ArticleThe Journal of biological chemistry2014
Activation of 3-phosphoinositide-dependent kinase 1 (PDK1) and serum- and glucocorticoid-induced protein kinase 1 (SGK1) by short-chain sphingolipid C4-ceramide rescues the trafficking defect of ΔF508-cystic fibrosis transmembrane conductance regulator (ΔF508-CFTR).
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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20 citing papers in PubMed, 33 citations in OpenAlex.
- Dissecting the Phospho-Regulatory Landscape of Protein Kinase N1 (PKN1) and Its Downstream Signaling: Functional Insights into the Activity-Dependent and Disease-Relevant Phosphosites.International journal of molecular sciences · 2026Article
- Epithelial Na+ Channels, Immune Cells, and Salt.Annual review of physiology · 2025Review
- Inflammation in the COVID-19 airway is due to inhibition of CFTR signaling by the SARS-CoV-2 spike protein.Scientific reports · 2024Article
- The mTORC2 signaling network: targets and cross-talks.The Biochemical journal · 2024Review
- AMPK/FOXO3a Pathway Increases Activity and/or Expression of ATM, DNA-PKcs, Src, EGFR, PDK1, and SOD2 and Induces Radioresistance under Nutrient Starvation.International journal of molecular sciences · 2023Article
- Pharmacological suppression of Nedd4-2 rescues the reduction of Kv11.1 channels in pathological cardiac hypertrophy.Frontiers in pharmacology · 2022Article
- Article
- SFPQ rescues F508del-CFTR expression and function in cystic fibrosis bronchial epithelial cells.Scientific reports · 2021Article
- Serum- and Glucocorticoid-Inducible Kinase 1 Promotes Alternative Macrophage Polarization and Restrains Inflammation through FoxO1 and STAT3 Signaling.Journal of immunology (Baltimore, Md. : 1950) · 2021Article
- Distinctive lipid signatures of bronchial epithelial cells associated with cystic fibrosis drugs, including Trikafta.JCI insight · 2020Article
- 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
- Phosphoproteome profiling provides insight into the mechanisms of ventilator-induced lung injury.Experimental and therapeutic medicine · 2020Article
- Is PI3K a Villain in Cystic Fibrosis?American journal of respiratory cell and molecular biology · 2020Article
- Bacterial Sphingomyelinase is a State-Dependent Inhibitor of the Cystic Fibrosis Transmembrane conductance Regulator (CFTR).Scientific reports · 2017Article
- Inhibition of mTORC2 component RICTOR impairs tumor growth in pancreatic cancer models.Oncotarget · 2017Article
- SGK1: The Dark Side of PI3K Signaling.Current topics in developmental biology · 2017Review
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- Article
- Hallmarks of therapeutic management of the cystic fibrosis functional landscape.Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society · 2015Review
- MicroRNA profiling identifies miR-129-5p as a regulator of EMT in tubular epithelial cells.International journal of clinical and experimental medicine · 2015Article
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
Abstract
Cystic fibrosis (CF) is due to a folding defect in the CF transmembrane conductance regulator (CFTR) protein. The most common mutation, ΔF508, prevents CFTR from trafficking to the apical plasma membrane. Here we show that activation of the PDK1/SGK1 signaling pathway with C4-ceramide (C4-CER), a non-toxic small molecule, functionally corrects the trafficking defect in both cultured CF cells and primary epithelial cell explants from CF patients. The mechanism of C4-CER action involves a series of mutual autophosphorylation and phosphorylation events between PDK1 and SGK1. Detailed mechanistic studies indicate that C4-CER initially induces autophosphorylation of SGK1 at Ser(422). SGK1[Ser(P)(422)] and C4-CER coincidently bind PDK1 and permit PDK1 to autophosphorylate at Ser(241). Then PDK1[Ser(P)(241)] phosphorylates SGK1[Ser(P)(422)] at Thr(256) to generate fully activated SGK1[Ser(422), Thr(P)(256)]. SGK1[Ser(P)(422),Thr(P)(256)] phosphorylates and inactivates the E3 ubiquitin ligase Nedd4-2. ΔF508-CFTR is thus free to traffic to the plasma membrane. Importantly, C4-CER-mediated activation of both PDK1 and SGK1 is independent of the PI3K/Akt/mammalian target of rapamycin signaling pathway. Physiologically, C4-CER significantly increases maturation and stability of ΔF508-CFTR (t½ ∼10 h), enhances cAMP-activated chloride secretion, and suppresses hypersecretion of interleukin-8 (IL-8). We suggest that candidate drugs for CF directed against the PDK1/SGK1 signaling pathway, such as C4-CER, provide a novel therapeutic strategy for a life-limiting disorder that affects one child, on average, each day.
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