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首页> 外文期刊>Cellular Signalling >RGS19 inhibits Ras signaling through Nm23H1/2-mediated phosphorylation of the kinase suppressor of Ras
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RGS19 inhibits Ras signaling through Nm23H1/2-mediated phosphorylation of the kinase suppressor of Ras

机译:RGS19通过Nm23H1 / 2介导的Ras激酶抑制剂的磷酸化抑制Ras信号传导

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Besides serving as signal terminators for G protein pathways, several regulators of G protein signaling (RGS) can also modulate cell proliferation. RGS19 has previously been shown to enhance Akt signaling despite impaired Ras signaling. The present study examines the mechanism by which RGS19 inhibits Ras signaling. In HEK293 cells stably expressing RGS19, serum-induced Ras activation and phosphorylations of Raf/MEK/ERK were significantly inhibited, while cells expressing RGS2, 4, 7, 8, 10, or 20 did not exhibit this inhibitory phenotype. Conversely, siRNA-mediated knockdown of RGS19 enabled partial recovery of serum-induced ERK phosphorylation. Interestingly, two isoforms of the tumor metastasis suppressor Nm23 (H1 and H2) were upregulated in 293/RGS19 cells. As a nucleoside diphosphate kinase, Nm23H1 can phosphorylate the kinase suppressor of Ras (KSR). Elevated levels of phosphorylated KSR were indeed detected in the nuclear fractions of 293/RGS19 cells. Co-immunoprecipitation assays revealed that Nm23H1/2 can form complexes with RGS19, Ras, or KSR. siRNA-mediated knockdown of Nm23H1/2 allowed 293/RGS19 cells to partially recover their ERK responses to serum treatment, while overexpression of Nm23H1/2 in HEK293 cells suppressed the serum-induced ERK response. This study demonstrates that expression of RGS19 can suppress Ras-mediated signaling via upregulation of Nm23.
机译:除了充当G蛋白途径的信号终止剂外,G蛋白信号传导(RGS)的几种调节剂还可调节细胞增殖。尽管Ras信号传导受损,但先前已证明RGS19可增强Akt信号传导。本研究探讨了RGS19抑制Ras信号传导的机制。在稳定表达RGS19的HEK293细胞中,血清诱导的Ras活化和Raf / MEK / ERK的磷酸化受到显着抑制,而表达RGS2、4、7、8、10或20的细胞则没有这种抑制表型。相反,siRNA介导的RGS19敲低能够部分恢复血清诱导的ERK磷酸化。有趣的是,在293 / RGS19细胞中,肿瘤转移抑制因子Nm23的两个亚型(H1和H2)被上调。作为核苷二磷酸激酶,Nm23H1可以磷酸化Ras的激酶抑制剂(KSR)。实际上在293 / RGS19细胞的核级分中检测到磷酸化的KSR水平升高。免疫共沉淀试验表明,Nm23H1 / 2可以与RGS19,Ras或KSR形成复合物。 siRNA介导的Nm23H1 / 2的敲低使293 / RGS19细胞能够部分恢复其对血清治疗的ERK反应,而Nm23H1 / 2在HEK293细胞中的过表达抑制了血清诱导的ERK反应。这项研究表明,RGS19的表达可以通过上调Nm23抑制Ras介导的信号传导。

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