ArticleMolecular and cellular biology2011
Antagonistic regulation of cystic fibrosis transmembrane conductance regulator cell surface expression by protein kinases WNK4 and spleen tyrosine kinase.
Article in Molecular and cellular biology, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 39 citations in OpenAlex.
- Regulation of CFTR stability at the plasma membrane-Mechanisms and therapeutic opportunities in cystic fibrosis.FEBS letters · 2026Review
- Beyond the mutations: spatiotemporal regulation of CFTR by cAMP and calcium signaling in epithelial physiology and cystic fibrosis.Cellular & molecular biology letters · 2025Review
- From CFTR to a CF signalling network: a systems biology approach to study Cystic Fibrosis.BMC genomics · 2024Article
- Cell type-specific regulation of CFTR trafficking-on the verge of progress.Frontiers in cell and developmental biology · 2024Review
- YES1 Kinase Mediates the Membrane Removal of Rescued F508del-CFTR in Airway Cells by Promoting MAPK Pathway Activation via SHC1.Biomolecules · 2023Article
- Molecular mechanisms of cystic fibrosis - how mutations lead to misfunction and guide therapy.Bioscience reports · 2022Review
- One Size Does Not Fit All: The Past, Present and Future of Cystic Fibrosis Causal Therapies.Cells · 2022Review
- CCT and CCT-Like Modular Protein Interaction Domains in WNK Signaling.Molecular pharmacology · 2022Review
- WNK4 kinase: from structure to physiology.American journal of physiology. Renal physiology · 2021Review
- A SYK/SHC1 pathway regulates the amount of CFTR in the plasma membrane.Cellular and molecular life sciences : CMLS · 2020Article
- A High-Content Screen for Mucin-1-Reducing Compounds Identifies Fostamatinib as a Candidate for Rapid Repurposing for Acute Lung Injury.Cell reports. Medicine · 2020Article
- A High Content Screen for Mucin-1-Reducing Compounds Identifies Fostamatinib as a Candidate for Rapid Repurposing for Acute Lung Injury during the COVID-19 pandemic.bioRxiv : the preprint server for biology · 2020Article
- Network Biology Identifies Novel Regulators of CFTR Trafficking and Membrane Stability.Frontiers in pharmacology · 2019Article
- Proteomic interaction profiling reveals KIFC1 as a factor involved in early targeting of F508del-CFTR to degradation.Cellular and molecular life sciences : CMLS · 2018Article
- Peripheral Protein Quality Control as a Novel Drug Target for CFTR Stabilizer.Frontiers in pharmacology · 2018Review
- Spleen Tyrosine Kinase as a Target Therapy for Pseudomonas aeruginosa Infection.Journal of innate immunity · 2018Review
- Signaling Cascade Involved in Rapid Stimulation of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) by Dexamethasone.International journal of molecular sciences · 2017Article
- Pharmacological targeting of SPAK kinase in disorders of impaired epithelial transport.Expert opinion on therapeutic targets · 2017Review
- WNK signalling pathways in blood pressure regulation.Cellular and molecular life sciences : CMLS · 2017Review
- From the endoplasmic reticulum to the plasma membrane: mechanisms of CFTR folding and trafficking.Cellular and molecular life sciences : CMLS · 2017Review
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Members of the WNK (with-no-lysine [K]) subfamily of protein kinases regulate various ion channels involved in sodium, potassium, and chloride homeostasis by either inducing their phosphorylation or regulating the number of channel proteins expressed at the cell surface. Here, we describe findings demonstrating that the cell surface expression of the cystic fibrosis transmembrane conductance regulator (CFTR) is also regulated by WNK4 in mammalian cells. This effect of WNK4 is independent of the presence of kinase and involves interaction with and inhibition of spleen tyrosine kinase (Syk), which phosphorylates Tyr512 in the first nucleotide-binding domain 1 (NBD1) of CFTR. Transfection of catalytically active Syk into CFTR-expressing baby hamster kidney cells reduces the cell surface expression of CFTR, whereas that of WNK4 promotes it. This is shown by biotinylation of cell surface proteins, immunofluorescence microscopy, and functional efflux assays. Mutation of Tyr512 to either glutamic acid or phenylalanine is sufficient to alter CFTR surface levels. In human airway epithelial cells, downregulation of endogenous Syk and WNK4 confirms their roles as physiologic regulators of CFTR surface expression. Together, our results show that Tyr512 phosphorylation is a novel signal regulating the prevalence of CFTR at the cell surface and that WNK4 and Syk perform an antagonistic role in this process.
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