Inhibitory phosphorylation of GSK-3β by AKT, PKA, and PI3K contributes to high NaCl-induced activation of the transcription factor NFAT5 (TonEBP/OREBP)

Zhou, Xiaoming; Wang, Hong; Burg, Maurice B.; Ferraris, Joan D.

doi:10.1152/ajprenal.00591.2012

Cited by 41 publications

(44 citation statements)

References 72 publications

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“…Co-expression of the catalytically active AKT1 with GSK3 in the GSK3 -/-mouse embryonic fibroblasts reverses the inhibitory effect of GSK3β on NFAT5. These data indicate that AKT1 contributes to tonicity-dependent activation of NFAT5 by attenuating the inhibitory effect of GSK3 [81] . Whether hypertonicity/hyperosmolality activates AKT remains controversial.…”

Section: Mitogen-activated Protein Kinasesmentioning

confidence: 69%

“…Therefore, GSK3β integrates, at least in part, the effects of PKA, PI3K and AKT1 on NFAT5. However, GSK3β is not involved in the effect of p38α on NFAT5, because coexpression of p38α and its constitutively active upstream kinase MKK6 does not increase phosphorylation of GSK3β-S9 or reverse the inhibitory effect of GSK3β-S9 on NFAT5 [81] , despite the observations in other settings that p38α inhibits GSK3β activity [132] . On the other hand, low NaCl reduces the inhibitory phosphorylation of GSK3β-S9, which leads to reduction of NFAT5 mRNA and protein abundance in the mouse inner medullary collecting duct cells [133] .…”

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

confidence: 95%

“…GSK3β inhibits NFAT5 transcriptional activity by reducing NFAT5 transactivating activity and protein abundance under the normal tonicity. High NaCl increases phosphorylation of GSK3β-S9 and decreases GSK3β activity, which results in an increase of NFAT5 transcriptional activity mediated by the increment of NFAT5 transactivating activity, but not by NFAT5 nuclear localization or protein abundance [81] . The lack of the effect of GSK3β on NFAT5 nucleo-cytoplasmic trafficking is in contrast to its effect on NFAT1-4.…”

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

confidence: 99%

“…Further, overexpression of the catalytic subunit of PKA (PKAc) alone increases NFAT5 transactivating and transcriptional activities under the isotonic condition [35] . Subsequent studies indicate that PKA contributes to tonicity-dependent activation of NFAT5 by suppressing the negative effect of GSK-3β on the transcription factor through increasing the inhibitory phosphorylation of GSK-3β at serine 9 [81] . PKA has also been suggested to contribute to tonicity-dependent activation of NFAT5 in the primary splenocytes, based on the inhibitory effect of H89 [61] .…”

Section: Mitogen-activated Protein Kinasesmentioning

confidence: 99%

“…The stimulatory effect of PKA, PI3K and AKT1 on NFAT5 is dependent on their attenuation of the GSK3β inhibitory effect on the transcription factor [81] . Therefore, GSK3β integrates, at least in part, the effects of PKA, PI3K and AKT1 on NFAT5.…”

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: Mitogen-activated Protein Kinasesmentioning

confidence: 69%

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

confidence: 95%

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

confidence: 99%

Section: Mitogen-activated Protein Kinasesmentioning

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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The fatty acid synthase inhibitor C75 differentially affects the adipogenic differentiation of multipotent cells and preadipocytes

Tseng

Liu

et al. 2022

FEBS Letters

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Edited by Lászl ó NagyPreviously, we revealed the dual enhancing effect of netoglitazone, an agonist of the peroxisome proliferator-activated receptor γ, on adipogenesis and osteoblastogenesis, and reported that fatty acid synthase (FASN) knockdown selectively repressed its pro-adipogenic effect. Here, we examined if a FASN inhibitor, C75, could selectively repress the pro-adipogenic effect of netoglitazone. Surprisingly, C75 promoted the adipogenic differentiation of multipotent C3H10T1/2 cells but inhibited 3T3-L1 preadipocytes. By identifying glycogen synthase kinase-3β and intracellular cAMP levels as regulatory targets of C75, we ultimately found the differential expression of adenosine receptor 3 (AR3) and AR2a on these cells. Inhibition of AR3 on C3H10T1/2 and AR2a on 3T3-L1 inhibited the effects of C75 on the differentiation of these cells. Our findings imply that cell-type-specific AR expression might account for the differential adipogenic effects of C75.

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Astaxanthin‐S‐Allyl Cysteine Ester Protects Pancreatic β‐Cell From Glucolipotoxicity by Suppressing Oxidative Stress, Endoplasmic Reticulum Stress and mTOR Pathway Dysregulation

Sakayanathan,

Loganathan,

Thayumanavan

2024

J Biochem & Molecular Tox

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Glucolipotoxicity (GLT) has emerged as established mechanism in the progression of diabetes. Identifying compounds that mitigate GLT‐induced deleterious effect on β‐cells are considered important strategy to overcome diabetes. Hence, in the present study, astaxanthin‐s‐allyl cysteine (AST‐SAC) diester was studied against GLT in β‐cells. Mus musculus pancreatic β‐cell line (βTC‐tet) was treated with high glucose (25 mM; HG) and 95 μM palmitate (PA) for 24 h to induce GLT. AST‐SAC at various concentrations (5, 10, and 15 μg/ml) were treated to understand the protective effect against HG + PA exposure in β‐cells. Under HG + PA exposure conditions oxidative stress, deregulation of mTOR pathway and endoplasmic reticulum (ER) stress are witnessed. AST‐SAC treatment eased oxidative stress, mitochondrial depolarization, DNA damage, calcium overload and accumulation of autophagosome against HG + PA exposure conditions thereby protected the cell viability of β‐cells. AST‐SAC maintained the level of proteins involved in mTOR pathway under HG + PA exposure conditions. Also, AST‐SAC treatment has mitigated the increased expression of genes and proteins such as IRE1 and PERK involved in ER stress‐mediated unfolded protein response (UPR) signaling pathways. In correspondence to it, the expression of genes involved in insulin secretion was preserved by AST‐SAC. Due to these protective effects of AST‐SAC the insulin secretion was well‐maintained in β‐cells under HG + PA exposure conditions. AST‐SAC through normalizing antioxidant status and mTOR axis as well as preventing the harmful effect of ER‐stress mediated UPR pathway has promoted the β‐cell survival and insulin secretion against GLT. Simultaneously targeting oxidative stress/mTOR axis/ER stress is required to efficiently overcome GLT in β‐cells.

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Inhibitory phosphorylation of GSK-3β by AKT, PKA, and PI3K contributes to high NaCl-induced activation of the transcription factor NFAT5 (TonEBP/OREBP)

Cited by 41 publications

References 72 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?

The fatty acid synthase inhibitor C75 differentially affects the adipogenic differentiation of multipotent cells and preadipocytes

Astaxanthin‐S‐Allyl Cysteine Ester Protects Pancreatic β‐Cell From Glucolipotoxicity by Suppressing Oxidative Stress, Endoplasmic Reticulum Stress and mTOR Pathway Dysregulation

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