Bimodal antagonism of PKA signalling by ARHGAP36

Protein kinase A (PKA) is a key mediator of cyclic AMP signalling. Here, Eccles et al. show that ARHGAP36 antagonizes PKA by acting as a kinase inhibitor and targeting the catalytic subunit for endolysosomal degradation, thus reducing sensitivity of cells to cAMP and promoting Hedgehog signalling.