Inhibition of protein kinase CK2 closes the CFTR Cl¯ channel, but has no effect on the cystic fibrosis mutant ΔF508-CFTR

KJ Treharne, Z Xu, J Chen, OG Best, DM Cassidy, DC Gruenert, P Hegyi, MA Gray, DN Sheppard, K Kunzelmann, A Mehta

Research output: Contribution to journalArticle (Academic Journal)peer-review

23 Citations (Scopus)

Abstract

Background: Deletion of phenylalanine-508 (ΔF508) from the first nucleotide-binding domain (NBD1) in the wild-type cystic fibrosis (CF)transmembrane conductance regulator (wtCFTR) causes CF. However, the mechanistic relationship between ΔF508-CFTR and the diversity of CF disease is unexplained. The surface location of F508 on NBD1 creates the potential for protein-protein interactions and nearby, lies a consensus sequence (SYDE) reported to control the pleiotropic protein kinase CK2. Methods: Electrophysiology, immunofluorescence and biochemistry applied to CFTR-expressing cells, Xenopus oocytes, pancreatic ducts and patient biopsies. Results: Irrespective of PKA activation, CK2 inhibition (ducts, oocytes, cells) attenuates CFTR dependent Cl- transport, closing wtCFTR in cell attached membrane patches. CK2 and wtCFTR coprecipitate and CK2 co-localized with wtCFTR (but not ΔF508-CFTR) in apical membranes of human airway biopsies. Comparing wild-type and ΔF508CFTR expressing oocytes, only ΔF508-CFTR Cl- currents were insensitive to two CK2 inhibitors. Furthermore, wtCFTR was inhibited by injecting a peptide mimicking the F508 region, whereas the ΔF508-equivalent peptide had no effect. Conclusions: CK2 controls wtCFTR, but not ΔF508-CFTR. Others find that peptides from the F508 region of NBD1 allosterically control CK2, acting through F508. Hence, disruption of CK2-CFTR interaction by ΔF508-CFTR might disrupt multiple, membrane-associated, CK2-dependent pathways, creating a new molecular disease paradigm for deleted F508 in CFTR.
Translated title of the contributionInhibition of protein kinase CK2 closes the CFTR Cl¯ channel, but has no effect on the cystic fibrosis mutant ΔF508-CFTR
Original languageEnglish
Pages (from-to)347 - 360
Number of pages14
JournalCellular Physiology and Biochemistry
Volume24
DOIs
Publication statusPublished - Nov 2009

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