The A-Kinase Anchoring Protein (AKAP) Glycogen Synthase Kinase 3ß Interaction Protein (GSKIP) Regulates ß-Catenin through Its Interactions with Both Protein Kinase A (PKA) and GSK3ß.

The A-kinase anchoring protein (AKAP) GSK3ß interaction protein (GSKIP) is a cytosolic scaffolding protein binding protein kinase A (PKA) and glycogen synthase kinase 3ß (GSK3ß). Here we show that both the AKAP function of GSKIP, i.e. its direct interaction with PKA, and its direct interaction with GSK3ß are required for the regulation of ß-catenin and thus Wnt signaling. A cytoplasmic destruction complex targets ß-catenin for degradation and thus prevents Wnt signaling. Wnt signals cause ß-catenin accumulation and translocation into the nucleus, where it induces Wnt target gene expression. GSKIP facilitates control of the ß-catenin stabilizing phosphorylation at Ser-675 by PKA. Its interaction with GSK3ß facilitates control of the destabilizing phosphorylation of ß-catenin at Ser-33/Ser-37/Thr-41. The influence of GSKIP on ß-catenin is explained by its scavenger function; it recruits the kinases away from the destruction complex without forming a complex with ß-catenin. The regulation of ß-catenin by GSKIP is specific for this AKAP as AKAP220, which also binds PKA and GSK3ß, did not affect Wnt signaling. We find that the binding domain of AKAP220 for GSK3ß is a conserved GSK3ß interaction domain (GID), which is also present in GSKIP. Our findings highlight an essential compartmentalization of both PKA and GSK3ß 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.

The Year 2022 in biomaterials research: A perspective from the editors of six leading journals.

The field of biomaterials science is highly active, with a steadily increasing number of publications and new journals being founded. This article brings together contributions from the editors of six leading journals in the area of biomaterials science and engineering. Each contributor highlights specific advances, topics, and trends that have emerged through the publications in their respective journal in the calendar year 2022. It presents a global perspective on a wide range of material types, functionalities, and applications. The highlighted topics include a diversity of biomaterials; from proteins, polysaccharides, and lipids to ceramics, metals, advanced composites, and a variety of new forms of these materials. Important advances in dynamically functional materials are presented, including a range of fabrication techniques such as bioassembly, 3D bioprinting and microgel formation. Similarly, several applications are highlighted in drug and gene delivery, biological sensing, cell guidance, immunoengineering, electroconductivity, wound healing, infection resistance, tissue engineering, and treatment of cancer. The goal of this paper is to provide the reader with both a broad view of recent biomaterials research, as well as expert commentary on some of the key advances that will shape the future of biomaterials science and engineering.

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.