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PKA catalytic subunit mutations in adrenocortical Cushing’s adenoma impair association with the regulatory subunit

Author

Listed:
  • Davide Calebiro

    (Institute of Pharmacology and Toxicology, University of Würzburg
    Rudolf Virchow Center)

  • Annette Hannawacker

    (Institute of Pharmacology and Toxicology, University of Würzburg)

  • Sandra Lyga

    (Institute of Pharmacology and Toxicology, University of Würzburg
    Rudolf Virchow Center)

  • Kerstin Bathon

    (Institute of Pharmacology and Toxicology, University of Würzburg
    Rudolf Virchow Center)

  • Ulrike Zabel

    (Institute of Pharmacology and Toxicology, University of Würzburg)

  • Cristina Ronchi

    (Comprehensive Cancer Center Mainfranken, University of Würzburg)

  • Felix Beuschlein

    (Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München)

  • Martin Reincke

    (Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München)

  • Kristina Lorenz

    (Institute of Pharmacology and Toxicology, University of Würzburg
    Comprehensive Heart Failure Center, Universitätsklinikum Würzburg)

  • Bruno Allolio

    (Endocrine and Diabetes Unit, University Hospital, University of Würzburg)

  • Caroline Kisker

    (Rudolf Virchow Center)

  • Martin Fassnacht

    (Comprehensive Cancer Center Mainfranken, University of Würzburg
    Endocrine and Diabetes Unit, University Hospital, University of Würzburg)

  • Martin J. Lohse

    (Institute of Pharmacology and Toxicology, University of Würzburg
    Rudolf Virchow Center
    Comprehensive Heart Failure Center, Universitätsklinikum Würzburg)

Abstract

We recently identified a high prevalence of mutations affecting the catalytic (Cα) subunit of protein kinase A (PKA) in cortisol-secreting adrenocortical adenomas. The two identified mutations (Leu206Arg and Leu199_Cys200insTrp) are associated with increased PKA catalytic activity, but the underlying mechanisms are highly controversial. Here we utilize a combination of biochemical and optical assays, including fluorescence resonance energy transfer in living cells, to analyze the consequences of the two mutations with respect to the formation of the PKA holoenzyme and its regulation by cAMP. Our results indicate that neither mutant can form a stable PKA complex, due to the location of the mutations at the interface between the catalytic and the regulatory subunits. We conclude that the two mutations cause high basal catalytic activity and lack of regulation by cAMP through interference of complex formation between the regulatory and the catalytic subunits of PKA.

Suggested Citation

  • Davide Calebiro & Annette Hannawacker & Sandra Lyga & Kerstin Bathon & Ulrike Zabel & Cristina Ronchi & Felix Beuschlein & Martin Reincke & Kristina Lorenz & Bruno Allolio & Caroline Kisker & Martin F, 2014. "PKA catalytic subunit mutations in adrenocortical Cushing’s adenoma impair association with the regulatory subunit," Nature Communications, Nature, vol. 5(1), pages 1-7, December.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms6680
    DOI: 10.1038/ncomms6680
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