The cyclic AMP phosphodiesterase 4D5 (PDE4D5)/receptor for activated C-kinase 1 (RACK1) signalling complex as a sensor of the extracellular nano-environment

The cyclic AMP and protein kinase C (PKC) signalling pathways regulate a wide range of cellular processes that require tight control, including cell proliferation and differentiation, metabolism and inflammation. The identification of a protein complex formed by receptor for activated C kinase 1 (RACK1), a scaffold protein for protein kinase C (PKC), and the cyclic AMP-specific phosphodiesterase, PDE4D5, demonstrates a potential mechanism for crosstalk between these two signalling routes. Indeed, RACK1-bound PDE4D5 is activated by PKCα, providing a route through which the PKC pathway can control cellular cyclic AMP levels. Although RACK1 does not appear to affect the intracellular localisation of PDE4D5, it does afford structural stability, providing protection against denaturation, and increases the susceptibility of PDE4D5 to inhibition by cyclic AMP-elevating pharmaceuticals, such as rolipram. In addition, RACK1 can recruit PDE4D5 and PKC to intracellular protein complexes that control diverse cellular functions, including activated G protein-coupled receptors (GPCRs) and integrins clustered at focal adhesions. Through its ability to regulate local cyclic AMP levels in the vicinity of these multimeric receptor complexes, the RACK1/PDE4D5 signalling unit therefore has the potential to modify the quality of incoming signals from diverse extracellular cues, ranging from neurotransmitters and hormones to nanometric topology. Indeed, PDE4D5 and RACK1 have been found to form a tertiary complex with integrin-activated focal adhesion kinase (FAK), which localises to cellular focal adhesion sites. This supports PDE4D5 and RACK1 as potential regulators of cell adhesion, spreading and migration through the non-classical exchange protein activated by cyclic AMP (EPAC1)/Rap1 signalling route.