Negative-feedback regulation of FGF signalling by DUSP6/MKP-3 is driven by ERK1/2 and mediated by Ets factor binding to a conserved site within the DUSP6/MKP-3 gene promoter.
Negative-feedback regulation of FGF signalling by DUSP6/MKP-3 is driven by ERK1/2 and mediated by Ets factor binding to a conserved site within the DUSP6/MKP-3 gene promoter.
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DUSP6/MKP-3对FGF信号传导的负反馈调节由ERK1/2驱动，并由ETS因子与DUSP6/MKP-3基因启动子内的保守位点结合介导。
DOI：
10.1042/bj20071512
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发表时间：
2008-06-01
期刊：
影响因子：
--
通讯作者：
Keyse SM
中科院分区：
文献类型：
--
作者：
Ekerot M;Stavridis MP;Delavaine L;Mitchell MP;Staples C;Owens DM;Keenan ID;Dickinson RJ;Storey KG;Keyse SM
DUSP6（双特异性磷酸酶 6），也称为 MKP-3 [MAPK（丝裂原激活蛋白激酶）磷酸酶-3] 在体外和体内特异性灭活 ERK1/2（细胞外信号调节激酶 1/2）。 DUSP6/MKP-3 可通过 FGF（成纤维细胞生长因子）信号传导诱导，并作为关键和离散信号传导中心中 ERK 活性的负调节因子，指导早期脊椎动物胚胎的生长和模式化。然而，FGF 诱导 DUSP6/MKP-3 表达并因此帮助设定 ERK1/2 信号传导水平的分子机制尚不清楚。在本研究中，我们使用药理学抑制剂和对小鼠 DUSP6/MKP-3 基因启动子的分析证明，ERK 通路对于 FGF 诱导的 DUSP6/MKP-3 转录至关重要。此外，我们发现这种反应是由 Ets (E 二十六) 转录调节因子家族的保守结合位点介导的，并且 Ets2 蛋白（ERK 信号传导的已知靶标）与内源 DUSP6/MKP-3 启动子结合。最后，与 EGFP（增强型绿色荧光蛋白）偶联的小鼠 DUSP6/MKP-3 启动子重现了鸡神经板中内源 DUSP6/MKP-3 mRNA 表达的特定模式，其活性取决于 FGFR（FGF 受体）和 MAPK 信号传导以及完整的 Ets 结合位点。这些发现确定了一种保守的 Ets 因子依赖性机制，通过该机制，ERK 信号传导激活 DUSP6/MKP-3 转录，从而传递 FGF 信号传导的 ERK1/2 特异性负反馈控制。
DUSP6 (dual-specificity phosphatase 6), also known as MKP-3 [MAPK (mitogen-activated protein kinase) phosphatase-3] specifically inactivates ERK1/2 (extracellular-signal-regulated kinase 1/2) in vitro and in vivo. DUSP6/MKP-3 is inducible by FGF (fibroblast growth factor) signalling and acts as a negative regulator of ERK activity in key and discrete signalling centres that direct outgrowth and patterning in early vertebrate embryos. However, the molecular mechanism by which FGFs induce DUSP6/MKP-3 expression and hence help to set ERK1/2 signalling levels is unknown. In the present study, we demonstrate, using pharmacological inhibitors and analysis of the murine DUSP6/MKP-3 gene promoter, that the ERK pathway is critical for FGF-induced DUSP6/MKP-3 transcription. Furthermore, we show that this response is mediated by a conserved binding site for the Ets (E twenty-six) family of transcriptional regulators and that the Ets2 protein, a known target of ERK signalling, binds to the endogenous DUSP6/MKP-3 promoter. Finally, the murine DUSP6/MKP-3 promoter coupled to EGFP (enhanced green fluorescent protein) recapitulates the specific pattern of endogenous DUSP6/MKP-3 mRNA expression in the chicken neural plate, where its activity depends on FGFR (FGF receptor) and MAPK signalling and an intact Ets-binding site. These findings identify a conserved Ets-factor-dependent mechanism by which ERK signalling activates DUSP6/MKP-3 transcription to deliver ERK1/2-specific negative-feedback control of FGF signalling.