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Inverted signaling hierarchy between RAS and RAC in T-lymphocytes

机译：T淋巴细胞中RAS和RAC之间的反向信号传递层次

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In order to generate coherent biological responses to extracellular stimuli, cells have established synergistic and antagonistic crosstalk between pathways with similar or opposing functions, respectively. Two routes cooperating in the generation of mitogenic and cytoskeletal functions are those induced by Ras and Rho/Rac GTPases. In these signaling interactions, Rho/Rac proteins have been always placed in a downstream position respect to Ras in all cell systems analysed so far. In this report, we describe that such signaling hierarchy does not apply to T-lymphocytes. Thus, we show that both Rac1 GDP/GTP exchange factors such as Vav and constitutively active versions of Rac1 can promote the effective stimulation of the Ras pathway in T-lymphocytes. The molecular link for this new type of pathway interconnectivity is RasGRP1, a diacylglycerol-dependent GDP/GTP exchange factor for Ras that translocates to the plasma membrane in a Vav- and Rac1-dependent manner. The effect of the Vav/Rac1 pathway on the Ras pathway is highly dependent on the activity of phospholipase C-, the key cellular supplier of intracellular diacylglycerol. Signaling experiments suggest that this crosstalk represents a signaling strategy used by the T-cell receptor to promote robust biological responses of both the Rac/Rho and Ras pathways upon antigen engagement.
机译：为了产生对细胞外刺激的连贯的生物学反应，细胞已经分别在具有相似或相反功能的途径之间建立了协同和拮抗的串扰。 Ras和Rho / Rac GTPases诱导的两条途径在促有丝分裂和细胞骨架功能的产生中协同作用。在这些信号相互作用中，到目前为止，在所有分析的细胞系统中，Rho / Rac蛋白始终位于Ras的下游位置。在此报告中，我们描述了这种信号传递层次结构不适用于T淋巴细胞。因此，我们显示Rac1 GDP / GTP交换因子（例如Vav）和Rac1的组成型活性形式都可以促进T淋巴细胞中Ras途径的有效刺激。这种新型途径互连的分子联系是RasGRP1，这是Ras的二酰基甘油依赖性GDP / GTP交换因子，它以Vav和Rac1依赖性方式转移到质膜上。 Vav / Rac1途径对Ras途径的影响高度依赖于磷脂酶C-（细胞内二酰基甘油的关键细胞供应商）的活性。信号实验表明，这种串扰代表了T细胞受体用来促进抗原结合后Rac / Rho和Ras途径的强大生物学反应的信号传导策略。

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