Phospholipase C-γ1 is involved in signaling the activation by high NaCl of the osmoprotective transcription factor TonEBP/OREBP

Irarrázabal, Carlos E.; Gallazzini, Morgan; Schnetz, Michael P.; Kunin, Margarita; Simons, Brigitte; Williams, Chester K.; Burg, Maurice B.; Ferraris, Joan D.

doi:10.1073/pnas.0913415107

Cited by 34 publications

(62 citation statements)

References 27 publications

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“…However, many reports have indicated that NFAT5 protein level is tightly regulated, particularly during differentiation and in response to hyper-osmotic stresses (Woo et al, 2000;Ferraris et al, 2002). It has been shown that NFAT5 protein level is regulated by several mechanisms involving protein stability and miRNA-mediated mRNA silencing (Dahl et al, 2001;Irarrazabal et al, 2010;Levy et al, 2010). We now report that NFAT5 protein level can also be regulated by the coupling of splicing to the NMD pathway (Figures 4, 5 and 6).…”

Section: Discussionmentioning

confidence: 51%

Dual role of the ddx5/ddx17 RNA helicases in the control of the pro-migratory NFAT5 transcription factor

et al. 2012

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Ddx5 and ddx17 are two highly related RNA helicases involved in both transcription and splicing. These proteins coactivate transcription factors involved in cancer such as the estrogen receptor alpha, p53 and beta-catenin. Ddx5 and ddx17 are part of the splicing machinery and can modulate alternative splicing, the main mechanism increasing the proteome diversity. Alternative splicing also has a role in gene expression level regulation when it is coupled to the nonsensemediated mRNA decay (NMD) pathway. In this work, we report that ddx5 and ddx17 have a dual role in the control of the pro-migratory NFAT5 transcription factor. First, ddx5 and ddx17 act as transcriptional coactivators of NFAT5 and are required for activating NFAT5 target genes involved in tumor cell migration. Second, at the splicing level, ddx5 and ddx17 increase the inclusion of NFAT5 exon 5. As exon 5 contains a pre-mature translation termination codon, its inclusion leads to the regulation of NFAT5 mRNAs by the NMD pathway and to a decrease in NFAT5 protein level. Therefore, we demonstrated for the first time that a transcriptional coregulator can simultaneously regulate the transcriptional activity and alternative splicing of a transcription factor. This dual regulation, where ddx5 and ddx17 enhance the transcriptional activity of NFAT5 although reducing its protein expression level, suggests a critical role for ddx5 and ddx17 in tumor cell migration through the fine regulation of NFAT5 pathway.

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Section: Discussionmentioning

confidence: 51%

Dual role of the ddx5/ddx17 RNA helicases in the control of the pro-migratory NFAT5 transcription factor

et al. 2012

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“…In addition, PLC-γ1 also regulates TonEBP/OREBP in a way that apparently does not involve Rac1. PLC-γ1, through its C-SH2 domain, regulates nuclear localization of TonEBP/OREBP, dependent on its lipase activity (3). This activation evidently is independent of Rac1 because Rac1 does not contribute to TonEBP/OREBP nuclear localization (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…osmotic stress | MAPK H ypertonicity (e.g., high NaCl) activates the transcription factor TonEBP/OREBP (also known as NFAT5), resulting in increased expression of osmoprotective genes (1). Hypertonicity increases TonEBP/OREBP activity by increasing its abundance (1), transactivating activity (1), nuclear localization (1), and phosphorylation (2,3). The regulatory increase of phosphorylation depends on both increased kinase activity and reduced phosphatase activity (4,5).…”

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confidence: 99%

Rac1/osmosensing scaffold for MEKK3 contributes via phospholipase C-γ1 to activation of the osmoprotective transcription factor NFAT5

Zhou

Yokoyama

Burg

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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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. osmotic stress | MAPK H ypertonicity (e.g., high NaCl) activates the transcription factor TonEBP/OREBP (also known as NFAT5), resulting in increased expression of osmoprotective genes (1). Hypertonicity increases TonEBP/OREBP activity by increasing its abundance (1), transactivating activity (1), nuclear localization (1), and phosphorylation (2, 3). The regulatory increase of phosphorylation depends on both increased kinase activity and reduced phosphatase activity (4, 5). The stress-activated MAP kinase p38 has been extensively studied in this regard, but understanding its role has been complicated because hypertonicity activates two different p38s, namely p38α (MAPK14) and p38δ (MAPK13), which have opposite effects on TonEBP/OREBP activity: p38α increases TonEBP/OREBP activity and p38δ decreases it (6). Furthermore, the phosphospecific antibodies commonly used to measure p38 activity do not directly distinguish between p38α activity and p38δ activity, nor do some forms of inhibition that have been used (6). In this article, we will continue to refer to "p38" unless p38α and p38δ are distinguished. Hypertonicity activates p38α via the upstream kinase MKK3 (MAP2K3) or MKK6 (MAP2K6) (7), and p38α and MEKK3 (MAP3K3) contribute to hypertonicity-induced activation of TonEBP/OREBP (6, 8, 9). Thus, p38α contributes to To...

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“…Through mass spectrometry, DNA mutation, immunocytochemistry and Western analyses, NFAT5 tyrosine 143 (Y143), threonine 135 (T135), serine 155 and 158 (S155 and S158) have been identified so far as the phosphorylation sites and play a critical role in regulation of NFAT5 activity. High NaCl increases phosphorylation of NFAT5-Y143, leading to increase of NFAT5 nuclear localization in cell culture [23][24][25] , and phosphorylation of NFAT5-Y143 is increased in the normal rat renal inner medulla and the Brattleboro rat inner medulla treated with vasopressin, known to increase the renal medullary tonicity [25] . The similar Zhou X. Kinases regulate NFAT5 activity phenomena are also observed with NFAT5-T135 [26] .…”

Section: Phosphorylation Of Nfat5mentioning

confidence: 99%

“…Diacylglycerol binds a conserved C1 domain in PKC, resulting in the plasma membrane translocation and activation of the kinase [89] . High NaCl increases PLCγ1 activity [24] , diacylglycerol and total PKC activity [90] . PKC inhibitors reduce NFAT5 transcriptional activity in mIMCD3 [91] and NIH3T3 cells [84] .…”

Section: Mitogen-activated Protein Kinasesmentioning

confidence: 99%

How do kinases contribute to tonicity-dependent regulation of the transcription factor NFAT5?

Zhou

2016

WJN

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NFAT5 plays a critical role in maintaining the renal functions. Its dis-regulation in the kidney leads to or is associated with certain renal diseases or disorders, most notably the urinary concentration defect. Hypertonicity, which the kidney medulla is normally exposed to, activates NFAT5 through phosphorylation of a signaling molecule or NFAT5 itself. Hypotonicity inhibits NFAT5 through a similar mechanism. More than a dozen of protein and lipid kinases have been identified to contribute to tonicity-dependent regulation of NFAT5. Hypertonicity activates NFAT5 by increasing its nuclear localization and transactivating activity in the early phase and protein abundance in the late phase. The known mechanism for inhibition of NFAT5 by hypotonicity is a decrease of nuclear NFAT5. The present article reviews the effect of each kinase on NFAT5 nuclear localization, transactivation and protein abundance, and the relationship among these kinases, if known. Cyclosporine A and tacrolimus suppress immune reactions by inhibiting the phosphatase calcineurin-dependent activation of NFAT1. It is hoped that this review would stimulate the interest to seek explanations from the NFAT5 regulatory pathways for certain clinical presentations and to explore novel therapeutic approaches based on the pathways. On the basic science front, this review raises two interesting questions. The first one is how these kinases can specifically signal to NFAT5 in the context of hypertonicity or hypotonicity, because they also regulate other cellular activities and even opposite activities in some cases. The second one is why these many kinases, some of which might have redundant functions, are needed to regulate NFAT5 activity. This review reiterates the concept of signaling through cooperation. Cells need these kinases working in a coordinated way to provide the signaling specificity that is lacking in the individual one. Redundancy in regulation of NFAT5 is a critical strategy for cells to maintain robustness against hypertonic or hypotonic stress. Core tip: NFAT5 is critical for kidney functions. Its disregulation results in or is associated with the renal diseases and disorders. More than a dozen of kinases have been identified to contribute to tonicity-dependent regulation of NFAT5. The present review is focused on how these kinases regulate NFAT5 activity under the context of hypertonicity or hypotonicity. Understanding these regulatory mechanisms will have therapeutic implications. A precedent example is that recognition of the cyclosporine immunosuppressive effect resulted from inhibition of the phosphatase calcineurin-dependent activation of NFAT1 allows combination use of cyclosporine with other mechanistically different immunosuppressants to improve their therapeutic efficacy and reduce their side effects.Zhou X. How do kinases contribute to tonicity-dependent regulation of the transcription factor NFAT5? World J Nephrol 2016; 5(1): 20-32 Available from:

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Phospholipase C-γ1 is involved in signaling the activation by high NaCl of the osmoprotective transcription factor TonEBP/OREBP

Cited by 34 publications

References 27 publications

Dual role of the ddx5/ddx17 RNA helicases in the control of the pro-migratory NFAT5 transcription factor

Dual role of the ddx5/ddx17 RNA helicases in the control of the pro-migratory NFAT5 transcription factor

Rac1/osmosensing scaffold for MEKK3 contributes via phospholipase C-γ1 to activation of the osmoprotective transcription factor NFAT5

How do kinases contribute to tonicity-dependent regulation of the transcription factor NFAT5?

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