ArticleThe Journal of biological chemistry2011
Neural precursor cell-expressed developmentally down-regulated protein 4-2 (Nedd4-2) regulation by 14-3-3 protein binding at canonical serum and glucocorticoid kinase 1 (SGK1) phosphorylation sites.
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 49 citations in OpenAlex.
- SUMOylation Protects Endothelial Cell-Expressed Leukocyte-Specific Protein 1 from Ubiquitination-Mediated Proteasomal Degradation and Facilitates Its Nuclear Export.International journal of molecular sciences · 2026Article
- Structural basis of ubiquitin ligase Nedd4-2 autoinhibition and regulation by calcium and 14-3-3 proteins.Nature communications · 2025Article
- Look for the Scaffold: Multifaceted Regulation of Enzyme Activity by 14-3-3 Proteins.Physiological research · 2024Review
- Primate-specific isoform of Nedd4-1 regulates substrate binding via Ser/Thr phosphorylation and 14-3-3 binding.Scientific reports · 2023Article
- Kidney and blood pressure regulation-latest evidence for molecular mechanisms.Clinical kidney journal · 2023Review
- Nedd4-2 binding to 14-3-3 modulates the accessibility of its catalytic site and WW domains.Biophysical journal · 2022Article
- Review
- Structural insights into the functional roles of 14-3-3 proteins.Frontiers in molecular biosciences · 2022Review
- AMPA Receptor Antagonists Facilitate NEDD4-2-Mediated GRIA1 Ubiquitination by Regulating PP2B-ERK1/2-SGK1 Pathway in Chronic Epilepsy Rats.Biomedicines · 2021Article
- 14-3-3-protein regulates Nedd4-2 by modulating interactions between HECT and WW domains.Communications biology · 2021Article
- Reduction of Glut1 in the Neural Retina But Not the RPE Alleviates Polyol Accumulation and Normalizes Early Characteristics of Diabetic Retinopathy.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2021Article
- Glucocorticoids and serum- and glucocorticoid-inducible kinase 1 are potent regulators of CFTR in the native intestine: implications for stress-induced diarrhea.American journal of physiology. Gastrointestinal and liver physiology · 2020Article
- AMPK phosphorylation of the βAmerican journal of physiology. Renal physiology · 2019Article
- PLPP/CIN-mediated NEDD4-2 S448 dephosphorylation regulates neuronal excitability via GluA1 ubiquitination.Cell death & disease · 2019Article
- Loss of fragile X protein FMRP impairs homeostatic synaptic downscaling through tumor suppressor p53 and ubiquitin E3 ligase Nedd4-2.Human molecular genetics · 2018Article
- βThe Journal of biological chemistry · 2018Article
- Orai3 calcium channel and resistance to chemotherapy in breast cancer cells: the p53 connection.Cell death and differentiation · 2018Article
- Epilepsy-associated gene Nedd4-2 mediates neuronal activity and seizure susceptibility through AMPA receptors.PLoS genetics · 2017Article
- Serum and Glucocorticoid Regulated Kinase 1 in Sodium Homeostasis.International journal of molecular sciences · 2016Review
- Renal tubular SGK1 deficiency causes impaired K+ excretion via loss of regulation of NEDD4-2/WNK1 and ENaC.American journal of physiology. Renal physiology · 2016Article
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
Abstract
Regulation of epithelial Na(+) channel (ENaC)-mediated transport in the distal nephron is a critical determinant of blood pressure in humans. Aldosterone via serum and glucocorticoid kinase 1 (SGK1) stimulates ENaC by phosphorylation of the E3 ubiquitin ligase Nedd4-2, which induces interaction with 14-3-3 proteins. However, the mechanisms of SGK1- and 14-3-3-mediated regulation of Nedd4-2 are unclear. There are three canonical SGK1 target sites on Nedd4-2 that overlap phosphorylation-dependent 14-3-3 interaction motifs. Two of these are termed "minor," and one is termed "major," based on weak or strong binding to 14-3-3 proteins, respectively. By mass spectrometry, we found that aldosterone significantly stimulates phosphorylation of a minor, relative to the major, 14-3-3 binding site on Nedd4-2. Phosphorylation-deficient minor site Nedd4-2 mutants bound less 14-3-3 than did wild-type (WT) Nedd4-2, and minor site Nedd4-2 mutations were sufficient to inhibit SGK1 stimulation of ENaC cell surface expression. As measured by pulse-chase and cycloheximide chase assays, a major binding site Nedd4-2 mutant had a shorter cellular half-life than WT Nedd4-2, but this property was not dependent on binding to 14-3-3. Additionally, a dimerization-deficient 14-3-3ε mutant failed to bind Nedd4-2. We conclude that whereas phosphorylation at the Nedd4-2 major site is important for interaction with 14-3-3 dimers, minor site phosphorylation by SGK1 may be the relevant molecular switch that stabilizes Nedd4-2 interaction with 14-3-3 and thus promotes ENaC cell surface expression. We also propose that major site phosphorylation promotes cellular Nedd4-2 protein stability, which potentially represents a novel form of regulation for turnover of E3 ubiquitin ligases.
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