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首页> 外文期刊>Cellular Signalling >Endogenous RGS proteins attenuate G alpha(i)-mediated lysophosphatidic acid signaling pathways in ovarian cancer cells
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Endogenous RGS proteins attenuate G alpha(i)-mediated lysophosphatidic acid signaling pathways in ovarian cancer cells

机译：内源性RGS蛋白减弱卵巢癌细胞中Gα（i）介导的溶血磷脂酸信号通路

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摘要

Lysophosphatidic acid is a bioactive phospholipid that is produced by and stimulates ovarian cancer cells, promoting proliferation, migration, invasion, and survival. Effects of LPA are mediated by cell surface G-protein coupled receptors'(GPCRs) that activate multiple heterotrimeric G-proteins. G-proteins are deactivated by Regulator of G-protein Signaling (RGS) proteins. This led us to hypothesize that RGS proteins may regulate G-protein signaling pathways initiated by LPA in ovarian cancer cells. To determine the effect of endogenous RGS proteins on LPA signaling in ovarian cancer cells, we compared LPA activity in SKOV-3 ovarian cancer cells expressing G(i) subunit constructs that are either insensitive to RGS protein regulation (RGSi) or their RGS wild-type (RGSwt) counterparts. Both forms of the G-protein contained a point mutation rendering them insensitive to inhibition with pertussis toxin, and cells were treated with pertussis toxin prior to experiments to eliminate endogenous G(i)/(o) signaling. The potency and efficacy of LPA-mediated inhibition of forskolin-stimulated adenylyl cyclase activity was enhanced in cells expressing RGSi G(i) proteins as compared to RGSwt Gi. We further showed that LPA signaling that is subject to RGS regulation terminates much faster than signaling thru RGS insensitive G-proteins. Finally, LPA-stimulated SKOV-3 cell migration, as measured in a wound-induced migration assay, was enhanced in cells expressing G alpha(i2) RGSi as compared to cells expressing G alpha(i2) RGSwt, suggesting that endogenous RGS proteins in ovarian cancer cells normally attenuate this LPA effect. These data establish RGS proteins as novel regulators of LPA signaling in ovarian cancer cells. (C) 2007 Elsevier Inc. All rights reserved.
机译：溶血磷脂酸是一种生物活性磷脂，由卵巢癌细胞产生并刺激卵巢癌细胞，从而促进增殖，迁移，侵袭和存活。 LPA的作用是由激活多个异三聚体G蛋白的细胞表面G蛋白偶联受体（GPCR）介导的。 G蛋白通过G蛋白信号（RGS）调节剂失活。这使我们假设RGS蛋白可能调节LPA在卵巢癌细胞中启动的G蛋白信号通路。为了确定内源性RGS蛋白对卵巢癌细胞LPA信号的影响，我们比较了表达G（i）亚基构建体的SKOV-3卵巢癌细胞中LPA的活性，这些亚基对RGS蛋白调节（RGSi）或它们的RGS野生型不敏感类型（RGSwt）对应项。两种形式的G蛋白都含有点突变，使其对百日咳毒素的抑制不敏感，并且在进行实验以消除内源性G（i）/（o）信号之前，先用百日咳毒素对细胞进行处理。与RGSwt Gi相比，在表达RGSi G（i）蛋白的细胞中LPA介导的抑制Forskolin刺激的腺苷酸环化酶活性的能力和功效得到了增强。我们进一步表明，受RGS调控的LPA信号终止比通过RGS不敏感G蛋白的信号终止快得多。最后，与表达G alpha（i2）RGSwt的细胞相比，在表达G alpha（i2）RGSi的细胞中，LPA刺激的SKOV-3细胞迁移在表达伤口的迁移试验中得到了增强，这表明内源性RGS蛋白在卵巢癌细胞通常会减弱这种LPA效应。这些数据建立了RGS蛋白作为卵巢癌细胞中LPA信号传导的新型调节剂。 （C）2007 Elsevier Inc.保留所有权利。

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