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, Oliver Rocks*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

26 Citations (Scopus)


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.

Original languageEnglish
Article number12963
JournalNature Communications
Publication statusPublished - 7 Oct 2016
Externally publishedYes


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