Phosphorylation of Nedd4-2 by Sgk1 regulates epithelial Na+ channel cell surface expression

Debonneville, Christophe; Flores, Sandra Y.; Kamynina, Elena; Plant, Pamela; Tauxe, Caroline; Thomas, Marc A.; Münster, Carole; Chraïbi, Ahmed; Pratt, J. Howard; Horisberger, Jean‐Daniel; Pearce, David; Loffing, Johannes; Staub, Olivier

doi:10.1093/emboj/20.24.7052

Cited by 641 publications

(702 citation statements)

References 61 publications

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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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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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“…This observation has potentially important physiologi-cal ramifications. SGK1, a member of the PKB/Akt family of serine/threonine kinases (20), is an immediate early aldosterone-induced gene product (21,22) in the renal collecting duct (22)(23)(24), which has been shown recently to regulate epithelial Na ϩ channel (ENaC) cell surface expression (25) and, consequently, act as a key mediator of the early aldosterone effect on sodium transport in the distal nephron. Conceivably, SGK1 might also control the number of functional ROMK channels at the plasmalemma and explain how aldosterone regulates renal potassium secretion.…”

Section: From the Department Of Physiology University Of Maryland Scmentioning

confidence: 99%

Cell Surface Expression of the ROMK (Kir 1.1) Channel Is Regulated by the Aldosterone-induced Kinase, SGK-1, and Protein Kinase A

Yoo¹,

Kim

Campo

et al. 2003

Journal of Biological Chemistry

159

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The Kir1.1 (ROMK) subtypes of inward rectifier K ؉ channels mediate potassium secretion and regulate sodium chloride reabsorption in the kidney. The density of ROMK channels on the cortical collecting duct apical membrane is exquisitely regulated in concert with physiological demands. Although protein kinase A-dependent phosphorylation of one of the three phospho-acceptors in Kir1.1, Ser-44, also a canonical serum-glucocorticoid-regulated kinase (SGK-1) phosphorylation site, controls the number of active channels, it is unknown whether this involves activating dormant channels already residing on the plasma membrane or recruiting new channels to the cell surface. Here we explore the mechanism and test whether SGK-1 phosphorylation of ROMK regulates cell surface expression. Removal of the phosphorylation site by point mutation (Kir1.1, S44A) dramatically attenuated the macroscopic current density in Xenopus oocytes. As measured by antibody binding of external epitope-tagged forms of Kir1.1, surface expression of Kir1.1 S44A was inhibited, paralleling the reduction in macroscopic current. In contrast, surface expression and macroscopic current density was augmented by a phosphorylation mimic mutation, Kir1.1 S44D. In vitro phosphorylation assays revealed that Ser-44 is a substrate of SGK-1 phosphorylation, and expression of SGK-1 with the wild type channel increased channel density to the same level as the phosphorylation mimic mutation. Moreover, the stimulatory effect of SGK-1 was completely abrogated by mutation of the phosphorylation site. In conclusion, SGK-1 phosphorylation of Kir1.1 drives expression on the plasmalemma. Because SGK-1 is an early aldosterone-induced gene, our results suggest a possible molecular mechanism for aldosterone-dependent regulation of the secretory potassium channel in the kidney.Extracellular potassium homeostasis, maintained by the regulation of renal potassium excretion, is dependent on the activity of weakly inward rectifying ''small conductance'' potassium channels (SK) 1 that are expressed on the apical membrane of epithelial cells in the distal nephron (1, 2). Encoded by the ROMK (Kir 1.1 or KCNJ1) gene (3, 4), these Kir channels are thought to be the major, but not exclusive (5, 6), route for potassium transport into the tubule lumen and constitute a final regulated component of the potassium secretory machinery of the kidney (7,8). Indeed, aldosterone, vasopressin, and other factors precisely regulate SK activity, controlling potassium excretion in accord with the demands of potassium balance. Because ROMK channels normally exhibit a very high open probability, near unity, physiologic augmentation of channel activity, as controlled by hormones and dietary potassium (9), is achieved largely by regulated changes in the number of active channels on the plasmalemma.Although the precise molecular mechanisms responsible for physiological augmentation of ROMK channel surface density have remained unclear, a growing body of evidence has pointed to an important role of protein kina...

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“…4 In contrast, phosphorylation of NEDD4-2 (neural precursor cell-expressed developmentally downregulated 4-2) inactivates it by preventing the binding to its substrate, ENaC (epithelial sodium channel). 5 In addition, other mechanisms of regulation exist, such as intermolecular and intramolecular interactions. Examples include p19/Arf (alternative reading frame) that binds to mouse double minute (Mdm2) and inhibits p53 conjugation, 6 and the polycomb group (PcG) protein BMI1 that stimulates the histone H2A ubiquitinating activity of RING1B.…”

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confidence: 99%

Ubiquitination of E3 ligases: self-regulation of the ubiquitin system via proteolytic and non-proteolytic mechanisms

2011

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Ubiquitin modification of many cellular proteins targets them for proteasomal degradation, but in addition can also serve non-proteolytic functions. Over the last years, a significant progress has been made in our understanding of how modification of the substrates of the ubiquitin system is regulated. However, little is known on how the ubiquitin system that is comprised of B1500 components is regulated. Here, we discuss how the biggest subfamily within the system, that of the E3 ubiquitin ligases that endow the system with its high specificity towards the numerous substrates, is regulated and in particular via self-regulation mediated by ubiquitin modification. Ligases can be targeted for degradation in a self-catalyzed manner, or through modification mediated by an external ligase(s). In addition, non-proteolytic functions of self-ubiquitination, for example activation of the ligase, of E3s are discussed. Cell Death and Differentiation (2011) 18, 1393-1402 doi:10.1038/cdd.2011; published online 4 March 2011One of the major roles of the covalent modification of cellular proteins by ubiquitin is signaling them for proteasomal degradation ( Figure 1). The first step of the modification is catalyzed by the ubiquitin-activating enzyme, E1, which generates a high-energy thiol ester intermediate that is subsequently transferred to the second enzyme, a ubiquitinconjugating enzyme, E2. The third step ascertains substrate specificity, and is catalyzed by one of the numerous (B650) ubiquitin ligases, E3s. Typically, it results in the formation of an isopeptide bond between the C-terminal Gly of ubiquitin and an e-NH 2 group of an internal Lys of the substrate. Less frequently, it can generate a linear peptide bond with the a-NH 2 group, a thiol ester bond with an internal Cys, or an ester bond with a Thr or Ser. The three-step cascade of reactions is repeated, where additional ubiquitin moieties are attached sequentially to one another in an isopeptide bond involving one of the seven internal Lys residues in the ubiquitin moiety, thus generating a polyubiquitin chain. Lys48-based chains serve as a signal for proteasomal degradation, whereas chains based on other internal Lys residues, or modification by single moiety(ies) can serve non-proteolytic functions.Ligases fall into two main families: RING (really interesting new gene) and HECT (homologous to the E6-AP carboxy terminus) domain-containing E3s. RING ligases serve as scaffolds that facilitate direct transfer of ubiquitin from the E2 to the target protein. HECT E3s contain an active Cys residue to which ubiquitin binds prior to its transfer to the substrate (Figure 1). There are B600 RING finger and B30 HECT ligases in humans. Smaller families of ligases (U-box, plant homology domain, and zinc finger) have also been described.An important problem relates to regulation of the ubiquitin system components, and in particular to that of the ligases that are the specific substrate-recognizing elements. 1,2 Phosphorylation of an E3 can activate the protein, such as the ca...

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Phosphorylation of Nedd4-2 by Sgk1 regulates epithelial Na+ channel cell surface expression

Cited by 641 publications

References 61 publications

Clinical implication of lung fluid balance in the perinatal period

Clinical implication of lung fluid balance in the perinatal period

Cell Surface Expression of the ROMK (Kir 1.1) Channel Is Regulated by the Aldosterone-induced Kinase, SGK-1, and Protein Kinase A

Ubiquitination of E3 ligases: self-regulation of the ubiquitin system via proteolytic and non-proteolytic mechanisms

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