Understanding protein kinase CK2 mis-regulation upon F508del CFTR expression

Andrea Venerando, Mario A. Pagano, Kendra Tosoni, Flavio Meggio, Diane Cassidy, Michelle Stobbart, Lorenzo A. Pinna, Anil Mehta

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    Abstract

    We review areas of overlap between nucleoside diphosphate kinase (NDPK; nm23) and two proteins manifesting an equivalent diversity of action, each with many thousands of publications. The first is a constitutively active protein kinase, CK2 (formerly casein kinase 2), that includes NDPK amongst its hundreds of targets. The second is an enigmatic member of the ATP-binding cassette (ABC) family of membrane pumps that normally hydrolyse ATP to transport substrates. Yet our unusual family member (ABCC7) is not a pump but, uniquely, acts as a regulated anion channel. ABCC7 is the cystic fibrosis transmembrane conductance regulator (CFTR), and we discuss the highly prevalent CFTR mutation (F508del CFTR) in terms of the uncertainties surrounding the molecular basis of cystic fibrosis that cloud approaches to corrective therapy. Using lysates from cells stably expressing either wild-type or F508del CFTR, incubated with the CK2 substrate GTP, we show that the phosphoproteome of F508del CFTR-expressing cells both differs from wild-type CFTR-expressing cells and is significantly enhanced in intensity by similar to 1.5-fold (p < 0.05, paired t test with Bonferroni correction, n = 4). Phosphorylation is about 50% attenuated with a specific CK2 inhibitor. We propose that a new function may exist for the CFTR region that is commonly mutated, noting that its sequence (PGTIKENIIF(508)GVSYDEYRYR) is not only highly conserved within the C sub-family of ABC proteins but also a related sequence is found in NDPK. We conclude that a latent path may exist between mutation of this conserved sequence, CK2 hyperactivity and disease pathogenesis that might also explain the heterozygote advantage for the common F508del CFTR mutant .

    Original languageEnglish
    Pages (from-to)473-488
    Number of pages16
    JournalNaunyn-Schmiedeberg's Archives of Pharmacology
    Volume384
    Issue number4-5
    DOIs
    Publication statusPublished - Oct 2011

    Keywords

    • Cystic fibrosis
    • Rare disease
    • Epithelial sodium channel
    • Protein kinase
    • Mutation
    • TRANSMEMBRANE CONDUCTANCE REGULATOR
    • NUCLEOSIDE DIPHOSPHATE KINASE
    • CYSTIC-FIBROSIS
    • PSEUDOMONAS-AERUGINOSA
    • ANION TRANSPORT
    • MUTATION
    • CHANNEL
    • PHOSPHORYLATION
    • INHIBITION
    • LUNG

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