Protein phosphatase 5 modulates SMAD3 function in the transforming growth factor-β pathway
Protein phosphatase 5 modulates SMAD3 function in the transforming growth factor-β pathway
复制标题
DOI：
10.1016/j.cellsig.2012.07.003
复制
发表时间：
2012-11-01
影响因子：
4.8
通讯作者：
Sapkota, Gopal P.
中科院分区：
文献类型：
--
作者：
Bruce, David L.;Macartney, Thomas;Sapkota, Gopal P.
蛋白质磷酸酶在平衡对转化生长因子-BETA（TGFβ）信号的细胞反应方面起着关键作用。几种蛋白质磷酸酶已归因于TGFβ途径的调节中的作用。其中。 PPM1A是唯一报道的磷酸化酶在细胞核中脱磷酸化的Smad2/3。但是，我们在所有测试细胞中独立于TOM治疗的细胞质级分中仅观察到PPM1A。这些观察结果表明，真正的核Smad2/3磷酸酶仍然难以捉摸。在这项研究中，我们报告了TGFβ途径中蛋白质磷酸酶5（PP5）的作用。我们将PP5确定为SMAD2/3的交互器。有趣的是，在源自PP5-NULL小鼠的小鼠胚胎成纤维细胞中，TGFβ诱导的转录反应显着增强。令人惊讶的是，这种增强是由于与野生型相比，PP5-NULL MEF中观察到的Smad3蛋白水平升高。野生型和pps-null MEF之间没有观察到SMAD3转录物水平的差异。虽然PP5能够在过表达测定中脱离磷酸化的SMAD3-尾，但我们证明其活性对于控制MEF中的Smad3蛋白水平至关重要。我们建议PP5通过调节SMAD3蛋白水平的表达来调节MEF中的TGFβ途径。 （c）2012 Elsevier Inc.保留所有权利。
Protein phosphatases play a key role in balancing the cellular responses to the transforming growth factor-beta (TGF beta) signals. Several protein phosphatases have been attributed roles in the regulation of the TGF beta pathway. Among these. PPM1A is the only phosphatase reported to dephosphorylate SMAD2/3 in the nucleus. However we observed PPM1A exclusively in the cytoplasmic fractions independently of TOM treatment in all cells tested. These observations imply that a bona fide nuclear SMAD2/3 phosphatase remains elusive. In this study, we report a role for protein phosphatase 5 (PP5) in the TGF beta pathway. We identified PP5 as an interactor of SMAD2/3. Interestingly, in mouse embryonic fibroblast cells derived from PP5-null mice, TGF beta-induced transcriptional responses were significantly enhanced. Rather surprisingly, this enhancement is due to the increased levels of SMAD3 protein observed in PP5-null MEFs compared to the wild type. No differences in the levels of SMAD3 transcripts were observed between the wild-type and PPS-null MEFs. While PP5 is capable of dephosphoiylating SMAD3-tail in overexpression assays, we demonstrate that its activity is essential in controlling SMAD3 protein levels in MEFs. We propose that PP5 regulates the TGF beta pathway in MEFs by regulating the expression of SMAD3 protein levels. (C) 2012 Elsevier Inc. All rights reserved.