Regulation of NHE3 by lysophosphatidic acid is mediated by phosphorylation of NHE3 by RSK2

No, Yi Ran; He, Peijian; Yoo, Byong Kwon; Yun, C. Chris

doi:10.1152/ajpcell.00067.2015

Cited by 30 publications

(29 citation statements)

References 51 publications

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“…4C), RSK1 phosphorylation was not significantly affected (data not shown). Treatment with BX795 inhibited the phosphorylation of PDK1 downstream effector RSK2 (Hao et al, 2016;No et al, 2015;Sun et al, 2017;Utepbergenov et al, 2016) (Fig. 4C).…”

Section: Ouabain Enhanced Pi3k Activation In Tgev Infected St Cells Cmentioning

confidence: 83%

The cardenolide ouabain suppresses coronaviral replication via augmenting a Na+/K+-ATPase-dependent PI3K_PDK1 axis signaling

Yang

Chang

Lee

et al. 2018

Toxicology and Applied Pharmacology

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Cardenolides are plant-derived toxic substances. Their cytotoxicity and the underlying mechanistic signaling axes have been extensively documented, but only a few anti-viral activities of cardenolides and the associated signaling pathways have been reported. Previously, we reported that a variety of cardenolides impart anti-transmissible gastroenteritis coronavirus (TGEV) activity in swine testicular (ST) cells, through targeting of the cell membrane sodium/potassium pump, Na/K-ATPase. Herein, we further explore the potential signaling cascades associated with this anti-TGEV activity in ST cells. Ouabain, a representative cardenolide, was found to potently diminish TGEV titers and inhibit the TGEV-induced production of IL-6 in a dose dependent manner, with 50% inhibitory concentrations of 37 nM and 23 nM respectively. By pharmacological inhibition and gene silencing, we demonstrated that PI3K_PDK1_RSK2 signaling was induced in TGEV-infected ST cells, and ouabain imparted a degree of anti-TGEV activity via further augmentation of this existing PI3K_PDK1 axis signaling, in a manner dependent upon its association with the Na/K-ATPase. Finally, inhibition of PI3K by LY294002 or PDK1 by BX795 antagonized the anti-viral activity of ouabain and restored the TGEV virus titer and yields. This finding is the first report of a PI3K_PDK1 signaling axis further induced by ouabain and implicated in the suppression of TGEV activity and replication; greatly illuminates the underlying mechanism of cardenolide toxicity; and is expected to result in one or more anti-viral applications for the cardenolides in the future.

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Section: Ouabain Enhanced Pi3k Activation In Tgev Infected St Cells Cmentioning

confidence: 83%

The cardenolide ouabain suppresses coronaviral replication via augmenting a Na+/K+-ATPase-dependent PI3K_PDK1 axis signaling

Yang

Chang

Lee

et al. 2018

Toxicology and Applied Pharmacology

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“…We have shown previously that LPA activates NHE3 via the LPA5 receptor in Caco2bbe cells and mouse ileum (11,32). The activation of NHE3 by LPA is independent of PI3K and is regulated by the ERK-RSK2 cascade (33), suggesting that LPA and insulin might regulate NHE3 through different pathways. Hence, we investigated whether LPA can restore NHE3 activity and fluid homeostasis Because ezrin also binds NHE3 indirectly via NHERF1 or NHERF2 (30), we determined whether the insulin-induced increase in ezrin-NHE3 interaction was dependent on NHERF1 or NHERF2.…”

Section: Activation Of Nhe3 By Insulin Requires the Assembly Of Ezrinmentioning

confidence: 93%

Restoration of Na+/H+ exchanger NHE3-containing macrocomplexes ameliorates diabetes-associated fluid loss

He¹,

Zhao²,

Zhu³

et al. 2015

Journal of Clinical Investigation

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“…A very promising factor is LPA. LPA is known to increase the trafficking of NHE3 to the IEC apical membrane through a pathway that involves the PLA 5 receptor, NHERF2, EGFR, and RSK2, and its oral administration was able to overcome diarrhea induced by cholera toxin or TNF-␣ in mice (86,105). The recent synthesis of OTP (octadecenyl thiophosphate), an oral LPA analog with greater resistance to pancreatic lipase and LPP1 and lower systemic absorption than the original molecule, further raises hopes on a new anti-diarrhea drug (37).…”

Section: Therapeutic Targets and Future Challengesmentioning

confidence: 99%

Role of epithelial ion transports in inflammatory bowel disease

Magalhães

Cabral

Soares‐da‐Silva

et al. 2016

American Journal of Physiology-Gastrointestinal and Liver Physi

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Inflammatory bowel disease (IBD) is a chronic inflammatory disorder with a complex pathogenesis. Diarrhea is a highly prevalent and often debilitating symptom of IBD patients that results, at least in part, from an intestinal hydroelectrolytic imbalance. Evidence suggests that reduced electrolyte absorption is more relevant than increased secretion to this disequilibrium. This systematic review analyses and integrates the current evidence on the roles of epithelial Na+-K+-ATPase (NKA), Na+/H+ exchangers (NHEs), epithelial Na+ channels (ENaC), and K+ channels (KC) in IBD-associated diarrhea. NKA is the key driving force of the transepithelial ionic transport and its activity is decreased in IBD. In addition, the downregulation of apical NHE and ENaC and the upregulation of apical large-conductance KC all contribute to the IBD-associated diarrhea by lowering sodium absorption and/or increasing potassium secretion.

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Regulation of NHE3 by lysophosphatidic acid is mediated by phosphorylation of NHE3 by RSK2

Cited by 30 publications

References 51 publications

The cardenolide ouabain suppresses coronaviral replication via augmenting a Na+/K+-ATPase-dependent PI3K_PDK1 axis signaling

The cardenolide ouabain suppresses coronaviral replication via augmenting a Na+/K+-ATPase-dependent PI3K_PDK1 axis signaling

Restoration of Na+/H+ exchanger NHE3-containing macrocomplexes ameliorates diabetes-associated fluid loss

Role of epithelial ion transports in inflammatory bowel disease

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