A Phospholipase C-γ1-Independent, RasGRP1-ERK-Dependent Pathway Drives Lymphoproliferative Disease in Linker for Activation of T Cells-Y136F Mutant Mice
A Phospholipase C-γ1-Independent, RasGRP1-ERK-Dependent Pathway Drives Lymphoproliferative Disease in Linker for Activation of T Cells-Y136F Mutant Mice
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DOI：
10.4049/jimmunol.1201458
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发表时间：
2013-01-01
影响因子：
4.4
通讯作者：
Sommers, Connie L.
中科院分区：
文献类型：
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作者：
Kortum, Robert L.;Rouquette-Jazdanian, Alexandre K.;Sommers, Connie L.
在T细胞激活连接物(LAT)的磷脂酶C-GMA1结合部位表达胚系突变的小鼠表现出进行性淋巴增殖，并最终在4-6个月龄死亡。在这些小鼠中，过度激活的T细胞表现出TCR诱导的钙通量缺陷，但增强了RAS/ERK的激活，这对疾病的进展至关重要。尽管LAT依赖的磷脂酶C-Gamma 1结合和激活丢失，但遗传分析显示，RASGRP1而不是Sos1或Sos2是这些小鼠ERK激活和淋巴增殖表型的主要Ras鸟嘌呤交换因子。对LAT-Y136F小鼠分离的CD4(+)T细胞的分析显示，近端TCR依赖的激酶信号发生了变化，激活了ZAP70和LAT不依赖的途径。此外，LAT-Y136F T细胞表现出依赖于Lck和/或Fyn、蛋白激酶C-theta和RASGRP1的ERK激活。这些数据显示了一种在病理环境下体内激活RAS的新途径。免疫学杂志，2013,190：147-158。
Mice expressing a germline mutation in the phospholipase C-gamma 1-binding site of linker for activation of T cells (LAT) show progressive lymphoproliferation and ultimately die at 4-6 mo age. The hyperactivated T cells in these mice show defective TCR-induced calcium flux but enhanced Ras/ERK activation, which is critical for disease progression. Despite the loss of LAT-dependent phospholipase C-gamma 1 binding and activation, genetic analysis revealed RasGRP1, and not Sos1 or Sos2, to be the major Ras guanine exchange factor responsible for ERK activation and the lymphoproliferative phenotype in these mice. Analysis of isolated CD4(+) T cells from LAT-Y136F mice showed altered proximal TCR-dependent kinase signaling, which activated a Zap70-and LAT-independent pathway. Moreover, LAT-Y136F T cells showed ERK activation that was dependent on Lck and/or Fyn, protein kinase C-theta, and RasGRP1. These data demonstrate a novel route to Ras activation in vivo in a pathological setting. The Journal of Immunology, 2013, 190: 147-158.