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

Local cyclic adenosine monophosphate signalling cascades - roles and targets in chronic kidney disease

The molecular mechanisms underlying chronic kidney disease (CKD) are poorly understood and treatment options are limited, a situation underpinning the need for elucidating the causative molecular mechanisms and for identifying innovative treatment options. It is emerging that cyclic 3′,5′‐adenosine monophosphate (cAMP) signalling occurs in defined cellular compartments within nanometre dimensions in processes whose dysregulation is associated with CKD. cAMP compartmentalization is tightly controlled by a specific set of proteins, including A‐kinase anchoring proteins (AKAPs) and phosphodiesterases (PDEs). AKAPs such as AKAP18, AKAP220, AKAP‐Lbc and STUB1, and PDE4 coordinate arginine‐vasopressin (AVP)‐induced water reabsorption by collecting duct principal cells. However, hyperactivation of the AVP system is associated with kidney damage and CKD. Podocyte injury involves aberrant AKAP signalling. cAMP signalling in immune cells can be local and slow the progression of inflammatory processes typical for CKD. A major risk factor of CKD is hypertension. cAMP directs the release of the blood pressure regulator, renin, from juxtaglomerular cells, and plays a role in Na+ reabsorption through ENaC, NKCC2 and NCC in the kidney. Mutations in the cAMP hydrolysing PDE3A that cause lowering of cAMP lead to hypertension. Another major risk factor of CKD is diabetes mellitus. AKAP18 and AKAP150 and several PDEs are involved in insulin release. Despite the increasing amount of data, an understanding of functions of compartmentalized cAMP signalling with relevance for CKD is fragmentary. Uncovering functions will improve the understanding of physiological processes and identification of disease‐relevant aberrations may guide towards new therapeutic concepts for the treatment of CKD

Many kinases for controlling the water channel aquaporin‐2

Aquaporin-2 (AQP2) is a member of the aquaporin water channel family. In the kidney, AQP2 is expressed in collecting duct principal cells where it facilitates water reabsorption in response to antidiuretic hormone (arginine vasopressin, AVP). AVP induces the redistribution of AQP2 from intracellular vesicles and its incorporation into the plasma membrane. The plasma membrane insertion of AQP2 represents the crucial step in AVP-mediated water reabsorption. Dysregulation of the system preventing the AQP2 plasma membrane insertion causes diabetes insipidus (DI), a disease characterised by an impaired urine concentrating ability and polydipsia. There is no satisfactory treatment of DI available. This review discusses kinases that control the localisation of AQP2 and points out potential kinase-directed targets for the treatment of DI

The A-kinase anchoring protein (AKAP) glycogen synthase kinase 3β interaction protein (GSKIP) regulates β-catenin through its interactions with both protein kinase A (PKA) and GSK3β

The A-kinase anchoring protein (AKAP) GSK3beta interaction protein (GSKIP) is a cytosolic scaffolding protein binding protein kinase A (PKA) and glycogen synthase kinase 3beta (GSK3beta). Here we show that both the AKAP function of GSKIP, i.e. its direct interaction with PKA, and its direct interaction with GSK3beta are required for the regulation of beta-catenin and thus Wnt signaling. A cytoplasmic destruction complex targets beta-catenin for degradation and thus prevents Wnt signaling. Wnt signals cause beta-catenin accumulation and translocation into the nucleus, where it induces Wnt target gene expression. GSKIP facilitates control of the beta-catenin stabilizing phosphorylation at Ser-675 by PKA. Its interaction with GSK3beta facilitates control of the destabilizing phosphorylation of beta-catenin at Ser-33/Ser-37/Thr-41. The influence of GSKIP on beta-catenin is explained by its scavenger function; it recruits the kinases away from the destruction complex without forming a complex with beta-catenin. The regulation of beta-catenin by GSKIP is specific for this AKAP as AKAP220, which also binds PKA and GSK3beta, did not affect Wnt signaling. We find that the binding domain of AKAP220 for GSK3beta is a conserved GSK3beta interaction domain (GID), which is also present in GSKIP. Our findings highlight an essential compartmentalization of both PKA and GSK3beta 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

Synergistic Effect of Ketone and Hydroperoxide in Brønsted Acid Catalyzed Oxidative Coupling Reactions

Waste not wasted: A mechanistic study of the autoxidative coupling of xanthene with cyclopentanone uncovered an autoinductive effect of the waste product hydrogen peroxide. It generates radicals in the presence of acid and ketones, which accelerate the reaction by providing an additional pathway to the reactive hydroperoxide intermediate. This discovery could be applied to achieve other Brønsted acid-catalyzed oxidative coupling reactions

The Effects of Twitter Sentiment on Stock Price Returns

Social media are increasingly reflecting and influencing behavior of other complex systems. In this paper we investigate the relations between a well-know micro-blogging platform Twitter and financial markets. In particular, we consider, in a period of 15 months, the Twitter volume and sentiment about the 30 stock companies that form the Dow Jones Industrial Average (DJIA) index. We find a relatively low Pearson correlation and Granger causality between the corresponding time series over the entire time period. However, we find a significant dependence between the Twitter sentiment and abnormal returns during the peaks of Twitter volume. This is valid not only for the expected Twitter volume peaks (e.g., quarterly announcements), but also for peaks corresponding to less obvious events. We formalize the procedure by adapting the well-known "event study" from economics and finance to the analysis of Twitter data. The procedure allows to automatically identify events as Twitter volume peaks, to compute the prevailing sentiment (positive or negative) expressed in tweets at these peaks, and finally to apply the "event study" methodology to relate them to stock returns. We show that sentiment polarity of Twitter peaks implies the direction of cumulative abnormal returns. The amount of cumulative abnormal returns is relatively low (about 1-2%), but the dependence is statistically significant for several days after the events

Cyclin-dependent kinase 18 controls trafficking of aquaporin-2 and its abundance through ubiquitin ligase STUB1, which functions as an AKAP

Arginine-vasopressin (AVP) facilitates water reabsorption in renal collecting duct principal cells through regulation of the water channel aquaporin-2 (AQP2). The hormone binds to vasopressin V2 receptors (V2R) on the surface of the cells and stimulates cAMP synthesis. The cAMP activates protein kinase A (PKA), which initiates signaling that causes an accumulation of AQP2 in the plasma membrane of the cells facilitating water reabsorption from primary urine and fine-tuning of body water homeostasis. AVP-mediated PKA activation also causes an increase in the AQP2 protein abundance through a mechanism that involves dephosphorylation of AQP2 at serine 261 and a decrease in its poly-ubiquitination. However, the signaling downstream of PKA that controls the localization and abundance of AQP2 is incompletely understood. We carried out an siRNA screen targeting 719 kinase-related genes, representing the majority of the kinases of the human genome and analyzed the effect of the knockdown on AQP2 by high-content imaging and biochemical approaches. The screening identified 13 hits whose knockdown inhibited the AQP2 accumulation in the plasma membrane. Amongst the candidates was the so far hardly characterized cyclin-dependent kinase 18 (CDK18). Our further analysis revealed a hitherto unrecognized signalosome comprising CDK18, an E3 ubiquitin ligase, STUB1 (CHIP), PKA and AQP2 that controls the localization and abundance of AQP2. CDK18 controls AQP2 through phosphorylation at serine 261 and STUB1-mediated ubiquitination. STUB1 functions as an A-kinase anchoring protein (AKAP) tethering PKA to the protein complex and bridging AQP2 and CDK18. The modulation of the protein complex may lead to novel concepts for the treatment of disorders which are caused or are associated with dysregulated AQP2 and for which a satisfactory treatment is not available, e.g., hyponatremia, liver cirrhosis, diabetes insipidus, ADPKD or heart failure

Mapping Pediatric Oncology Clinical Trial Collaborative Groups on the Global Stage

The global pediatric oncology clinical research landscape, particularly in Central and South America, Africa, and Asia, which bear the highest burden of global childhood cancer cases, is less characterized in the literature. Review of how existing pediatric cancer clinical trial groups internationally have been formed and how their research goals have been pursued is critical for building global collaborative research and data-sharing efforts, in line with the WHO Global Initiative for Childhood Cancer. METHODS: A narrative literature review of collaborative groups performing pediatric cancer clinical research in each continent was conducted. An inventory of research groups was assembled and reviewed by current pediatric cancer regional and continental leaders. Each group was narratively described with identification of common structural and research themes among consortia. RESULTS: There is wide variability in the structure, history, and goals of pediatric cancer clinical trial collaborative groups internationally. Several continental regions have longstanding endogenously-formed clinical trial groups that have developed and published numerous adapted treatment regimens to improve outcomes, whereas other regions have consortia focused on developing foundational database registry infrastructure supported by large multinational organizations or twinning relationships. CONCLUSION: There cannot be a one-size-fits-all approach to increasing collaboration between international pediatric cancer clinical trial groups, as this requires a nuanced understanding of local stakeholders and resources necessary to form partnerships. Needs assessments, performed either by local consortia or in conjunction with international partners, have generated productive clinical trial infrastructure. To achieve the goals of the Global Initiative for Childhood Cancer, global partnerships must be sufficiently granular to account for the distinct needs of each collaborating group and should incorporate grassroots approaches, robust twinning relationships, and implementation science