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Bimodal antagonism of PKA signalling by ARHGAP36

Author

Listed:
  • Rebecca L. Eccles

    (Max-Delbrück-Center for Molecular Medicine)

  • Maciej T. Czajkowski

    (Max-Delbrück-Center for Molecular Medicine
    Berlin Institute of Health (BIH))

  • Carolin Barth

    (Max-Delbrück-Center for Molecular Medicine)

  • Paul Markus Müller

    (Max-Delbrück-Center for Molecular Medicine)

  • Erik McShane

    (Max-Delbrück-Center for Molecular Medicine)

  • Stephan Grunwald

    (Max-Delbrück-Center for Molecular Medicine)

  • Patrick Beaudette

    (Max-Delbrück-Center for Molecular Medicine)

  • Nora Mecklenburg

    (Max-Delbrück-Center for Molecular Medicine)

  • Rudolf Volkmer

    (Leibniz-Institut für Molekulare Pharmakologie)

  • Kerstin Zühlke

    (Max-Delbrück-Center for Molecular Medicine)

  • Gunnar Dittmar

    (Max-Delbrück-Center for Molecular Medicine)

  • Matthias Selbach

    (Max-Delbrück-Center for Molecular Medicine)

  • Annette Hammes

    (Max-Delbrück-Center for Molecular Medicine)

  • Oliver Daumke

    (Max-Delbrück-Center for Molecular Medicine
    Institute for Chemistry and Biochemistry, Freie Universität Berlin)

  • Enno Klussmann

    (Max-Delbrück-Center for Molecular Medicine
    DZHK, German Centre for Cardiovascular Research)

  • Sylvie Urbé

    (Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool)

  • Oliver Rocks

    (Max-Delbrück-Center for Molecular Medicine)

Abstract

Protein kinase A is a key mediator of cAMP signalling downstream of G-protein-coupled receptors, a signalling pathway conserved in all eukaryotes. cAMP binding to the regulatory subunits (PKAR) relieves their inhibition of the catalytic subunits (PKAC). Here we report that ARHGAP36 combines two distinct inhibitory mechanisms to antagonise PKA signalling. First, it blocks PKAC activity via a pseudosubstrate motif, akin to the mechanism employed by the protein kinase inhibitor proteins. Second, it targets PKAC for rapid ubiquitin-mediated lysosomal degradation, a pathway usually reserved for transmembrane receptors. ARHGAP36 thus dampens the sensitivity of cells to cAMP. We show that PKA inhibition by ARHGAP36 promotes derepression of the Hedgehog signalling pathway, thereby providing a simple rationale for the upregulation of ARHGAP36 in medulloblastoma. Our work reveals a new layer of PKA regulation that may play an important role in development and disease.

Suggested Citation

  • Rebecca L. Eccles & Maciej T. Czajkowski & Carolin Barth & Paul Markus Müller & Erik McShane & Stephan Grunwald & Patrick Beaudette & Nora Mecklenburg & Rudolf Volkmer & Kerstin Zühlke & Gunnar Dittma, 2016. "Bimodal antagonism of PKA signalling by ARHGAP36," Nature Communications, Nature, vol. 7(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms12963
    DOI: 10.1038/ncomms12963
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    Cited by:

    1. Uirá Souto Melo & Jerome Jatzlau & Cesar A. Prada-Medina & Elisabetta Flex & Sunhild Hartmann & Salaheddine Ali & Robert Schöpflin & Laura Bernardini & Andrea Ciolfi & M-Hossein Moeinzadeh & Marius-Ko, 2023. "Enhancer hijacking at the ARHGAP36 locus is associated with connective tissue to bone transformation," Nature Communications, Nature, vol. 14(1), pages 1-13, December.

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