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首页> 外文期刊>Molecular and Cellular Biology >A Diacylglycerol-Protein Kinase C-RasGRP1 Pathway Directs Ras Activation upon Antigen Receptor Stimulation of T Cells
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A Diacylglycerol-Protein Kinase C-RasGRP1 Pathway Directs Ras Activation upon Antigen Receptor Stimulation of T Cells

机译：二酰基甘油蛋白激酶C-RasGRP1通路指导抗原激活T细胞后Ras激活。

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Ras GTPases are on/off switches regulating numerous cellular responses by signaling to various effector molecules. In T lymphocytes, Ras can be activated by two Ras exchange factors, SOS and RasGRP1, which are recruited through the adapters Grb2 and LAT and via the second-messenger diacylglycerol (DAG), respectively. Mitogen-activated protein (MAP) kinase phosphorylation patterns induced by active Ras can vary and contribute to distinct cellular responses. The different consequences of Ras activation by either guanine exchange factor are unknown. DAG also recruits and activates the kinase protein kinase Cθ (PKCθ) turning on the Erk MAP kinase pathway, but the biochemical mechanism responsible is unclear. We generated T-cell clones deficient in phorbol myristate acetate (a surrogate for DAG)-induced Ras activation. Analysis of a RasGRP1-deficient Jurkat T-cell clone and RasGRP1 RNA interference in wild-type cells revealed that RasGRP1 is required for optimal, antigen receptor-triggered Ras-Erk activation. RasGRP1 relies on its DAG-binding domain to selectively activate Erk kinases. Activation of Erk correlates with the phosphorylation of threonine residue 184 in RasGRP1. This phosphorylation event requires the activities of novel PKC kinases. Conversely, active PKCθ depends on RasGRP1 sufficiency to effectively trigger downstream events. Last, DAG-PKC-RasGRP1-driven Ras-Erk activation in T cells is a unique signaling event, not simply compensated for by SOS activity.
机译：Ras GTPases是通过向各种效应分子发出信号来调节众多细胞反应的开/关开关。在T淋巴细胞中，Ras可以被两个Ras交换因子SOS和RasGRP1激活，这两个因子分别通过衔接子Grb2和LAT以及第二信使二酰基甘油（DAG）募集。活性Ras诱导的丝裂原激活蛋白（MAP）激酶磷酸化模式可能会有所不同，并有助于产生不同的细胞反应。鸟嘌呤交换因子激活Ras的不同结果尚不清楚。 DAG还募集并激活激酶蛋白激酶Cθ（PKCθ），从而开启Erk MAP激酶途径，但尚不清楚其负责的生化机制。我们生成了缺乏佛波醇肉豆蔻酸酯乙酸盐（DAG的替代物）引起的Ras激活的T细胞克隆。对野生型细胞中缺乏RasGRP1的Jurkat T细胞克隆和RasGRP1 RNA干扰的分析显示，RasGRP1是最佳的，由抗原受体触发的Ras-Erk激活所必需的。 RasGRP1依靠其DAG结合域选择性激活Erk激酶。 Erk的激活与RasGRP1中苏氨酸残基184的磷酸化有关。该磷酸化事件需要新型PKC激酶的活性。相反，有效的PKCθ取决于RasGRP1的充分性来有效触发下游事件。最后，DAG-PKC-RasGRP1驱动的Ras-Erk在T细胞中的激活是独特的信号事件，不能简单地通过SOS活性来补偿。

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