Rac1/osmosensing scaffold for MEKK3 contributes via phospholipase C-γ1 to activation of the osmoprotective transcription factor NFAT5. Proceedings of the National Academy of Sciences of the United States of America

Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 06/2011; 108(29):12155-60. DOI: 10.1073/pnas.1108107108
Source: PubMed


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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    • "In addition to p38/ MAPK, several other signaling cascades have been induced in response to osmotic stress. These include the phosphatidylinositol 3-kinase signaling cascades (Irarrazabal et al., 2004), protein kinase A dependent processes (Ferraris et al., 2002), as well as a Rac1/osmosensing scaffold (Zhou et al., 2011). More recently, a sucrose nonfermenting-1-related serine/ threonine kinase (SIK1) was identified as a sensor of extracellular Na+ gradients, subsequently transducing this information into signaling cascades which modulates cellular function (Sjostrom et al., 2007). "
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    ABSTRACT: Macrophages are not only involved in inflammatory and anti-infective processes, but also play an important role in maintaining tissue homeostasis. In this review, we summarize recent evidence investigating the role of macrophages in controlling angiogenesis, metabolism as well as salt and water balance. Particularly, we summarize the importance of macrophage tonicity enhancer binding protein (TonEBP, also termed nuclear factor of activated T-cells 5 [NFAT5]) expression in the regulation of salt and water homeostasis. Further understanding of homeostatic macrophage function may lead to new therapeutic approaches to treat ischemia, hypertension and metabolic disorders.
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    • "A number of signaling molecules, including PKA [79], ATM [78], c-Abl [69], HSP90 [80], PARP-1 [80], and MDC1 [81], respectively, are found to be associated with NFAT5 and implicated in the regulation of its transactivation. Furthermore, reactive oxygen species [82], PI3K [83], Fyn and p38 [84], as well as a Rac1/PLC-γ1 signaling cascade [85], may act as more upstream regulators. Although how these molecules are coordinated and regulated during hypertonic signaling remains elusive, the Fyn- and p38-signaling cascades are likely to play important roles in NFAT5 activation; this is because NFAT5 activation and target gene induction could be almost completely abolished by simultaneous deletion/inhibition of p38 and Fyn. "
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    ABSTRACT: The Nuclear Factor of Activated T Cells-5 (NFAT5), also known as OREBP or TonEBP, is a member of the nuclear factors of the activated T cells family of transcription factors. It is also the only known tonicity-regulated transcription factor in mammals. NFAT5 was initially known for its role in the hypertonic kidney inner medulla for orchestrating a genetic program to restore the cellular homeostasis. Emerging evidence, however, suggests that NFAT5 might play a more diverse functional role, including a pivotal role in blood pressure regulation and the development of autoimmune diseases. Despite the growing significance of NFAT5 in physiology and diseases, our understanding of how its activity is regulated remains very limited. Furthermore, how changes in tonicities are converted into functional outputs via NFAT5 remains elusive. Therefore, this review aims to summarize our current knowledge on the functional roles of NFAT5 in osmotic stress adaptation and the signaling pathways that regulate its activity.
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