The four distal tyrosines are required for LAT-dependent signaling in FcepsilonRI-mediated mast cell activation.
The four distal tyrosines are required for LAT-dependent signaling in FcepsilonRI-mediated mast cell activation.
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DOI：
10.1084/jem.20030574
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发表时间：
2003-09-01
影响因子：
15.3
通讯作者：
Samelson, LE
中科院分区：
文献类型：
--
作者：
Saitoh, S;Odom, S;Gomez, G;Sommers, CL;Young, HA;Rivera, J;Samelson, LE
T细胞活化连接子（LAT）是一种对Fc ε RI介导的肥大细胞活化至关重要的衔接蛋白。LAT是TCR和Fc γ RI结合后激活的酪氨酸激酶的底物。LAT胞质结构域磷酸化后，多种信号分子如磷脂酶C-γ1、Grb 2和Gads通过其SH 2结构域与磷酸化LAT结合。四个远端酪氨酸在TCR介导的信号传导和T细胞发育中的重要作用已经通过使用LAT缺陷细胞系和遗传修饰小鼠的实验证明。为了研究LAT的这四个酪氨酸在Fc γ-受体介导的肥大细胞活化中的作用，用设计用于表达野生型或突变型LAT的逆转录病毒载体感染来自LAT缺陷小鼠的骨髓来源的肥大细胞。LAT中表达各种酪氨酸至苯丙氨酸突变体的骨髓源性肥大细胞的检查证明了对这些不同结合位点的差异要求。在这些研究中，进行了生化途径、脱粒以及细胞因子和趋化因子释放的测定。最后，这些酪氨酸的作用也进行了评估，在体内使用转基因动物。缺失所有四种远端酪氨酸，特别是主要磷脂酶C-γ结合酪氨酸的缺失对抗原诱导的组胺释放具有显著影响。
The linker for activation of T cells (LAT) is an adaptor protein critical for FcɛRI-mediated mast cell activation. LAT is a substrate of the tyrosine kinases activated after TCR and FcɛRI engagement. After phosphorylation of the cytosolic domain of LAT, multiple signaling molecules such as phospholipase C–γ1, Grb2, and Gads associate with phosphorylated LAT via their SH2 domains. The essential role of the four distal tyrosines in TCR-mediated signaling and T cell development has been demonstrated by experiments using LAT-deficient cell lines and genetically modified mice. To investigate the role of these four tyrosines of LAT in FcɛRI-mediated mast cell activation, bone marrow–derived mast cells from LAT-deficient mice were infected with retroviral vectors designed to express wild-type or mutant LAT. Examination of bone marrow–derived mast cells expressing various tyrosine to phenylalanine mutants in LAT demonstrates a differential requirement for these different binding sites. In these studies, assays of biochemical pathways, degranulation, and cytokine and chemokine release were performed. Finally, the role of these tyrosines was also evaluated in vivo using genetically modified animals. Deletion of all four distal tyrosines, and in particular, loss of the primary phospholipase C–γ-binding tyrosine had a significant effect on antigen-induced histamine release.
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DOI：
10.1084/jem.20021806
发表时间：
2003-06-02
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Gonzalez-Espinosa C;Odom S;Olivera A;Hobson JP;Martinez ME;Oliveira-Dos-Santos A;Barra L;Spiegel S;Penninger JM;Rivera J
通讯作者：
Rivera J
影响因子：
12.4
作者：
Mizuguchi, H;Xu, ZL;Hayakawa, T
通讯作者：
Hayakawa, T
影响因子：
5.3
作者：
Manetz, TS;Gonzalez-Espinosa, C;Rivera, J
通讯作者：
Rivera, J
DOI：
10.1073/pnas.90.18.8392
发表时间：
1993-09-15
影响因子：
11.1
作者：
PEAR, WS;NOLAN, GP;BALTIMORE, D
通讯作者：
BALTIMORE, D
影响因子：
4.8
作者：
HendricksTaylor, LR;Motto, DG;Koretzky, GA
通讯作者：
Koretzky, GA