Knock-in mutation of the distal four tyrosines of linker for activation of T cells blocks murine T cell development.
Knock-in mutation of the distal four tyrosines of linker for activation of T cells blocks murine T cell development.
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DOI：
10.1084/jem.194.2.135
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发表时间：
2001-07-16
期刊：
影响因子：
--
通讯作者：
Love PE
中科院分区：
文献类型：
--
作者：
Sommers CL;Menon RK;Grinberg A;Zhang W;Samelson LE;Love PE
用于活化T细胞（LAT）的整合膜衔接蛋白接头通过将TCR偶联至下游信号传导途径而在T细胞抗原受体（TCR）信号转导中执行关键功能。在TCR接合后，LAT被ZAP-70酪氨酸磷酸化，从而为含有多种src同源性2的效应蛋白产生对接位点。在Jurkat T细胞系中，LAT的远端四个酪氨酸结合PLC γ-1、Grb 2和Gads。这四个酪氨酸残基突变为苯丙氨酸（4YF）阻断了TCR介导的钙动员、Erk活化和核因子（NF）-AT活化。在这项研究中，我们研究了这四个酪氨酸残基是否是必不可少的T细胞的发展，通过产生LAT "敲入"突变小鼠表达的4YF突变蛋白的内源性LAT调控序列的控制下。值得注意的是，4YF基因敲入小鼠的表型与LAT −/−（null）小鼠相同;胸腺细胞发育停滞在未成熟的CD4 − CD8 −阶段，不存在成熟的T细胞。通过类似的策略产生的表达野生型LAT蛋白的敲入小鼠显示出正常的T细胞发育特征。这些结果表明，LAT的远端四个酪氨酸残基是体内preTCR信号传导和T细胞发育所必需的。
The integral membrane adapter protein linker for activation of T cells (LAT) performs a critical function in T cell antigen receptor (TCR) signal transduction by coupling the TCR to downstream signaling pathways. After TCR engagement, LAT is tyrosine phosphorylated by ZAP-70 creating docking sites for multiple src homology 2–containing effector proteins. In the Jurkat T cell line, the distal four tyrosines of LAT bind PLCγ-1, Grb2, and Gads. Mutation of these four tyrosine residues to phenylalanine (4YF) blocked TCR-mediated calcium mobilization, Erk activation, and nuclear factor (NF)-AT activation. In this study, we examined whether these four tyrosine residues were essential for T cell development by generating LAT “knock-in” mutant mice that express the 4YF mutant protein under the control of endogenous LAT regulatory sequences. Significantly, the phenotype of 4YF knock-in mice was identical to LAT−/− (null) mice; thymocyte development was arrested at the immature CD4−CD8− stage and no mature T cells were present. Knock-in mice expressing wild-type LAT protein, generated by a similar strategy, displayed a normal T cell developmental profile. These results demonstrate that the distal four tyrosine residues of LAT are essential for preTCR signaling and T cell development in vivo.
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影响因子：
4.8
作者：
Zhang, WG;Trible, RP;Samelson, LE
通讯作者：
Samelson, LE
影响因子：
64.5
作者：
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通讯作者：
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影响因子：
32.4
作者：
Saitoh, S;Arudchandran, R;Samelson, LE
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作者：
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通讯作者：
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DOI：
10.1073/pnas.95.25.14909
发表时间：
1998-12-08
影响因子：
11.1
作者：
DeJarnette, JB;Sommers, CL;Love, PE
通讯作者：
Love, PE