14-3-3 Proteins Modulate the Expression of Epithelial Na+ Channels by Phosphorylation-dependent Interaction with Nedd4-2 Ubiquitin Ligase*

The ubiquitin E3 protein ligase Nedd4-2 is a physiological regulator of the epithelial sodium channel ENaC, which is essential for transepithelial Na+ transport and is linked to Liddle's syndrome, an autosomal dominant disorder of human salt-sensitive hypertension. Nedd4-2 function is negatively regulated by phosphorylation via a serum- and glucocorticoid-inducible protein kinase (Sgk1), which serves as a mechanism to inhibit the ubiquitination-dependent degradation of ENaC. We report here that 14-3-3 proteins participate in this regulatory process through a direct interaction with a phosphorylated form of human Nedd4-2 (a human gene product of KIAA0439, termed hNedd4-2). The interaction is dependent on Sgk1-catalyzed phosphorylation of hNedd4-2 at Ser-468. We found that this interaction preserved the activity of the Sgk1-stimulated ENaC-dependent Na+ current while disrupting the interaction decreased ENaC density on the Xenopus laevis oocytes surface possibly by enhancing Nedd4-2-mediated ubiquitination that leads to ENaC degradation. Our findings suggest that 14-3-3 proteins modulate the cell surface density of ENaC cooperatively with Sgk1 kinase by maintaining hNedd4-2 in an inactive phosphorylated state.

• Publication year

  2005

• Venue

  Journal of Biological Chemistry

• Publication date

  2005-04-01

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1074/jbc.M412884200PMID 15677482
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Regulation of glucose transporter SGLT1 by ubiquitin ligase Nedd4-2 and kinases SGK1, SGK3, and PKB.

  2004cited by this paper
• Regulation of intestinal phosphate cotransporter NaPi IIb by ubiquitin ligase Nedd4-2 and by serum- and glucocorticoid-dependent kinase 1.

  2004cited by this paper
• A Novel Pathway of Epithelial Sodium Channel Activation Involves a Serum- and Glucocorticoid-inducible Kinase Consensus Motif in the C Terminus of the Channel's α-Subunit*

  2004cited by this paper
• Comprehensive Proteomic Analysis of Interphase and Mitotic 14-3-3-binding Proteins*

  2004cited by this paper
• A naturally occurring human Nedd4-2 variant displays impaired ENaC regulation in Xenopus laevis oocytes.

  2004cited by this paper
• Regulation of Neuronal Voltage-gated Sodium Channels by the Ubiquitin-Protein Ligases Nedd4 and Nedd4-2*

  2004cited by this paper
• Dynamic interactions between 14-3-3 proteins and phosphoproteins regulate diverse cellular processes.

  2004cited by this paper
• Serum and glucocorticoid inducible kinases functionally regulate ClC-2 channels.

  2004cited by this paper
• Participation of the Ubiquitin-Conjugating Enzyme UBE2E3 in Nedd4-2-Dependent Regulation of the Epithelial Na+ Channel

  2004cited by this paper
• Capsazepine is a novel activator of the delta subunit of the human epithelial Na+ channel.

  2004cited by this paper
• Relative Contribution of Nedd4 and Nedd4-2 to ENaC Regulation in Epithelia Determined by RNA Interference*

  2004cited by this paper
• cAMP and Serum and Glucocorticoid-inducible Kinase (SGK) Regulate the Epithelial Na+ Channel through Convergent Phosphorylation of Nedd4-2*

  2004cited by this paper
• 14-3-3-affinity purification of over 200 human phosphoproteins reveals new links to regulation of cellular metabolism, proliferation and trafficking.

  2004cited by this paper
• Functional association between Wwox tumor suppressor protein and p73, a p53 homolog.

  2004cited by this paper
• Capsazepine Is a Novel Activator of the δ Subunit of the Human Epithelial Na+ Channel*

  2004cited by this paper
• Protons activate the delta-subunit of the epithelial Na+ channel in humans.

  2004cited by this paper
• Regulation of the voltage gated K+ channel Kv1.3 by the ubiquitin ligase Nedd4‐2 and the serum and glucocorticoid inducible kinase SGK1

  2004cited by this paper
• Protons Activate the δ-Subunit of the Epithelial Na+ Channel in Humans*

  2004cited by this paper
• Properties and regulation of glutamine transporter SN1 by protein kinases SGK and PKB.

  2003cited by this paper
• 14-3-3ε is important for neuronal migration by binding to NUDEL: a molecular explanation for Miller–Dieker syndrome

  2003cited by this paper
• Regulation of the glutamate transporter EAAT1 by the ubiquitin ligase Nedd4‐2 and the serum and glucocorticoid‐inducible kinase isoforms SGK1/3 and protein kinase B

  2003cited by this paper
• A direct nanoflow liquid chromatography-tandem mass spectrometry system for interaction proteomics.

  2002cited by this paper
• Ubiquitin-protein ligase WWP2 binds to and downregulates the epithelial Na(+) channel.

  2002cited by this paper
• WW and SH3 domains, two different scaffolds to recognize proline‐rich ligands

  2002cited by this paper
• Regulation of the Epithelial Sodium Channel by N4WBP5A, a Novel Nedd4/Nedd4-2-interacting Protein*

  2002cited by this paper
• Phosphorylation-dependent interaction of kinesin light chain 2 and the 14-3-3 protein.

  2002cited by this paper
• Can we infer peptide recognition specificity mediated by SH3 domains?

  2002cited by this paper
• The WW domain: linking cell signalling to the membrane cytoskeleton.

  2002cited by this paper
• Serum and Glucocorticoid-regulated Kinase Modulates Nedd4-2-mediated Inhibition of the Epithelial Na+Channel*

  2002cited by this paper
• 14-3-3 Proteins: Active Cofactors in Cellular Regulation by Serine/Threonine Phosphorylation*

  2002cited by this paper
• The Nedd4-like Protein KIAA0439 Is a Potential Regulator of the Epithelial Sodium Channel*

  2001cited by this paper
• Proteins related to the Nedd4 family of ubiquitin protein ligases interact with the L domain of Rous sarcoma virus and are required for gag budding from cells

  2001cited by this paper
• Solution structure of a Nedd4 WW domain–ENaC peptide complex

  2001cited by this paper
• A novel mouse Nedd4 protein suppresses the activity of the epithelial Na+ channel

  2001cited by this paper
• Nedd4 Regulates Ubiquitination and Stability of the Guanine-Nucleotide Exchange Factor CNrasGEF*

  2001cited by this paper
• A novel multiple affinity purification tag and its use in identification of proteins associated with a cyclin-CDK complex.

  2001cited by this paper
• Phosphorylation of Nedd4‐2 by Sgk1 regulates epithelial Na+ channel cell surface expression

  2001cited by this paper
• A PPxY motif within the VP40 protein of Ebola virus interacts physically and functionally with a ubiquitin ligase: implications for filovirus budding.

  2000cited by this paper
• 14-3-3 proteins: structure, function, and regulation.

  2000cited by this paper
• Structural basis for phosphoserine-proline recognition by group IV WW domains

  2000cited by this paper
• The Epstein-Barr virus latent membrane protein 2A PY motif recruits WW domain-containing ubiquitin-protein ligases.

  2000cited by this paper
• Latent Membrane Protein 2A of Epstein-Barr Virus Binds WW Domain E3 Protein-Ubiquitin Ligases That Ubiquitinate B-Cell Tyrosine Kinases

  2000cited by this paper
• Converging on proline: the mechanism of WW domain peptide recognition

  2000cited by this paper
• Suppression of apoptosis signal-regulating kinase 1-induced cell death by 14-3-3 proteins.

  1999cited by this paper
• Epithelial sodium channel regulated by aldosterone-induced protein sgk.

  1999cited by this paper
• Interaction of 14-3-3 with a nonphosphorylated protein ligand, exoenzyme S of Pseudomonas aeruginosa.

  1999cited by this paper
• sgk Is an Aldosterone-induced Kinase in the Renal Collecting Duct

  1999cited by this paper
• Nedd4-like proteins: an emerging family of ubiquitin-protein ligases implicated in diverse cellular functions.

  1999cited by this paper
• Serum and glucocorticoid‐inducible kinase (SGK) is a target of the PI 3‐kinase‐stimulated signaling pathway

  1999cited by this paper
• Disorders of the epithelial sodium channel: insights into the regulation of extracellular volume and blood pressure.

  1999cited by this paper
• A generic protein purification method for protein complex characterization and proteome exploration

  1999cited by this paper
• Characterization of the structure and regulation of two novel isoforms of serum- and glucocorticoid-induced protein kinase.

  1999cited by this paper
• The prolyl isomerase Pin1 restores the function of Alzheimer-associated phosphorylated tau protein

  1999cited by this paper
• Regulation of stability and function of the epithelial Na+ channel (ENaC) by ubiquitination

  1997cited by this paper
• Autophosphorylation of Activation Loop Tyrosines Regulates Signaling by the TRK Nerve Growth Factor Receptor*

  1997cited by this paper
• The structural basis for 14-3-3:phosphopeptide binding specificity.

  1997cited by this paper
• Epithelial sodium channels: function, structure, and regulation.

  1997cited by this paper
• Interaction of 14-3-3 with signaling proteins is mediated by the recognition of phosphoserine.

  1996cited by this paper
• Cell surface expression of the epithelial Na channel and a mutant causing Liddle syndrome: a quantitative approach.

  1996cited by this paper
• Mutations in subunits of the epithelial sodium channel cause salt wasting with hyperkalaemic acidosis, pseudohypoaldosteronism type 1

  1996cited by this paper
• Identification of a PY motif in the epithelial Na channel subunits as a target sequence for mutations causing channel activation found in Liddle syndrome.

  1996cited by this paper
• 14-3-3 and its possible role in co-ordinating multiple signalling pathways.

  1996cited by this paper
• WW domains of Nedd4 bind to the proline‐rich PY motifs in the epithelial Na+ channel deleted in Liddle's syndrome.

  1996cited by this paper
• Reversal of Raf-1 activation by purified and membrane-associated protein phosphatases.

  1995cited by this paper
• Mechanism by which Liddle's syndrome mutations increase activity of a human epithelial Na+ channel.

  1995cited by this paper
• Identification of the Site of Interaction of the 14-3-3 Protein with Phosphorylated Tryptophan Hydroxylase (*)

  1995cited by this paper
• Liddle's syndrome: heritable human hypertension caused by mutations in the β subunit of the epithelial sodium channel

  1994cited by this paper
• Liddle's syndrome: heritable human hypertension caused by mutations in the beta subunit of the epithelial sodium channel.

  1994cited by this paper
• Amiloride-sensitive epithelial Na+ channel is made of three homologous subunits

  1994cited by this paper
• Identification of a set of genes with developmentally down-regulated expression in the mouse brain.

  1992cited by this paper
• Molecular cloning of cDNA coding for brain-specific 14-3-3 protein, a protein kinase-dependent activator of tyrosine and tryptophan hydroxylases.

  1988cited by this paper
• Establishment of a noradrenergic clonal line of rat adrenal pheochromocytoma cells which respond to nerve growth factor.

  1976cited by this paper

• Structural basis of ubiquitin ligase Nedd4-2 autoinhibition and regulation by calcium and 14-3-3 proteins

  2025cites this paper
• Interpretable prediction of drug synergy for breast cancer by random forest with features from Boolean modeling of signaling pathways

  2025cites this paper
• Baxdrostat: A Next-Generation Aldosterone Synthase Inhibitor Offering New Hope in Resistant Hypertension

  2025cites this paper
• The role of sex hormones in aldosterone biosynthesis and their potential impact on its mineralocorticoid receptor

  2024cites this paper
• The Effect of Aldosterone on Cardiorenal and Metabolic Systems

  2023cites this paper
• Primate-specific isoform of Nedd4-1 regulates substrate binding via Ser/Thr phosphorylation and 14-3-3 binding

  2023cites this paper
• Lysosomal trafficking of the glucose transporter GLUT1 requires sequential regulation by TXNIP and ubiquitin

  2023cites this paper
• Structural insights into the functional roles of 14-3-3 proteins

  2022cites this paper
• Nedd4-2 binding to 14-3-3 modulates the accessibility of its catalytic site and WW domains.

  2022cites this paper
• Associations of genetic variations in NEDD4L with salt sensitivity, blood pressure changes and hypertension incidence in Chinese adults

  2022cites this paper
• Metformin Inhibits Na+/H+ Exchanger NHE3 Resulting in Intestinal Water Loss

  2022cites this paper
• Adaptors as the regulators of HECT ubiquitin ligases

  2021cites this paper
• Function and Regulation of the Epithelial Na+ Channel ENaC.

  2021cites this paper
• 14-3-3-protein regulates Nedd4-2 by modulating interactions between HECT and WW domains

  2021cites this paper
• Extracellular vesicles regulate purinergic signaling and epithelial sodium channel expression in renal collecting duct cells

  2021cites this paper
• 14-3-3-protein regulates Nedd4-2 by modulating interactions between HECT and WW domains

  2021cites this paper
• The Importance of Protein Phosphorylation for Signaling and Metabolism in Response to Diel Light Cycling and Nutrient Availability in a Marine Diatom

  2020cites this paper
• Melatonin Attenuates Sepsis-Induced Acute Lung Injury Through Improvement of Epithelial Sodium Channel-Mediated Alveolar Fluid Clearance Via Activation of SIRT1/SGK1/Nedd4-2 Signaling Pathway

  2020cites this paper
• The ubiquitin E3 ligase Nedd4‐2 relieves mechanical allodynia through the ubiquitination of TRPA1 channel in db/db mice

  2020cites this paper
• The Global Phosphorylation Landscape of SARS-CoV-2 Infection

  2020cites this paper
• Co-option of Plasmodium falciparum PP1 for egress from host erythrocytes

  2020cites this paper
• Unbiased proteomic screening identifies a novel role for the E3 ubiquitin ligase Nedd4‐2 in translational suppression during ER stress

  2020cites this paper
• Identification of a herpes simplex virus 1 gene encoding neurovirulence factor by chemical proteomics

  2020cites this paper
• MAL protein stabilizes luminal membrane PLCβ3 and negatively regulates ENaC in mouse cortical collecting duct cells.

  2019cites this paper
• Annexin II Light Chain p11 Interacts With ENaC to Increase Functional Activity at the Membrane

  2019cites this paper
• Richard Lifton, 2005

  2019cites this paper
• beta1Pix exchange factor stabilizes the ubiquitin ligase Nedd4-2 and plays a critical role in ENaC regulation by AMPK in kidney epithelial cells

  2019influential citation
• C2‐lacking isoform of Nedd4‐2 regulates excitatory synaptic strength through GluA1 ubiquitination‐independent mechanisms

  2019cites this paper
• AMPK phosphorylation of the β1Pix exchange factor regulates the assembly and function of an ENaC inhibitory complex in kidney epithelial cells.

  2019cites this paper
• AMPK phosphorylation of the (cid:2) 1 Pix exchange factor regulates the assembly and function of an ENaC inhibitory complex in kidney epithelial cells

  2019cites this paper
• Methionine triggers Ppz-mediated dephosphorylation of Art1 to promote cargo-specific endocytosis

  2019cites this paper
• 14-3-3 scaffold proteins mediate the inactivation of trim25 and inhibition of the type I interferon response by herpesvirus deconjugases

  2019cites this paper
• PLPP/CIN-mediated NEDD4-2 S448 dephosphorylation regulates neuronal excitability via GluA1 ubiquitination

  2019cites this paper
• Ubiquitination as a Key Regulator of Endosomal Signaling by GPCRs

  2019cites this paper
• Aldosterone and Myocardial Pathology.

  2019cites this paper
• Regulation of DVL2 ubiquitylation by USP9X biases participation in canonical or non-canonical WNT signalling

  2018cites this paper
• β1Pix exchange factor stabilizes the ubiquitin ligase Nedd4-2 and plays a critical role in ENaC regulation by AMPK in kidney epithelial cells

  2018cites this paper
• Aldosterone and Mineralocorticoid Receptor System in Cardiovascular Physiology and Pathophysiology

  2018influential citation
• The serine/threonine protein kinase of Streptococcus suis serotype 2 affects the ability of the pathogen to penetrate the blood–brain barrier

  2018cites this paper
• Physiological Functions of Nedd4-2: Lessons from Knockout Mouse Models.

  2018cites this paper
• TRIM32-Cytoplasmic-Body Formation Is an ATP-Consuming Process Stimulated by HSP70 in Cells

  2017cites this paper
• COMMD10 Regulates Protein Trafficking

  2017cites this paper
• Aldosterone‐induced protein kinase signalling and the control of electrolyte balance

  2017cites this paper
• Genomic analysis of an infant with intractable diarrhea and dilated cardiomyopathy

  2017cites this paper
• Lipidomic and proteomic analysis of exosomes from mouse cortical collecting duct cells

  2017cites this paper
• Exophilin-8 assembles secretory granules for exocytosis in the actin cortex via interaction with RIM-BP2 and myosin-VIIa

  2017influential citation
• Rab2a and Rab27a cooperatively regulate the transition from granule maturation to exocytosis through the dual effector Noc2

  2017cites this paper
• The E3 ubiquitin ligase HACE1 : characterization of its regulation by phosphorylation and demonstration of its role in cellular cohesion

  2017cites this paper
• Fbxo4-mediated degradation of Fxr1 suppresses tumorigenesis in head and neck squamous cell carcinoma

  2017cites this paper
• University of Southern Denmark Regulation of the Water Channel Aquaporin-2 via 14-3-3 θ and

  2016cites this paper
• The AGC kinase serum-and glucocorticoid-regulated kinase 1 ( SGK 1 ) regulates T H 1 and T H 2 differentiation downstream of mTORC 2

  2016cites this paper
• Influence de l'ubiquitylation initiale des substrats SH3 sur leur régulation par la ligase Itch

  2016influential citation
• Renal tubular SGK1 deficiency causes impaired K+ excretion via loss of regulation of NEDD4-2/WNK1 and ENaC.

  2016cites this paper
• Chapter Five - Ubiquitination of Ion Channels and Transporters.

  2016cites this paper
• Regulation of the Yeast Hxt6 Hexose Transporter by the Rod1 α-Arrestin, the Snf1 Protein Kinase, and the Bmh2 14-3-3 Protein*

  2016cites this paper
• Regulation of epithelial Na channels by aldosterone

  2016cites this paper
• Protein interactions of membrane protein U24 from Roseolovirus and implications for its function

  2016cites this paper
• Blood Pressure Balance and + Ubiquitylation and Control of Renal Na

  2016cites this paper
• Ubiquitin-specific Protease 36 (USP36) Controls Neuronal Precursor Cell-expressed Developmentally Down-regulated 4-2 (Nedd4-2) Actions over the Neurotrophin Receptor TrkA and Potassium Voltage-gated Channels 7.2/3 (Kv7.2/3)*

  2016cites this paper
• Phosphorylation Impacts N-end Rule Degradation of the Proteolytically Activated Form of BMX Kinase*

  2016cites this paper
• Nedd4-2 regulation of voltage-gated ion channels: an update on structure–function relationships and the pathophysiological consequences of dysfunction

  2015cites this paper
• Differential p16/INK4A cyclin-dependent kinase inhibitor expression correlates with chemotherapy efficacy in a cohort of 88 malignant pleural mesothelioma patients

  2015cites this paper
• Role of ubiquitination of ERCC1 in DNA repair in melanoma

  2015influential citation
• Mechanisms of prolonged lithium therapy-induced nephrogenic diabetes insipidus.

  2015cites this paper
• Inhibition of ENaC by endothelin-1.

  2015cites this paper
• NEDD4-2 (NEDD4L): the ubiquitin ligase for multiple membrane proteins.

  2015cites this paper
• The MLLE Domain of the Ubiquitin Ligase UBR5 Binds to Its Catalytic Domain to Regulate Substrate Binding*

  2015cites this paper
• Lessons learned from comparative and evolutionary physiology.

  2015cites this paper
• NEDD4-2 and salt-sensitive hypertension

  2015cites this paper
• Regulation of αENaC transcription.

  2015cites this paper
• Regulation of the water channel Aquaporin-2 via 14-3-3 Theta (θ) and Zeta (ζ)

  2015cites this paper
• Regulation of the Water Channel Aquaporin-2 via 14-3-3θ and -ζ*

  2015cites this paper
• Mammalian HECT ubiquitin-protein ligases: biological and pathophysiological aspects.

  2014cites this paper
• Ubiquitylation and control of renal Na+ balance and blood pressure.

  2014cites this paper
• Imaging a Single Living Cell via Shear Force-based Scanning Ion Conductance Microscopy in Standing Approach Mode with Differential Control

  2014cites this paper
• Serum and Glucocorticoid-Regulated Kinase Signaling in Breast Cancer

  2014cites this paper
• Crosstalk between kinases and Nedd4 family ubiquitin ligases.

  2014cites this paper
• The AGC kinase serum- and glucocorticoid-regulated kinase 1 (SGK1) regulates TH1 and TH2 differentiation downstream of mTORC2

  2014cites this paper
• Blood pressure and amiloride-sensitive sodium channels in vascular and renal cells

  2014cites this paper
• The UL12 Protein of Herpes Simplex Virus 1 Is Regulated by Tyrosine Phosphorylation

  2014cites this paper
• A Phosphoinositide 3-Kinase (PI3K)-serum- and glucocorticoid-inducible Kinase 1 (SGK1) Pathway Promotes Kv7.1 Channel Surface Expression by Inhibiting Nedd4-2 Protein*

  2013influential citation
• Endocytic regulation of alkali metal transport proteins in mammals, yeast and plants

  2013cites this paper
• Dynamic Regulation at the Neuronal Plasma Membrane: Novel Endocytic Mechanisms Control Anesthetic-Activated Potassium Channels and Amphetamine-Sensitive Dopamine Transporters: A Dissertation

  2013cites this paper
• 14-3-3 proteins sequester a pool of soluble TRIM32 ubiquitin ligase to repress autoubiquitylation and cytoplasmic body formation

  2013influential citation
• The Coming of Age of Phosphoproteomics—from Large Data Sets to Inference of Protein Functions*

  2013cites this paper
• Locomotor hyperactivity in 14-3-3ζ KO mice is associated with dopamine transporter dysfunction

  2013cites this paper
• Par14 Protein Associates with Insulin Receptor Substrate 1 (IRS-1), Thereby Enhancing Insulin-induced IRS-1 Phosphorylation and Metabolic Actions

  2013cites this paper
• Regulation of ion channels by the serum‐ and glucocorticoid‐inducible kinase SGK1

  2013cites this paper
• Mitosis-coupled, microtubule-dependent clustering of endosomal vesicles around centrosomes.

  2013cites this paper
• Global analysis of phosphorylation and ubiquitylation cross-talk in protein degradation

  2013cites this paper
• Molecular Mechanism of Ubiquitin-Dependent Traffic

  2013cites this paper
• Epithelial Na + Channels

  2013cites this paper
• Hormone-induced expression of the epithelial sodium channel in human airway cells

  2013cites this paper
• Hepatitis C virus RNA replication is regulated by FKBP 8 and Hsp 90

  2013influential citation
• 4-2 Protein Channel Surface Expression by Inhibiting Kinase 1 ( SGK 1 ) Pathway Promotes Kv 7 . 1 glucocorticoid-inducible ( PI 3 K )-serum-and A Phosphoinositide 3-Kinase Cell Biology :

  2013influential citation
• Nedd4-2 and the Regulation of Epithelial Sodium Transport

  2012cites this paper
• The Role of the Ubiquitin Ligase Nedd4-1 in Skeletal Muscle Atrophy

  2012influential citation
• Serum- and glucocorticoid-inducible kinase 1 in the regulation of renal and extrarenal potassium transport

  2012cites this paper
• Role of βPix in the Kidney

  2012cites this paper
• Signaling-mediated control of ubiquitin ligases in endocytosis

  2012cites this paper