MEK/ERK pathway mediates insulin-promoted degradation of MKP-3 protein in liver cells.
MEK/ERK pathway mediates insulin-promoted degradation of MKP-3 protein in liver cells.
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DOI：
10.1016/j.mce.2012.03.025
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发表时间：
2012-09-25
影响因子：
4.1
通讯作者：
Xu, Haiyan
中科院分区：
文献类型：
--
作者：
Feng, Bin;Jiao, Ping;Yang, Zaiqing;Xu, Haiyan
MAP 激酶磷酸酶 3 (MKP-3) 最近被确定为肝脏葡萄糖稳态的重要调节因子，其表达可在转录后水平被胰岛素抑制。在本研究中，使用培养的肝细胞，在放线菌酮存在的情况下，通过免疫印迹分析研究 MKP-3 蛋白的稳定性，从而研究胰岛素促进 MKP-3 蛋白减少的机制。对多种途径进行了检查，发现 MEK/ERK 途径的激活可介导响应胰岛素的 MKP-3 蛋白表达减少。 MEK 抑制剂显着减缓 MKP-3 蛋白降解。 MKP-3 上两个 ERK 磷酸化位点的突变使其对胰岛素具有抗性，并具有组成型活性 MEK 诱导的 MKP-3 蛋白降解。为了了解 MKP-3 蛋白稳定性对肝细胞葡萄糖输出的生物学影响，通过操纵 MEK 信号传导的实时 PCR 分析来检查 G6Pase 基因的表达水平，G6Pase 基因编码控制肝细胞中从头合成葡萄糖的最后一步的关键酶。 Fao 细胞中 MEK 通路的激活导致 G6Pase 基因表达减少并降低葡萄糖输出。与此结果一致，MEK 抑制剂增加了 Fao 细胞中 G6Pase 基因的表达和葡萄糖输出。总之，胰岛素可能通过激活肝细胞中的MEK/ERK通路促进MKP-3蛋白降解，并且MKP-3蛋白水平影响Fao细胞输出葡萄糖的能力。
MAP kinase Phosphatase 3 (MKP-3) was recently identified as an important regulator of glucose homeostasis in the liver and its expression can be repressed by insulin at post transcriptional level. In this study, the mechanism underlying insulin promoted decrease of MKP-3 protein was investigated by studying MKP-3 protein stability via immunoblot analysis in the presence of cycloheximide using cultured liver cells. Several pathways were examined and activation of the MEK/ERK pathway was found to mediate reduction of MKP-3 protein expression in response to insulin. MEK inhibitor markedly slowed down MKP-3 protein degradation. Mutation of two ERK phosphorylation sites on MKP-3 rendered it resistant to insulin and constitutively active MEK-induced MKP-3 protein degradation. To understand the biological effect of MKP-3 protein stability on liver cell glucose output, expression level of G6Pase gene, which encodes the key enzyme controlling the last step of de novo glucose synthesis in liver cells, was examined by real time PCR analysis upon manipulation of MEK signaling. Activation of MEK pathway in Fao cells resulted in decreased expression of G6Pase gene and lowered glucose output. Consistent with this result, MEK inhibitor increased expression of G6Pase gene and glucose output in Fao cells. In conclusion, insulin likely promotes MKP-3 protein degradation through activation of MEK/ERK pathway in liver cells and MKP-3 protein level affects the capability of Fao cells to output glucose.
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影响因子：
4.8
作者：
Zhao, Y;Zhang, ZY
通讯作者：
Zhang, ZY
影响因子：
4.1
作者：
Reffas, S;Schlegel, W
通讯作者：
Schlegel, W
影响因子：
4.8
作者：
Jurek, Aleksandra;Amagasaki, Kenichi;Lennartsson, Johan
通讯作者：
Lennartsson, Johan
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
发表时间：
2008-06-01
期刊：
The Biochemical journal
影响因子：
--
作者：
Ekerot M;Stavridis MP;Delavaine L;Mitchell MP;Staples C;Owens DM;Keenan ID;Dickinson RJ;Storey KG;Keyse SM
通讯作者：
Keyse SM
影响因子：
3.5
作者：
Camps, M;Chabert, C;Arkinstall, S
通讯作者：
Arkinstall, S