Contribution of SHP-1 protein tyrosine phosphatase to osmotic regulation of the transcription factor TonEBP/OREBP

Zhou, Xiaoming; Gallazzini, Morgan; Burg, Maurice B.; Ferraris, Joan D.

doi:10.1073/pnas.1002795107

Cited by 27 publications

(54 citation statements)

References 34 publications

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“…Consistent with the observations that phosphorylation regulates NFAT5 activation are that more than a dozen of kinases ( Figure 1) and a few phosphatases have been identified to regulate NFAT5 transcriptional activity [22,23,[29][30][31][32] . However, all of these kinases and phosphatases also regulate other cellular activities and even opposite activities.…”

Section: Signaling Regulation Through Coordinationsupporting

confidence: 60%

“…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%

“…Instead, its nucleo-cytoplasmic distribution is regulated by phosphorylation of other amino acids in the terminus such as tyrosine 143 [23][24][25] , threonine 135 [26] and serines 155 and 158 [27] . The difference in amino acid composition explains why GSK-3β affects nuclear localization of NFAT5 differently from that of NFAT1-4.…”

Section: Glycogen Synthase Kinase 3β Casein Kinase 1 and 5' -Ampkmentioning

confidence: 99%

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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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Section: Signaling Regulation Through Coordinationsupporting

confidence: 60%

Section: Phosphorylation Of Nfat5mentioning

confidence: 99%

Section: Glycogen Synthase Kinase 3β Casein Kinase 1 and 5' -Ampkmentioning

confidence: 99%

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

Zhou

2016

WJN

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“…Thus, "Protein tyrosine phosphatase activity" (Table 2) includes NFAT5-regulated genes that code for phosphatases that dephosphorylate and thus affect the activity of signaling molecules that regulate the activity of NFAT5 itself. We had not previously screened for phosphatases regulated by NFAT5, but we had screened for phosphatases that affect NFAT5 activity (40,41). Interestingly, Ptprb*, which codes for a phosphatase that supports high NaCl-induced NFAT5 activity in HEK293 cells (40), is also upregulated by NFAT5 activity, raising the possibility of a positive feedback loop that supports NFAT5 activity.…”

Section: High Nacl Alters Expression Of Very Few Genes In Common Betwmentioning

confidence: 99%

RNA-Seq analysis of high NaCl-induced gene expression

Yokoyama

Yang

Zhu

et al. 2015

Physiological Genomics

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High extracellular NaCl is known to change expression of numerous genes, many of which are regulated by the osmoprotective transcription factor nuclear factor of activated T cells-5 (NFAT5). In the present study we employed RNA-Seq to provide a comprehensive, unbiased account of genes regulated by high NaCl in mouse embryonic fibroblast cells (MEFs). To identify genes regulated by NFAT5 we compared wild-type MEFs (WT-MEFs) to MEFs in which mutation of the NFAT5 gene inhibits its transcriptional activity (Null-MEFs). In WT-MEFs adding NaCl to raise osmolality from 300 to 500 mosmol/kg for 24 h increases expression of 167 genes and reduces expression of 412. Raising osmolality through multiple passages (adapted cells) increases expression of 196 genes and reduces expression of 528. In Null-MEFs, after 24 h of high NaCl, expression of 217 genes increase and 428 decrease, while in adapted Null-MEFs 143 increase and 622 decrease. Fewer than 10% of genes are regulated in common between WT-and null-MEFs, indicating a profound difference in regulation of highNaCl induced genes induced by NFAT5 compared with those induced in the absence of NFAT5. Based on our findings we suggest a mechanism for this phenomenon, which had previously been unexplained. The NFAT5 DNA-binding motif (osmotic response element) is overrepresented in the vicinity of genes that NFAT5 upregulates, but not genes that it downregulates. We used Gene Ontology and manual curation to determine the function of the genes targeted by NFAT5, revealing many novel consequences of NFAT5 transcriptional activity.NFAT5; hypertonicity; GO analysis; osmotic; RNA HYPERTONICITY, WHICH IS INDUCED by high extracellular concentrations of solutes such as NaCl, can damage and even kill cells, but cells generally protect themselves by responses including accumulation of compatible organic osmolytes (reviewed in Ref.2). The highest interstitial concentrations of NaCl in mammals occur in their renal medullas, consequent to the operation of the urinary concentrating mechanism, but interstitial NaCl can be elevated in other tissues as well, although not nearly to as great an extent in the renal medulla.Hypertonicity decreases gene expression in general (30) but also increases expression of many genes (8). Nuclear factor of activated T cells-5 (NFAT5) (16, 22) is a transcription factor that increases expression of genes clearly involved in osmoprotection, but also of other genes in which the connection is not obvious (9). Previous screens identified many hypertonicity-induced genes, including those regulated by NFAT5. Most of those screens employed DNA microarrays, for example (17,20,24,31). Recently, the development of RNA sequencing (RNA-Seq) has provided a means for a more comprehensive profiling of gene expression than previous methods, including DNA microarrays (3).In the present study we employed RNA-Seq to provide a comprehensive, unbiased account of genes regulated by high NaCl in mouse embryonic fibroblast cells (MEFs). To distinguish which of the genes are regulated b...

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“…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).…”

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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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Contribution of SHP-1 protein tyrosine phosphatase to osmotic regulation of the transcription factor TonEBP/OREBP

Cited by 27 publications

References 34 publications

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

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

RNA-Seq analysis of high NaCl-induced gene expression

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

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