ArticleProceedings of the National Academy of Sciences of the United States of America2010
Contribution of SHP-1 protein tyrosine phosphatase to osmotic regulation of the transcription factor TonEBP/OREBP.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 27 citations in OpenAlex.
- NFAT5: a stress-related transcription factor with multiple functions in health and disease.Cell stress · 2025Review
- Regulation of PPARγ2 Stability and Activity by SHP-1.Molecular and cellular biology · 2024Article
- NFAT5-Mediated Signalling Pathways in Viral Infection and Cardiovascular Dysfunction.International journal of molecular sciences · 2021Review
- Dexamethasone upregulates mitochondrial Tom20, Tom70, and MnSOD through SGK1 in the kidney cells.Journal of physiology and biochemistry · 2021Article
- EAE-induced upregulation of mitochondrial MnSOD is associated with increases of mitochondrial SGK1 and Tom20 protein in the mouse kidney cortex.The journal of physiological sciences : JPS · 2019Article
- Sickle cell disease up-regulates vasopressin, aquaporin 2, urea transporter A1, Na-K-Cl cotransporter 2, and epithelial Na channels in the mouse kidney medulla despite compromising urinary concentration ability.Physiological reports · 2019Article
- Regulation of Inflammatory Functions of Macrophages and T Lymphocytes by NFAT5.Frontiers in immunology · 2019Review
- Article
- Peptide affinity analysis of proteins that bind to an unstructured region containing the transactivating domain of the osmoprotective transcription factor NFAT5.Physiological genomics · 2016Article
- Peptide affinity analysis of proteins that bind to an unstructured NH2-terminal region of the osmoprotective transcription factor NFAT5.Physiological genomics · 2016Article
- How do kinases contribute to tonicity-dependent regulation of the transcription factor NFAT5?World journal of nephrology · 2016Review
- RNA-Seq analysis of high NaCl-induced gene expression.Physiological genomics · 2015Article
- PKC-α contributes to high NaCl-induced activation of NFAT5 (TonEBP/OREBP) through MAPK ERK1/2.American journal of physiology. Renal physiology · 2015Article
- Database of osmoregulated proteins in mammalian cells.Physiological reports · 2014Article
- High NaCl-induced inhibition of PTG contributes to activation of NFAT5 through attenuation of the negative effect of SHP-1.American journal of physiology. Renal physiology · 2013Article
- Inhibitory phosphorylation of GSK-3β by AKT, PKA, and PI3K contributes to high NaCl-induced activation of the transcription factor NFAT5 (TonEBP/OREBP).American journal of physiology. Renal physiology · 2013Article
- Mutations that reduce its specific DNA binding inhibit high NaCl-induced nuclear localization of the osmoprotective transcription factor NFAT5.American journal of physiology. Cell physiology · 2012Article
- Elevated extracellular glucose and uncontrolled type 1 diabetes enhance NFAT5 signaling and disrupt the transverse tubular network in mouse skeletal muscle.Experimental biology and medicine (Maywood, N.J.) · 2012Article
- Rac1/osmosensing scaffold for MEKK3 contributes via phospholipase C-gamma1 to activation of the osmoprotective transcription factor NFAT5.Proceedings of the National Academy of Sciences of the United States of America · 2011Article
- High NaCl-induced activation of CDK5 increases phosphorylation of the osmoprotective transcription factor TonEBP/OREBP at threonine 135, which contributes to its rapid nuclear localization.Molecular biology of the cell · 2011Article
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Authors and funding
4 authors at 3 institutions in 1 country.
Funding
Abstract
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 transcriptional activity. We found that siRNAs against 57 phosphatases significantly alter TonEBP/OREBP transcriptional activity during normotonicity (290 mosmol/kg) or hypertonicity (500 mosmol/kg, NaCl 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 transactivating activity. SHP-1 coimmunoprecipitates with TonEBP/OREBP and vice versa, suggesting that they are physically associated in the cell. High NaCl 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 NaCl increases phosphorylation of TonEBP/OREBP at Y143, contributing to the nuclear localization and activation of TonEBP/OREBP.
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