ArticleProceedings of the National Academy of Sciences of the United States of America2011
Rac1/osmosensing scaffold for MEKK3 contributes via phospholipase C-gamma1 to activation of the osmoprotective transcription factor NFAT5.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 48 citations in OpenAlex.
- NFAT5: a stress-related transcription factor with multiple functions in health and disease.Cell stress · 2025Review
- Rac1 deficiency impairs postnatal development of the renal papilla.Scientific reports · 2022Article
- Regulation of the p38-MAPK pathway by hyperosmolarity and by WNK kinases.Scientific reports · 2022Article
- Article
- Colchicine protects against cartilage degeneration by inhibiting MMP13 expression via PLC-γ1 phosphorylation.Osteoarthritis and cartilage · 2021Article
- NFAT5 Regulated by STUB1, Facilitates Malignant Cell Survival and p38 MAPK Activation by Upregulating AQP5 in Chronic Lymphocytic Leukemia.Biochemical genetics · 2021Article
- Articular Chondrocyte Phenotype Regulation through the Cytoskeleton and the Signaling Processes That Originate from or Converge on the Cytoskeleton: Towards a Novel Understanding of the Intersection between Actin Dynamics and Chondrogenic Function.International journal of molecular sciences · 2021Review
- Signalling through cerebral cavernous malformation protein networks.Open biology · 2020Review
- TonEBP-deficiency accelerates intervertebral disc degeneration underscored by matrix remodeling, cytoskeletal rearrangements, and changes in proinflammatory gene expression.Matrix biology : journal of the International Society for Matrix Biology · 2020Article
- Arp2/3 inactivation causes intervertebral disc and cartilage degeneration with dysregulated TonEBP-mediated osmoadaptation.JCI insight · 2020Article
- Regulation of Inflammatory Functions of Macrophages and T Lymphocytes by NFAT5.Frontiers in immunology · 2019Review
- Recent advances in cerebral cavernous malformation research.Vessel plus · 2018Article
- How do kinases contribute to tonicity-dependent regulation of the transcription factor NFAT5?World journal of nephrology · 2016Review
- A Novel MGC4607/CCM2 Gene Mutation Associated with Cerebral Spinal and Cutaneous Cavernous Angiomas.Journal of molecular neuroscience : MN · 2015Article
- Signaling pathways and the cerebral cavernous malformations proteins: lessons from structural biology.Cellular and molecular life sciences : CMLS · 2014Review
- Cerebral cavernous malformation proteins at a glance.Journal of cell science · 2014Review
- 14-3-3-β and -{varepsilon} contribute to activation of the osmoprotective transcription factor NFAT5 by increasing its protein abundance and its transactivating activity.Physiological reports · 2014Article
- Macrophages in homeostatic immune function.Frontiers in physiology · 2014Review
- 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
- NFAT5 in cellular adaptation to hypertonic stress - regulations and functional significance.Journal of molecular signaling · 2013Article
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
Separate reports that hypertonicity activates p38 via a Rac1-OSM-MEKK3-MKK3-p38 pathway and that p38α contributes to activation of TonEBP/OREBP led us to the hypothesis that Rac1 might activate TonEBP/OREBP via p38. The present studies examine that possibility. High NaCl is hypertonic. We find that siRNA knockdown of Rac1 reduces high NaCl-induced increase of TonEBP/OREBP transcriptional activity (by reducing its transactivating activity but not its nuclear localization). Similarly, siRNA knockdown of osmosensing scaffold for MEKK3 (OSM) also reduces high NaCl-dependent TonEBP/OREBP transcriptional and transactivating activities. Simultaneous siRNA knockdown of Rac1 and OSM is not additive in reduction of TonEBP/OREBP transcriptional activity, indicating a common pathway. However, siRNA knockdown of MKK3 does not reduce TonEBP/OREBP transcriptional activity, although siRNA knockdown of MKK6 does. Nevertheless, the effect of Rac1 on TonEBP/OREBP is also independent of MKK6 because it occurs in MKK6-null cells. Furthermore, we find that siRNA knockdown of Rac1 or OSM actually increases activity (phosphorylation) of p38, rather than decreasing it, as previously reported. Thus, the effect of Rac1 on TonEBP/OREBP is independent of p38. We find instead that phospholipase C-γ1 (PLC-γ1) is involved. When transfected into PLC-γ1-null mouse embryonic fibroblast cells, catalytically active Rac1 does not increase TonEBP/OREBP transcriptional activity unless PLC-γ1 is reconstituted. Similarly, dominant-negative Rac1 also does not inhibit TonEBP/OREBP in PLC-γ1-null cells unless PLC-γ1 is reconstituted. We conclude that Rac1/OSM supports TonEBP/OREBP activity and that this activity is mediated via PLC-γ1, not p38.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.