ArticleProceedings of the National Academy of Sciences of the United States of America2004
Stimulatory and inhibitory protein kinase C consensus sequences regulate the cystic fibrosis transmembrane conductance regulator.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2004. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 85 citations in OpenAlex.
- Cholangiocyte biology in primary sclerosing cholangitis and other cholangiopathies: pathogenesis, clinical insights, and experimental tools.Physiological reviews · 2026Review
- Targeting PI3Kγ anchoring enhances CFTR membrane localization and modulator efficacy via PKD1.JCI insight · 2026Article
- Cryo-EM reveals a phosphorylated R-domain envelops the NBD1 catalytic domain in an ABC transporter.Life science alliance · 2024Article
- Cystic Fibrosis: A Journey through Time and Hope.International journal of molecular sciences · 2024Review
- Functional Consequences of CFTR Interactions in Cystic Fibrosis.International journal of molecular sciences · 2024Review
- Structural basis for the modulation of MRP2 activity by phosphorylation and drugs.Nature communications · 2024Article
- Pathogenic Relationships in Cystic Fibrosis and Renal Diseases: CFTR, SLC26A9 and Anoctamins.International journal of molecular sciences · 2023Review
- Differential CFTR-Interactome Proximity Labeling Procedures Identify Enrichment in Multiple SLC Transporters.International journal of molecular sciences · 2022Article
- PKC regulation of ion channels: The involvement of PIPThe Journal of biological chemistry · 2022Review
- Intestinal secretory mechanisms and diarrhea.American journal of physiology. Gastrointestinal and liver physiology · 2022Review
- Mechanistic analysis and significance of sphingomyelinase-mediated decreases in transepithelial CFTR currents in nHBEs.Physiological reports · 2021Article
- Protein kinase A phosphorylation potentiates cystic fibrosis transmembrane conductance regulator gating by relieving autoinhibition on the stimulatory C terminus of the regulatory domain.The Journal of biological chemistry · 2020Article
- Changes in the R-region interactions depend on phosphorylation and contribute to PKA and PKC regulation of the cystic fibrosis transmembrane conductance regulator chloride channel.FASEB bioAdvances · 2020Article
- Agonists that stimulate secretion promote the recruitment of CFTR into membrane lipid microdomains.The Journal of general physiology · 2019Article
- Gq activity- and β-arrestin-1 scaffolding-mediated ADGRG2/CFTR coupling are required for male fertility.eLife · 2018Article
- CaOncotarget · 2017Review
- Trafficking and function of the cystic fibrosis transmembrane conductance regulator: a complex network of posttranslational modifications.American journal of physiology. Lung cellular and molecular physiology · 2016Review
- Potential sites of CFTR activation by tyrosine kinases.Channels (Austin, Tex.) · 2016Article
- Regulatory Crosstalk by Protein Kinases on CFTR Trafficking and Activity.Frontiers in chemistry · 2016Review
- Regulation of the cystic fibrosis transmembrane conductance regulator anion channel by tyrosine phosphorylation.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2015Article
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Protein kinase C (PKC) phosphorylation stimulates the cystic fibrosis transmembrane conductance regulator (CFTR) channel and enhances its activation by protein kinase A (PKA) through mechanisms that remain poorly understood. We have examined the effects of mutating consensus sequences for PKC phosphorylation and report here evidence for both stimulatory and inhibitory sites. Sequences were mutated in subsets and the mutants characterized by patch clamping. Activation of a 4CA mutant (S707A/S790A/T791A/S809A) by PKA was similar to that of wild-type CFTR and was enhanced by PKC, whereas responses of 3CA (T582A/T604A/S641A) and 2CA (T682A/S686A) channels to PKA were both drastically reduced (>90%). When each mutation in the 3CA and 2CA constructs was studied individually in a wild-type background, T582, T604, and S686 were found to be essential for PKA activation. Responses were restored when these three residues were reintroduced simultaneously into a 9CA mutant lacking all nine PKC consensus sequences (R6CA revertant); however, PKC phosphorylation was not required for this rescue. Nevertheless, two of the sites (T604 and S686) were phosphorylated in vitro, and PKC alone partially activated wild-type CFTR, the 4CA mutant, and the point mutants T582A and T604A, but not S686A channels, indicating that PKC does act at S686. The region encompassing S641 and T682 is inhibitory, because S641A enhanced activation by PKA, and T682A channels had 4-fold larger responses to PKC compared to wild-type channels. These results identify functionally important PKC consensus sequences on CFTR and will facilitate studies of its convergent regulation by PKC and PKA.
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