1) 的磷酸化和相应的细胞内钙浓度 ([Ca2+](i)) 升高完好无损。因此，表达LckW97A的细胞在MAPK途径的激活中表现出选择性缺陷。这些结果表明，Lck 在 TCR 信号传导启动之外的信号传导通路激活中发挥作用，并表明 MAPK 通路可以通过调节 Lck 的功能来选择性控制。
Initiation of T-cell antigen receptor (TCR) signaling is dependent upon the activity of protein tyrosine kinases, The Src family kinase Lck is required for the initial events in TCR signaling, such as the phosphorylation of the TCR complex and the activation of ZAP-70, but little is known of its role in downstream signaling. Expression of a mutated form of Lck lacking SH3 domain function (LckW97A) in the Lck-deficient T-cell line JCaM1 revealed a requirement for Lck beyond the initiation of TCR signaling. In cells expressing LckW97A, stimulation of the TCR failed to activate the mitogen-activated protein kinase (MAPK) pathway, despite normal TCR zeta chain phosphorylation, ZAP-70 recruitment, and ZAP-70 activation. Activation of extracellular signal-regulated kinase (ERK) and MAPK kinase (MEK), as well as the induction of CD69 expression, was greatly impaired in JCaM1/LckW97A cells. In contrast, the phosphorylation of phospholipase C gamma 1 (PLC gamma 1) and corresponding elevations in intracellular calcium concentration ([Ca2+](i)) were intact. Thus, cells expressing LckW97A exhibit selective defect in the activation of the MAPK pathway. These results demonstrate that Lck has a role in the activation of signaling pathways beyond the initiation of TCR signaling and suggest that the MAPK pathway may be selectively controlled by regulating the function of Lck.