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Bimodal antagonism of PKA signalling by ARHGAP36

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Official URL:https://doi.org/10.1038/ncomms12963
PubMed:View item in PubMed
Creators Name:Eccles, R.L. and Czajkowski, M.T. and Barth, C. and Mueller, P.M. and McShane, E. and Grunwald, S. and Beaudette, P. and Mecklenburg, N. and Volkmer, R. and Zuehlke, K. and Dittmar, G. and Selbach, M. and Hammes, A. and Daumke, O. and Klussmann, E. and Urbe, S. and Rocks, O.
Journal Title:Nature Communications
Journal Abbreviation:Nat Commun
Volume:7
Page Range:12963
Date:7 October 2016
Keywords:Lysosomes, Oncogenes, Phosphorylation, Ubiquitylation
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.
ISSN:2041-1723
Publisher:Nature Publishing Group (U.K.)
Item Type:Article

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