Modulation of lysine acetylation-stimulated repressive activity by Erk2-mediated phosphorylation of RIP140 in adipocyte differentiation.
Modulation of lysine acetylation-stimulated repressive activity by Erk2-mediated phosphorylation of RIP140 in adipocyte differentiation.
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DOI：
10.1016/j.cellsig.2008.07.001
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发表时间：
2008-10
影响因子：
4.8
通讯作者：
Wei, Li-Na
中科院分区：
文献类型：
--
作者：
Ho, Ping-Chih;Gupta, Pawan;Tsui, Yao-Chen;Ha, Sung Gil;Huq, Mostaqul;Wei, Li-Na
关键词：
受体相互作用蛋白140是许多转录因子的共调节因子。以前的质谱研究表明，磷酸化或赖氨酸乙酰化的RIP 140直接增强其反式抑制活性。在这项研究中，我们首先确定p300作为一个特定的赖氨酸乙酰转移酶，和胞外信号相关激酶2（Erk 2）作为一个特定的激酶苏氨酸磷酸化，在体内的RIP 140。我们进一步确定了两个特定的乙酰化赖氨酸残基（Lys 158/Lys 287）和磷酸化苏氨酸残基（Thr 202/Thr 207），这是其基因抑制活性的关键。然后，我们描绘了ERK 2介导的RIP 140磷酸化的信号转导，增强了其随后的赖氨酸乙酰化的招募p300，并证明了这种信号转导途径在分化的脂肪细胞中的激活动力学。最后，该细胞信号转导途径的生理学意义在拯救实验中得到说明，其中通过重新表达野生型RIP 140或其磷酸模拟突变体而不是其乙酰化缺陷突变体来拯救RIP 140缺失培养物的脂肪积累缺陷。这些结果表明，信号转导途径，从Erk 2激活特定的苏氨酸磷酸化，随后由p300招募赖氨酸乙酰化，最终增强RIP 140的基因抑制活性和其功能作用，脂肪积累在分化adipopotyes。
Receptor-interacting protein 140 is a co-regulator for many transcription factors. Previous mass spectrometry studies showed that either phosphorylation or lysine acetylation of RIP140 directly enhanced its trans-repressive activity. In this study, we first identified p300 as a specific lysine acetyltransferase, and extracellular-signal-related kinase 2 (Erk2) as a specific kinase for threonine phosphorylation, of RIP140 in vivo. We further determined two specific acetylated lysine residues (Lys158/Lys287) and phosphorylated threonine residues (Thr202/Thr207) that were critical for its gene repressive activity. We then delineated signal transduction from Erk2-mediated phosphorylation of RIP140 that enhanced its recruiting p300 for subsequent lysine acetylation, and demonstrated the kinetics of activation of this signal transduction pathway in differentiating adipocytes. Finally, the physiological significance of this cell signal transduction pathway was illustrated in rescuing experiments where the defect in fat accumulation of RIP140-null cultures was rescued by re-expressing the wild type RIP140 or its phospho-mimetic mutant, but not its acetylation deficient mutant. These results demonstrate the signal transduction pathway, initiated from Erk2 activation for specific threonine phosphorylation, followed by p300 recruitment for lysine acetylation, which ultimately enhances the gene-repressive activity of RIP140 and its functional role in fat accumulation in differentiated adipoctyes.
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