Stimulation of oncogenic metabotropic glutamate receptor 1 in melanoma cells activates ERK1/2 via PKCε
Stimulation of oncogenic metabotropic glutamate receptor 1 in melanoma cells activates ERK1/2 via PKCε
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DOI：
10.1016/j.cellsig.2005.10.012
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发表时间：
2006-08-01
影响因子：
4.8
通讯作者：
Chen, Suzie
中科院分区：
文献类型：
--
作者：
Marin, Yari E.;Namkoong, Jin;Chen, Suzie
代谢型谷氨酸受体 1（Grm1，以前称为 mGluR1）是一种 G 蛋白偶联受体 (GPCR)，通常在中枢神经系统中表达并发挥作用。我们的转基因小鼠黑色素瘤模型 (TG-3) 的研究表明，黑色素细胞中 Grm1 的异位表达足以诱导体内黑色素瘤的发展 [P.M.波洛克、K. 科恩-索拉尔、R. 苏德、J. Namkoong、J.J.马蒂诺、A. Koganti、H. Zhu、C. Robbins、I. Makalowska、S.S. Shin、Y. Marin、K.G.罗伯茨、L.M. Yudt、A. Chen、J. Cheng、A. Incao、H.W.平克特，C.L.格雷厄姆，K.邓恩，S.M.克雷斯波-卡伯恩，K.R.麦卡森，K.B. Ryan, D. Sinsimer, J. Goydos, K.R. Reuhl, M. Eckhaus, P.S. Meltzer、W.J. Pavan、J.M. Trent、S. Chen、Nat。热内特. 34（2003）108-112。]。我们已经在体外建立并表征了来自独立小鼠黑色素瘤肿瘤的几种细胞系 [Y.E. Marin、J. Namkoong、S.S. Shin、J. Raines、K. Degenhardt、E. White、S. Chen，Neurophannacol。 49（2005）70-79。]。这些细胞系是研究转化黑素细胞中 Grm1 介导的信号事件的有用工具。在这里，我们发现，L-quisqualate（一种 I 类代谢型谷氨酸受体激动剂）对 Grm1 的刺激会导致肌醇三磷酸 (IP3) 积累，并激活这些细胞系中的 ERK1/2。用 Grm1 特异性拮抗剂 (LY367385) 或 Grin 1 显性失活突变体预处理特纳细胞，可抑制 IP3 积累和 ERK1/2 激活，证明这些事件的特异性。我们还表明 Grm1 激活 ERK1/2 是 PKC 依赖性的，但与 cAMP 和 PKA 无关。 PKC epsilon 在 Grm1 介导的 ERK1/2 磷酸化中发挥着关键作用。深入了解黑色素瘤细胞中 Grm1 介导的信号级联可能有助于确定未来设计黑色素瘤联合疗法的关键分子靶点。 (c) 2005 Elsevier Inc. 保留所有权利。
Metabotropic glutamate receptor 1(Grm1, formerly mGluR1) is a G protein coupled receptor (GPCR) normally expressed and functional in the central nervous system. Studies of our transgenic mouse melanoma model (TG-3) revealed that ectopic expression of Grm1 in melanocytes is sufficient to induce melanoma development in vivo [P.M. Pollock, K. Cohen-Solal, R. Sood, J. Namkoong, J.J. Martino, A. Koganti, H. Zhu, C. Robbins, I. Makalowska, S.S. Shin, Y. Marin, K.G. Roberts, L.M. Yudt, A. Chen, J. Cheng, A. Incao, H.W. Pinkett, C.L. Graham, K. Dunn, S.M. Crespo-Carbone, K.R. Mackason, K.B. Ryan, D. Sinsimer, J. Goydos, K.R. Reuhl, M. Eckhaus, P.S. Meltzer, W.J. Pavan, J.M. Trent, S. Chen, Nat. Genet. 34 (2003) 108-112.]. We have established and characterized several cell lines in vitro from independent mouse melanoma tumors [Y.E. Marin, J. Namkoong, S.S. Shin, J. Raines, K. Degenhardt, E. White, S. Chen, Neurophannacol. 49 (2005) 70-79.]. These cell lines are useful tools in the studies of signaling events that may be mediated by Grm1 in transformed melanocytes. Here we show that stimulation of Grm1 by L-quisqualate, a group I metabotropic glutamate receptor agonist, results in inositol triphosphate (IP3) accumulation, and the activation of ERK1/2 in these cell lines. IP3 accumulation and ERK1/2 activation were inhibited by pretreatment of the turner cells with a Grm1-specific antagonist (LY367385) or by dominant negative mutants of Grin 1, demonstrating the specificity of these events. We also show that ERK1/2 activation by Grm1 was PKC-dependent, but cAMP and PKA-independent. PKC epsilon was shown to play a pivotal role in Grm1-mediated ERK1/2 phosphorylation. Insights into the signaling cascades mediated by Grm1 in melanoma cells may aid in the identification of key molecular targets for the future design of combined therapies for melanoma. (c) 2005 Elsevier Inc. All rights reserved.