Defective formation of PKA/CnA-dependent annexin 2-S100A10/CFTR complex in Delta F508 cystic fibrosis cells

Lee Anthony Borthwick, Claudia Riemen, Catharine Goddard, William H. Colledge, Anil Mehta, Volker Gerke, Richmond Muimo

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    11 Citations (Scopus)

    Abstract

    Cystic fibrosis (CF) is characterised by impaired epithelial ion transport and is caused by mutations in the cystic fibrosis conductance regulator protein (CFTR), a cAMP/PKA and ATP-regulated chloride channel. We recently demonstrated a cAMP/PKA/calcineurin (CnA)-driven association between annexin 2 (anx 2), its cognate partner -S100A10 and cell surface CFTR. The complex is required for CFTR and outwardly rectifying chloride channel function in epithelia. Since the cAMP/PKA-induced Cl- current is absent in CF epithelia, we hypothesized that the anx 2-S100A10/CFTR complex may be defective in CFBE41o cells expressing the commonest F508del-CFTR (Delta F-CFTR) mutation. Here, we demonstrate that, despite the presence of cell surface Delta F-CFTR, cAMP/PKA fails to induce anx 2-S100A10/CFTR complex formation in CFBE41o- cells homozygous for F508del-CFTR. Mechanistically, PKA-dependent serine phosphorylation of CnA, CnA-anx 2 complex formation and CnA-dependent depbosphorylation of anx 2 are all defective in CFBE41o- cells. Immumohistochemical analysis confirms an abnormal cellular distribution of anx 2 in human and CIF mouse epithelia.

    Thus, we demonstrate that cAMP/PKA/CnA signaling pathway is defective in CF cells and suggest that loss of anx 2-S100A10/CFTR complex formation may contribute to defective cAMP/PKA-dependent CFTR channel function. (C) 2008 Elsevier Inc. All rights reserved.

    Original languageEnglish
    Pages (from-to)1073-1083
    Number of pages11
    JournalCellular Signalling
    Volume20
    Issue number6
    DOIs
    Publication statusPublished - Jun 2008

    Keywords

    • cystic fibrosis
    • CFTR
    • annexin 2
    • S100A10
    • cAMP
    • calcineurin A
    • PKA
    • protein phosphatase
    • phosphorylation
    • PROTEIN-KINASE-A
    • TRANSMEMBRANE CONDUCTANCE REGULATOR
    • AIRWAY EPITHELIAL-CELLS
    • CHANNEL FUNCTION
    • CL-CHANNEL
    • CFTR
    • CALCINEURIN
    • EXPRESSION
    • PHOSPHATASE
    • PHOSPHORYLATION

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