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.4

The A-kinase anchoring protein (AKAP) GSK3␤ interaction protein (GSKIP) is a cytosolic scaffolding protein binding protein kinase A (PKA) and glycogen synthase kinase 3␤ (GSK3␤). Here we show that both the AKAP function of GSKIP, i.e. its direct interaction with PKA, and its direct interaction with GSK3␤ are required for the regulation of ␤-catenin and thus Wnt signaling. A cytoplasmic destruction complex targets ␤-catenin for degradation and thus prevents Wnt signaling. Wnt signals cause ␤-catenin accumulation and translocation into the nucleus, where it induces Wnt target gene expression. GSKIP facilitates control of the ␤-catenin stabilizing phosphorylation at Ser-675 by PKA. Its interaction with GSK3␤ facilitates control of the destabilizing phosphorylation of ␤-catenin at Ser-33/Ser-37/Thr-41. The influence of GSKIP on ␤-catenin is explained by its scavenger function; it recruits the kinases away from the destruction complex without forming a complex with ␤-catenin. The regulation of ␤-catenin by GSKIP is specific for this AKAP as AKAP220, which also binds PKA and GSK3␤, did not affect Wnt signaling. We find that the binding domain of AKAP220 for GSK3␤ is a conserved GSK3␤ interaction domain (GID), which is also present in GSKIP. Our findings highlight an essential compartmentalization of both PKA and GSK3␤ by GSKIP, and ascribe a function to a cytosolic AKAP-PKA interaction as a regulatory factor in the control of canonical Wnt signaling. Wnt signaling controls different biological processes, including embryonic development, cell cycle progression, glycogen metabolism, and immune regulation; deregulation is associated with diseases such as cancer, type 2 diabetes, inflammatory, and Alzheimer's and Parkinson's diseases.A-kinase anchoring proteins (AKAPs) 3 are a family of about 50 scaffolding proteins. Their conserved function is the compartmentalization of protein kinase A (PKA). PKA holoenzyme consists of a dimer of regulatory (RI␣, RI␤, RII␣, or RII␤) and two catalytic subunits each bound to one R subunit. AKAPs directly interact with R subunits and tether the kinase to defined cellular compartments such as vesicles, the sarcoplasmic reticulum, or the cytoskeleton. This compartmentalization confers a tight spatiotemporal control to PKA signaling, and enables PKA to elicit a specific cellular response to each of the many stimuli that cause cAMP elevation and thereby lead to activation of this ubiquitous kinase. AKAPs directly interact with further signaling proteins, thus mediating crosstalk between signaling systems: phosphatases, dephosphorylating PKA-phosphorylated substrates, adenylyl cyclases, synthesizing cAMP, and phosphodiesterases (PDEs), hydrolyzing cAMP. Several AKAPs bind further kinases such as protein kinase C (PKC), which are activated by signals other than cAMP, e.g. Ca 2ϩ . AKAPs and their interactions play key roles in a variety of physiological processes such as vasopressin-mediated water reabsorption in renal principal cells and cardiac myocyte contractility (1-5, 7, 8).A new example...

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The results suggest that the direct intratumoral insertion of a PdTMPyP4-containing polymeric rod would be of benefit as an adjuvant treatment for patients undergoing chemo- or radiotherapy. By preventing the lengthening of telomeres and therefore the unrestricted growth of cancer cells, our DDS will provide a significant therapeutic advantage to these treatments without affecting normal tissues.