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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Contribution of SHP-1 protein tyrosine phosphatase to osmotic regulation of the transcription factor TonEBP/OREBP
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Contribution of SHP-1 protein tyrosine phosphatase to osmotic regulation of the transcription factor TonEBP/OREBP

机译：SHP-1蛋白酪氨酸磷酸酶对转录因子TonEBP / OREBP渗透调节的贡献

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摘要

Hypertonicity activates the transcription factor TonEBP/OREBP, resulting in increased expression of osmoprotective genes, including those responsible for accumulation of organic osmolytes and heat-shock proteins. Phosphorylation of TonEBP/OREBP contributes to its activation. Several of the kinases that are involved were previously identified, but the phosphatases were not. In the present studies we screened a genomewide human phosphatase siRNA library in human embryonic kidney (HEK)293 cells for effects on TonEBP/OREBP tran-scriptional activity. We found that siRNAs against 57 phosphatases significantly alter TonEBP/OREBP transcriptional activity during nor-motonicity (290 mosmol/kg) or hypertonicity (500 mosmol/kg, NaCI added) or both. Most siRNAs increase TonEBP/OREBP activity, implying that the targeted phosphatases normally reduce that activity. We further studied in detail SHP-1, whose knockdown by its specific siRNA increases TonEBP/OREBP transcriptional activity at 500 mosmol/kg. We confirmed that SHP-1 is inhibitory by overexpressing it, which reduces TonEBP/OREBP transcriptional activity at 500 mosmol/kg. SHP-1 dephosphorylates TonEBP/OREBP at a known regulatory site, Y143, both in vivo and in vitro. It inhibits TonEBP/OREBP by both reducing TonEBP/OREBP nuclear localization, which is Y143 dependent, and by lowering high NaCl-induced TonEBP/OREBP transactivat-ing activity. SHP-1 coimmunoprecipitates with TonEBP/OREBP and vice versa, suggesting that they are physically associated in the cell. High NaCI inhibits the effect of SHP-1 on TonEBP/OREBP by increasing phosphorylation of SHP-1 on Ser591, which reduces its phosphatase activity and localization to the nucleus. Thus, TonEBP/OREBP is extensively regulated by phosphatases, including SHP-1, whose inhibition by high NaCI increases phosphorylation of TonEBP/OREBP at Y143, contributing to the nuclear localization and activation of TonEBP/OREBP.
机译：高渗性激活转录因子TonEBP / OREBP，导致渗透保护基因的表达增加，包括负责有机渗透压和热激蛋白积累的基因。 TonEBP / OREBP的磷酸化有助于其活化。先前已经鉴定了涉及的几种激酶，但并未鉴定出磷酸酶。在本研究中，我们筛选了人类胚胎肾脏（HEK）293细胞中的全基因组人类磷酸酶siRNA文库，以研究其对TonEBP / OREBP转录活性的影响。我们发现，针对57个磷酸酶的siRNA会在非运动性（290 mosmol / kg）或高渗性（500 mosmol / kg，添加NaCl）或两者期间显着改变TonEBP / OREBP转录活性。大多数siRNA会增加TonEBP / OREBP活性，这意味着靶向磷酸酶通常会降低该活性。我们进一步详细研究了SHP-1，SHP-1通过其特异性siRNA的敲低提高了500 mosmol / kg的TonEBP / OREBP转录活性。我们证实SHP-1通过过表达具有抑制作用，从而降低了500 mosmol / kg的TonEBP / OREBP转录活性。 SHP-1在体内和体外都在已知的调控位点Y143上使TonEBP / OREBP脱磷酸。它通过降低依赖于Y143的TonEBP / OREBP核定位以及降低高NaCl诱导的TonEBP / OREBP反式激活活性来抑制TonEBP / OREBP。 SHP-1与TonEBP / OREBP共免疫沉淀，反之亦然，表明它们在细胞中物理相关。高NaCl会通过增加Ser591上SHP-1的磷酸化来抑制SHP-1对TonEBP / OREBP的作用，这会降低SHP-1的磷酸酶活性和其在细胞核中的定位。因此，TonEBP / OREBP受到磷酸酶（包括SHP-1）的广泛调控，磷酸酶的高NaCl抑制作用会增加TonEBP / OREBP在Y143的磷酸化，从而有助于TonEBP / OREBP的核定位和激活。

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