Serum and Glucocorticoid-regulated Kinase Modulates Nedd4-2-mediated Inhibition of the Epithelial Na+Channel

Snyder, Peter M.; Olson, Diane R.; Thomas, Brittany C.

doi:10.1074/jbc.c100623200

Cited by 404 publications

(345 citation statements)

References 31 publications

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“…Similar cooperative effects were seen on Nedd4-2-dependent ubiquitin ligase activity when using ENaC as substrate ( Fig. 3B): ENaC (␣-subunit) was heavily ubiquitinated in a Nedd4-2-dependent fashion, and SGK1 had a substantial inhibitory effect, as has been shown (24,25). We also observed modest but consistent inhibition of Nedd4-2 by GILZ1 alone (Fig.…”

supporting

confidence: 66%

Epithelial sodium channel regulated by differential composition of a signaling complex

Soundararajan¹,

Melters²,

Shih³

et al. 2009

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

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Hormonal control of transepithelial sodium (Na ؉ ) transport utilizes phosphatidylinositide 3 -kinase (PI3K) and Raf-MAPK/ERK kinase (MEK)-ERK-dependent signaling pathways, which impact numerous cell functions. How signals transmitted by these pathways are sorted and appropriately transmitted to alter Na ؉ transport without altering other physiologic processes is not well understood. Here, we report the identification of a signaling complex that selectively modulates the cell surface expression of the epithelial sodium channel (ENaC), an ion channel that is essential for fluid and electrolyte balance in mammals. Raf-1 and the ubiquitin ligase, Nedd4-2, are constitutively-expressed inhibitory components of this ENaC regulatory complex, which interact with, and decrease the expression of, cell surface ENaC. The activities of Nedd4-2 and Raf-1 are inhibited cooperatively by the PI3K-dependent kinase serum-and glucocorticoid-induced kinase 1 (SGK1), and the Raf-1-interacting protein glucocorticoid-induced leucine zipper (GILZ1), which are aldosterone-stimulated components of the complex. Together, SGK1 and GILZ1 synergistically stimulate ENaC cell surface expression. Interestingly, GILZ1 and SGK1 do not have synergistic, and in fact have opposite, effects on an unrelated activity, FKHRL1-driven gene transcription. Together, these data suggest that GILZ1 and SGK1 provide a physical and functional link between the PI3K-and Raf-1-dependent signaling modules and represent a unique mechanism for specifically controlling Na ؉ transport without inappropriately activating other cell functions.glucocorticoid-induced leucine zipper protein ͉ Nedd4-2 ͉ Raf-1 ͉ serum-and glucocorticoid-induced kinase 1

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supporting

confidence: 66%

Epithelial sodium channel regulated by differential composition of a signaling complex

Soundararajan¹,

Melters²,

Shih³

et al. 2009

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

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“…Indeed, glucocorticosteroids have been shown to induce a-ENaC transcription, 57,58 and in human fetal lung explant cultures all three ENaC subunits were upregulated by glucocorticosteroids. 59,60 Glucocorticosteroids also increase the number of available sodium channels by increasing ENaC trafficking and decreasing the rate of degradation of existing channels 61,62 and improving lung responsiveness to b2 stimulants and thyroid hormones. 63 Stutchfield et al 64 have shown that two doses of betamethasone given 48 h before cesarean section significantly decreased admissions due to respiratory distress.…”

Section: Lung Fluid During and Immediately After Birthmentioning

confidence: 99%

Clinical implication of lung fluid balance in the perinatal period

2011

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At birth, lung fluid produced during fetal life must be cleared immediately and efficiently before the first breath takes place, in order for infants to achieve a normal and successful transition from prenatal to postnatal life. Postnatal lung fluid resorption is mediated through activation of airway epithelial sodium channels (ENaC). The observation that ENaC expression is a gestational age-dependent process contributes to our understanding of the development of respiratory distress in both term and preterm infants due to impaired clearing of fluid from their lungs. As fluid absorption, mediated by ENaC activity, in postnatal life has a significant biological role in preventing respiratory distress, any strategy that enhances ENaC activity can potentially help to decrease its incidence and associated morbidity.

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“…17 A central function of SGK1 is to increase the cell surface expression of the epithelial sodium channel by inhibiting the ubiquitin ligase Nedd4-2. 18,19 Activation of SGK1 is dependent on phosphorylation of S422 within its HM domain 20,21 ; however, despite considerable progress in understanding the molecular mechanisms underlying SGK1 regulation of solute and ion transport, 22 the signaling mechanisms involved in controlling SGK1 activation through HM phosphorylation have remained uncertain. In particular, the HM kinase has remained unknown.…”

mentioning

confidence: 99%

mTOR Complex-2 Activates ENaC by Phosphorylating SGK1

Wang²,

Jones³

et al. 2010

Journal of the American Society of Nephrology

101

102

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The serum-and glucocorticoid-induced kinase 1 (SGK1) plays a central role in hormone regulation of epithelial sodium (Na ϩ ) channel (ENaC)-dependent Na ϩ transport in the distal nephron. Phosphorylation within a carboxy-terminal domain, designated the hydrophobic motif (HM), determines the activity of SGK1, but the identity of the HM kinase is unknown. Here, we show that the highly conserved serine-threonine kinase mammalian target of rapamycin (mTOR) is essential for the phosphorylation of the HM of SGK1 and the activation of ENaC. We observed that mTOR, in conjunction with rictor (mTORC2), phosphorylated SGK1 and stimulated ENaC. In contrast, when mTOR assembled with raptor in the rapamycin-inhibited complex (mTORC1), it did not phosphorylate SGK1 or stimulate ENaC. Inhibition of mTOR blocked both SGK1 phosphorylation and ENaC-mediated Na ϩ transport, whereas specific inhibition of mTORC1 had no effect.Similarly, small hairpin RNA-mediated knockdown of rictor inhibited SGK1 phosphorylation and Na ϩ current, whereas knockdown of raptor had no effect. Finally, in co-immunoprecipitation experiments, SGK1 interacted selectively with rictor but not with raptor, suggesting selective recruitment of SGK1 to mTORC2. We conclude that mTOR, specifically mTORC2, is the HM kinase for SGK1 and is required for ENaC-mediated Na ϩ transport, thereby extending our understanding of the molecular mechanisms underlying Na ϩ balance.

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Serum and Glucocorticoid-regulated Kinase Modulates Nedd4-2-mediated Inhibition of the Epithelial Na+Channel

Cited by 404 publications

References 31 publications

Epithelial sodium channel regulated by differential composition of a signaling complex

Epithelial sodium channel regulated by differential composition of a signaling complex

Clinical implication of lung fluid balance in the perinatal period

mTOR Complex-2 Activates ENaC by Phosphorylating SGK1

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