Kinases Phosphatases, Volume 3, Issue 3 (September 2025) – 7 articles

We have evaluated the quality of all 325 deposits in the PDB (as of December 2024) that correspond to (or contain) the catalytic domain of cAMP-dependent protein kinases (PKA). Detailed analysis was possible for 289 deposits of crystal structures that included not only the atomic coordinates but also structure factors. These structures represent 35 years of studies, and it is not surprising that the more recent structures are generally of better quality than the older ones. We did not encounter deposits with very severe problems, although some minor problems were found. To assess whether a uniform method of structure re-refinement, as implemented in the pipeline and website PDB-REDO, leads to significant improvement of structural models, we compared structure quality indicators for the originally refined structures and their counterparts resulting from PDB-REDO refinement. The re-refinement procedure significantly improved only some older structures, while its success was generally limited. We paid particular attention to the quality of small-molecule ligands, finding that most of them fit the electron density very well. This type of analysis helps identify the highest quality structures among many deposits for certain protein families and, thus, could be extended to other groups of proteins as well. Full article

Digital twin is a mathematical model that virtually represents a physical object or process and predicts its behavior at future time points. These simulation models enable a deeper understanding of tumorigenic processes and improve biomarker discovery in cancer research. Tumor microenvironment is marked by dysregulated signaling pathways, where kinases and phosphatases serve as critical regulators and promising sources for biomarker discovery. These enzymes operate within multiscale and context-dependent processes where spatial and temporal coordination determine cellular outcomes. Digital Twin technology provides a platform for multimodal and multiscale modeling of kinase and phosphatase processes at the patient-specific level. These models have the potential to transform biomarker validation processes, enhance the prediction of therapeutic responses, and support precision decision-making. In this review, we present the major alterations affecting kinases and phosphatase functions within the tumor microenvironment and their clinical relevance as biomarkers, and we address how digital twins in oncology can augment and refine each stage of the biomarker discovery pipeline. Introducing this emerging technology for cancer biomarker discovery will assist in accelerating its adoption and translation into precision diagnostics and targeted therapies. Full article

Non-alcoholic fatty liver disease (NAFLD) is a common metabolic condition characterized by hepatic lipid deposits, insulin resistance, and inflammation which may progress to non-alcoholic steatohepatitis (NASH) and fibrosis. Protein kinases play an important role in NAFLD development by regulating metabolic and inflammatory pathways. Mitogen-activated protein kinases (MAPKs), protein kinase C (PKC), AMP-activated protein kinase (AMPK), phosphoinositide 3-kinase (PI3K)/AKT, and mechanistic target of rapamycin (mTOR) are all involved in NAFLD and NASH progression. Emerging evidence indicates that Farnesoid X Receptor (FXR) agonists have therapeutic potential by modulating bile acid metabolism, lipid balance, and inflammatory responses. This review examines the mechanistic interplay between FXR agonists and important protein kinases in NAFLD and NASH. FXR agonists activate AMPK, which promotes fatty acid oxidation and reduces hepatic steatosis. They also regulate MAPK signaling, which reduces c-Jun NH2-terminal kinase (JNK)- and p38 MAPK-mediated inflammation. Furthermore, FXR agonists activate the PI3K/AKT pathway, enhancing insulin sensitivity and modulating mTOR signaling to reduce hepatic fibrosis. Clinical studies in NAFLD/NASH indicate that FXR agonists confer metabolic and anti-inflammatory benefits, although optimizing efficacy and minimizing adverse effects remain challenging. Future studies should focus on combination therapies targeting FXR alongside specific kinases to improve therapeutic outcomes. This review highlights the potential of FXR agonists to modulate protein kinase signaling, opening new avenues for targeted NAFLD/NASH therapy. Full article

CK2α is a kinase important for essential cellular and biological processes. CK2α is ubiquitously expressed, albeit at different tissue levels, and its transcript levels are dysregulated in disease. However, there is limited knowledge on the regulation of CK2α gene expression. The best one studied, the human CSNK2A1 (CK2α) gene promoter, contains uncharacterized binding motifs for NF-κB. Our goal was to investigate the role of NF-κB in Csnk2a1 promoter regulation. We cloned the mouse Csnk2a1 promoter which had significant sequence homology with the human CSNK2A1 promoter. Using promoter deletions, we identified a minimal promoter region containing transcription factor motifs (NF-κB, Ets-1, Sp1) consistent with those published for the CSNK2A1 promoter. Electrophoretic mobility shift assays demonstrated specific NF-κB subunit binding to the minimal promoter. NF-κB subunit transfection and extracellular NF-κB stimulation in non-tumor cell lines led to increased transactivation of the mouse minimal promoter. These data, together with data on the regulation of NF-κB by CK2 kinase activity, suggest a positive-feedback loop between CK2α and NF-κB. Non-tumor cell line re-plating and increased percent confluence upregulated Csnk2a1 transcript levels which differed from tumor cell line published data. In summary, Csnk2a1 promoter is regulated by NF-κB signaling and during cellular proliferation. Full article

Protein kinases and phosphatases are essential for post-translational regulation, enabling bacteria to adapt to environmental stresses and modulate virulence. While prior reviews have broadly covered their roles in stress response, antibiotic resistance, and virulence, this article updates specifically on the roles of histidine kinases (HKs) and serine/threonine kinases (STKs) in mediating phage-bacteria interactions. A key aspect is phage-encoded kinases, which hijack bacterial signalling by phosphorylating and disrupting host processes to promote infection. Despite their importance, significant gaps remain in understanding these regulatory networks. This microreview highlights both the unresolved mechanisms and the therapeutic potential of targeting kinase pathways—for instance, by disrupting phage evasion strategies or enhancing phage-based antimicrobial therapies. Full article

Obesity causes lifestyle-related diseases such as hypertension and type 2 diabetes and has become a global health concern. L-fucose (Fuc), a monosaccharide that can be derived from brown algae, has been shown to strongly suppress lipid droplet accumulation in 3T3-L1 murine adipocytes at high concentrations via the activation of AMP-activated kinase (AMPK). Although low concentrations of Fuc also exhibited similar effects, the underlying mechanisms remain unclear. In this study, we investigated the effects of low-level Fuc on lipid metabolism, focusing on the role of fucosylation. Low-level Fuc did not induce AMPK phosphorylation but suppressed lipid droplet accumulation. This suppressive effect was abolished by co-treatment with the fucosylation inhibitor 2F-Peracetyl-Fucose (2F-PAF), suggesting that fucosylation plays a key role in the observed metabolic regulation. Furthermore, proteomic analysis combined with click chemistry pulldown suggested that proteins involved in the regulation of lipid metabolism, such as acetoacetyl-CoA synthetase enzymes and catalytic subunit alpha of cAMP-dependent protein kinase, are fucosylated or interact with fucose. These findings provide novel insights into the anti-obesity mechanisms of Fuc and highlight the physiological significance of protein fucosylation in adipocyte lipid metabolism. Full article