Pharmacological interference with protein-protein interactions of A-kinase anchoring proteins as a strategy for the treatment of disease

A-kinase anchoring proteins (AKAPs) control the localization of cAMP-dependent protein kinase A (PKA) by tethering PKA to distinct cellular compartments. Through additional direct protein-protein interactions with PKA substrates and other signaling molecules they form multi-protein complexes. Thereby, AKAPs regulate the access of PKA to its substrates in a temporal and spatial manner as well as the local crosstalk of cAMP/PKA with other signaling pathways. Due to the increasing information on their molecular functioning and three-dimensional structures, and their emerging roles in the development of diseases, AKAPs move into the focus as potential drug targets. In particular, targeting AKAP-dependent protein-protein interactions for interference with local signal processing inside cells potentially allows for the development of therapeutics with high selectivity and fewer side effects

Pharmacological targeting of AKAP-directed compartmentalized cAMP signalling

The second messenger cyclic adenosine monophosphate (cAMP) can bind and activate protein kinase A (PKA). The cAMP/PKA system is ubiquitous and involved in a wide array of biological processes and therefore requires tight spatial and temporal regulation. Important components of the safeguard system are the A-kinase anchoring proteins (AKAPs), a heterogeneous family of scaffolding proteins defined by its ability to directly bind PKA. AKAPs tether PKA to specific subcellular compartments, and they bind further interaction partners to create local signalling hubs. The recent discovery of new AKAPs and advances in the field that shed light on the relevance of these hubs for human disease highlight unique opportunities for pharmacological modulation. This review exemplifies how interference with signalling, particularly cAMP signalling, at such hubs can reshape signalling responses and discusses how this could lead to novel pharmacological concepts for the treatment of disease with an unmet medical need such as cardiovascular disease and cancer

The A-kinase anchoring protein GSKIP regulates GSK3β activity and controls palatal shelf fusion in mice

A-kinase anchoring proteins (AKAPs) represent a family of structurally diverse proteins, all of which bind protein kinase A (PKA). A member of this family is Glycogen synthase kinase 3{beta} (GSK3{beta}) interaction protein (GSKIP). GSKIP interacts with PKA and also directly with GSK3{beta}. The physiological function of the GSKIP protein in vivo is unknown. We developed and characterized a conditional knockout mouse model and found that GSKIP deficiency caused lethality at birth. Embryos obtained through Caesarean section at embryonic day E18.5 were cyanotic, suffered from respiratory distress, and failed to initiate breathing properly. Additionally, all GSKIP-deficient embryos showed an incomplete closure of the palatal shelves accompanied by a delay in ossification along the fusion area of secondary palatal bones. On the molecular level, GSKIP deficiency resulted in decreased phosphorylation of GSK3{beta} at Ser9 starting early in development (E 10.5), leading to enhanced GSK3{beta} activity. At embryonic day 18.5 GSK3{beta} activity decreased to levels close to that of wild type. Our findings reveal a novel, crucial role for GSKIP in the coordination of GSK3{beta} signaling in palatal shelf fusion