Bimodal antagonism of PKA signalling by ARHGAP36

Rebecca L. Eccles, Maciej T. Czajkowski, Carolin Barth, Paul Markus Müller, Erik McShane, Stephan Grunwald, Patrick Beaudette, Nora Mecklenburg, Rudolf Volkmer, Kerstin Zühlke, Gunnar Dittmar, Matthias Selbach, Annette Hammes, Oliver Daumke, Enno Klussmann, Sylvie Urbé and Oliver Rocks ()
Additional contact information
Rebecca L. Eccles: Max-Delbrück-Center for Molecular Medicine
Maciej T. Czajkowski: Max-Delbrück-Center for Molecular Medicine
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
Enno Klussmann: Max-Delbrück-Center for Molecular Medicine
Sylvie Urbé: Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool
Oliver Rocks: Max-Delbrück-Center for Molecular Medicine

Nature Communications, 2016, vol. 7, issue 1, 1-16

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms12963

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