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RIG1 inhibits the Ras/mitogen-activated protein kinase pathway by suppressing the activation of Ras

机译：RIG1通过抑制Ras的激活来抑制Ras /丝裂原激活的蛋白激酶途径

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摘要

The retinoid-inducible gene 1 (RIG 1) protein is a retinoid-inducible growth regulator. Previous studies have shown that the RIG1 protein inhibits the signaling pathways of Ras/mitogen-activated protein kinases. However, neither the mode of action nor the site of inhibition of RIG1 is known. This study investigated the effects of RIG1, and the mechanisms responsible for these effects, on the activation of Ras proteins in HtTA cervical cancer cells. RIG1 reduced the levels of activated Ras (Ras-GTP) and total Ras protein in cells transfected with mutated H-, N-, or K-Ras(G12V), or in cells transfected with the wild type H- or N-Ras followed by stimulation with epidermal growth factor. The half-life of Ras protein decreased from more than 36 h in control cells to 18 h in RIG1-transfected cells. RIG1 immunoprecipitated with the Ras protein in co-transfected cellular lysates. In contrast to the predominant plasma membrane localization in control cells, the H-Ras fusion protein EGFP-H-Ras was localized within a discrete cytoplasmic compartment where it co-localized with RIG1. RIG1 inhibited more than 93% of the Elk- and CHOP-mediated transactivation induced by H- or K-Ras(G12V). However, RIG1 did not inhibit the transactivation induced by MEK1 or MEK3, and failed to suppress the phosphorylation of extracellular signal-regulated kinases 1 and 2 induced by the constitutively activated B-Raf(V599E). The RIG1 with carboxyl terminal truncation (RIG1 Delta C) did not immunoprecipitate with Ras and had no effect on Ras activation or transactivation of the downstream signal pathways. These data indicate that RIG1 exerts its inhibitory effect at the level of Ras activation, which is independent of Ras subtype but dependent on the membrane localization of the RIG1 protein. This inhibition of Ras activation may be mediated through downregulation of Ras levels and alteration of Ras subcellular distribution. (c) 2005 Elsevier Inc. All rights reserved.
机译：类维生素A诱导基因1（RIG 1）蛋白是类维生素A诱导的生长调节剂。先前的研究表明，RIG1蛋白可抑制Ras /促分裂原激活的蛋白激酶的信号传导途径。但是，RIG1的作用方式和抑制位点均未知。这项研究调查了RIG1对HtTA子宫颈癌细胞中Ras蛋白活化的影响及其机制。 RIG1降低了用突变的H-，N-或K-Ras（G12V）转染的细胞或随后用野生型H-或N-Ras转染的细胞中激活的Ras（Ras-GTP）和总Ras蛋白的水平通过表皮生长因子刺激。 Ras蛋白的半衰期从对照细胞的36小时以上降至RIG1转染的细胞的18小时。在共转染的细胞裂解液中，RIG1与Ras蛋白免疫沉淀。与对照细胞中主要的质膜定位相反，H-Ras融合蛋白EGFP-H-Ras定位在离散的细胞质区室中，在该处与RIG1共定位。 RIG1抑制了H-或K-Ras（G12V）诱导的Elk和CHOP介导的反式激活的93％以上。但是，RIG1不能抑制由MEK1或MEK3诱导的反式激活，并且不能抑制由组成型激活的B-Raf（V599E）诱导的细胞外信号调节激酶1和2的磷酸化。具有羧基末端截短的RIG1（RIG1 Delta C）不会与Ras免疫沉淀，并且对Ras激活或下游信号通路的反式激活没有影响。这些数据表明，RIG1在Ras活化水平上发挥其抑制作用，该作用与Ras亚型无关，但取决于RIG1蛋白的膜定位。 Ras激活的这种抑制可以通过Ras水平的下调和Ras亚细胞分布的改变来介导。 （c）2005 Elsevier Inc.保留所有权利。

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