Thrombin protease-activated receptor-1 signals through Gq- and G13-initiated MAPK cascades regulating c-Jun expression to induce cell transformation
Thrombin protease-activated receptor-1 signals through Gq- and G13-initiated MAPK cascades regulating c-Jun expression to induce cell transformation
复制标题
DOI：
10.1074/jbc.m305709200
复制
发表时间：
2003-11-21
影响因子：
4.8
通讯作者：
Gutkind, JS
中科院分区：
文献类型：
--
作者：
Marinissen, MJ;Servitja, JM;Gutkind, JS
尽管G蛋白偶联受体刺激正常和异常细胞生长的能力已被深入研究，但其转化潜力背后的分子机制的确切性质仍不完全清楚。在本研究中，我们利用凝血酶的强有丝分裂作用及其受体之一（蛋白酶激活受体-1）的焦点形成活性，来剖析该受体如何与 Galpha(i)、Galpha(q/11) 和 Galpha(12/13) 偶联，将信号从膜转导到细胞核，以启动参与细胞转化的转录事件。使用 NIH 3T3 细胞中的内源性和转染的凝血酶受体、与 Galpha(q) 和 Galpha(i) 偶联的毒蕈碱受体的异位表达、嵌合 G 蛋白 α 亚基和缺乏 Galpha(q/11) 和 Galpha(12/13) 的鼠成纤维细胞，我们在此表明，尽管与 Galpha(i) 偶联就足够了 为了诱导 ERK 激活，与 Galpha(q) 和/或 Galpha(13) 偶联的能力对于诱导 c-jun 表达和细胞转化是必要的。此外，我们发现 Galpha(q) 和 Galpha(13) 可以启动 MAPK 级联的激活，包括 JNK、p38 和 ERK5，进而调节控制 c-jun 启动子表达的转录因子的活性。我们还提供了证据，表明 c-Jun 和调节其表达的激酶是蛋白酶激活受体 1 启动的转化途径的组成部分。
Although the ability of G protein-coupled receptors to stimulate normal and aberrant cell growth has been intensely investigated, the precise nature of the molecular mechanisms underlying their transforming potential are still not fully understood. In this study, we have taken advantage of the potent mitogenic effect of thrombin and the focus-forming activity of one of its receptors, protease-activated receptor-1, to dissect how this receptor coupled to Galpha(i), Galpha(q/11), and Galpha(12/13) transduces signals from the membrane to the nucleus to initiate transcriptional events involved in cell transformation. Using endogenous and transfected thrombin receptors in NIH 3T3 cells, ectopic expression of muscarinic receptors coupled to Galpha(q) and Galpha(i), and chimeric G protein alpha subunits and murine fibroblasts deficient in Galpha(q/11), and Galpha(12/13), we show here that, although coupling to Galpha(i) is sufficient to induce ERK activation, the ability to couple to Galpha(q) and/or Galpha(13) is necessary to induce c-jun expression and cell transformation. Furthermore, we show that Galpha(q) and Galpha(13) can initiate the activation of MAPK cascades, including JNK, p38, and ERK5, which in turn regulate the activity of transcription factors controlling expression from the c-jun promoter. We also present evidence that c-Jun and the kinases regulating its expression are integral components of the transforming pathway initiated by protease-activated receptor-1.