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The Role of Protein Kinase in Health and Diseases

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: 20 April 2026 | Viewed by 15166

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Dr. Manuela Loi

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Department of Biomedical and Neuromotor Sciences, University of Bologna, Piazza di Porta San Donato 2, 40126 Bologna, Italy
Interests: protein kinases; phosphorylation; CDKL5; neurological disorder; targeted therapies
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Dear Colleagues,

Protein kinases are enzymes that modify other proteins by adding phosphate groups, playing a vital role in cellular processes such as growth, differentiation, and apoptosis. They are classified into two main types: serine/threonine kinases, which target serine and threonine residues, and tyrosine kinases, which phosphorylate tyrosine residues. Dysregulated kinase activity is linked to various diseases, including cancer, neurological disorders (such as Alzheimer's and Parkinson's), and metabolic diseases like diabetes and obesity. Abnormal kinase function can lead to uncontrolled cell proliferation and disrupt essential signaling pathways. Understanding the roles of protein kinases in disease is crucial for developing targeted therapies aimed at restoring cellular balance and improving patient outcomes. This Special Issue calls for original research and reviews on protein kinases in disease and potential therapeutic interventions.

Dr. Manuela Loi
Guest Editor

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Keywords

protein kinases
phosphorylation
cancer
neurological disorder
targeted therapies
metabolic diseases

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Published Papers (9 papers)

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Research

Jump to: Review

26 pages, 2812 KB

Open AccessArticle

Endocannabinoid Enhancement via MAGL Inhibition in CDKL5 Deficiency: Selective Cellular Benefits and Domain-Specific Functional Effects in Adult Cdkl5 KO Mice

by Manuela Loi, Nicola Mottolese, Giorgio Medici, Feliciana Iannibelli, Nicolò Interino, Giulia Candini, Federica Trebbi, Angelica Marina Bove, Jessica Fiori, Stefania Trazzi and Elisabetta Ciani

Int. J. Mol. Sci. 2026, 27(6), 2773; https://doi.org/10.3390/ijms27062773 - 19 Mar 2026

Viewed by 151

Abstract

CDKL5 Deficiency Disorder (CDD) is a severe neurodevelopmental encephalopathy characterized by early disruptions of synaptic maturation and network stability, leading to persistent motor, cognitive, and behavioral impairments. Given the role of the endocannabinoid system in synaptic development, neuroinflammation, and neuronal resilience, we investigated whether the sustained enhancement of endogenous 2-arachidonoylglycerol (2-AG) signaling via monoacylglycerol lipase (MAGL) inhibition could mitigate key pathological features in adult Cdkl5 knockout (KO) mice. Using an intermittent 6-week treatment, the MAGL inhibitor JZL184 robustly increased plasma 2-AG levels, reduced MAGL protein levels, and activated CB1-AKT signaling without evidence of receptor desensitization. Despite this clear pharmacodynamic efficacy, behavioral effects were domain-specific: neither dose ameliorated core behavioral deficits, although the higher dose selectively reduced stereotypic jumping and modestly improved cue-dependent associative memory. At the cellular level, JZL184 induced biologically meaningful effects, partially restoring dendritic spine maturation in the primary somatosensory cortex and increasing neuronal survival in the vulnerable CA1 hippocampal region. In contrast, microglial responses were dose-dependent and divergent, with the lower dose exerting anti-inflammatory effects, while the higher dose increased cortical microglial density and Allograft Inflammatory Factor-1 (AIF-1) expression, suggesting engagement of compensatory or off-target mechanisms. Overall, these findings show that MAGL inhibition activates neuroprotective pathways and ameliorates select structural deficits in adult Cdkl5 KO mice, but is insufficient to produce broad behavioral recovery, highlighting the domain-specific effects of selective 2-AG enhancement via MAGL inhibition and the need for developmentally informed or multimodal therapeutic strategies in CDD. Full article

(This article belongs to the Special Issue The Role of Protein Kinase in Health and Diseases)

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20 pages, 9448 KB

Open AccessArticle

Dissecting the Phospho-Regulatory Landscape of Protein Kinase N1 (PKN1) and Its Downstream Signaling: Functional Insights into the Activity-Dependent and Disease-Relevant Phosphosites

by Sreeshma Ravindran Kammarambath, Leona Dcunha, Athira Perunelly Gopalakrishnan, Yashi Shailendra Gautam, Furqaan Ahmed Basha, Prathik Basthikoppa Shivamurthy, Inamul Hasan Madar and Rajesh Raju

Int. J. Mol. Sci. 2026, 27(5), 2137; https://doi.org/10.3390/ijms27052137 - 25 Feb 2026

Viewed by 350

Abstract

Protein Kinase N1 (PKN1) is a PKC-related serine/threonine kinase of the AGC group within the eukaryotic protein kinase superfamily (ePK) that orchestrates oncogenic, metabolic, and cytoskeletal signaling. Despite these critical roles, the phosphorylation-dependent regulatory network of PKN1 remains largely undefined. We performed a large-scale phosphoproteomic data integration of publicly available human datasets (892 profiling datasets and 191 differential datasets) to identify recurrent PKN1 phosphorylation sites. This analysis identified two predominant PKN1 phosphosites, S562 and S916, that were frequently observed and differentially regulated across studies. The S916 maps to a turn motif (TM) in the AGC group of kinases, which is evolutionarily conserved among PKN paralogs, while S562 is non-conserved and appears to be PKN1-specific. Co-regulation and enrichment analyses suggest that S916 is associated with insulin/AMPK signaling and metabolic pathways, whereas S562 co-occurs with phosphosites involved in cell division, cytoskeletal regulation, and microtubule cytoskeleton organization. Integrating predicted and experimentally validated kinases, substrates, and interactors, we reconstructed a phospho-regulatory network that positions PKN1 at the crossroads of cytoskeleton organization and metabolic signaling. To assess the disease relevance of these phosphorylation events, we integrated transcriptomic and phosphoproteomic data from the hepatocellular carcinoma database (HCCDB). PKN1 was markedly up-regulated in HCC, and its phosphorylation at S916 was positively co-regulated with multiple oncogenic and proliferation-associated protein phosphosites. These results predict S562 and S916 as potential sites for targeted biochemical validation and functional experiments. The identification of S562 and S916 as key regulatory sites provides new mechanistic insight into PKN1 activation and highlights potential avenues for therapeutic targeting. Full article

(This article belongs to the Special Issue The Role of Protein Kinase in Health and Diseases)

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25 pages, 5642 KB

Open AccessArticle

Pharmacological Inhibition of JNK Signalling Exerts Anti-Neoplastic Effects on SH-SY5Y Human Neuroblastoma Cells

by Zuzanna Granek, Natalia Siwecka, Kamil Saramowicz, Grzegorz Galita, Michał Golberg, Ireneusz Majsterek and Wioletta Rozpędek-Kamińska

Int. J. Mol. Sci. 2025, 26(24), 11894; https://doi.org/10.3390/ijms262411894 - 10 Dec 2025

Viewed by 697

Abstract

Neuroblastoma (NB) is the most prevalent paediatric extracranial solid tumour, which remains a major therapeutic challenge, especially in cases of recurrent and disseminated disease. c-Jun N-terminal kinases (JNKs) are increasingly evidenced to play a key role in NB tumourigenesis and progression through apoptosis regulation, making selective JNK inhibitors promising candidates for use in targeted anticancer drugs in NB. Our study comprehensively investigated the acute antineoplastic potential of the selective JNK inhibitor AS601245 (JNK inhibitor V) on the human MYCN-non-amplified neuroblastoma cell line, SH-SY5Y, with particular focus on its effects on NB cell viability, proliferation, migration, apoptosis, gene and protein expression, and mitochondrial metabolism. JNK V selectively impaired NB cell survival and function, without exerting cytotoxicity toward normal human Schwann cells (HSC) and fibroblasts (BJ). Our findings highlighted a dose-dependent inhibition of proliferation (XTT assay), colony formation (clonogenic assay), and migration (wound healing assay), accompanied by increased caspase-3 activity (caspase-3 assay), pro-apoptotic genes (qRT-PCR) and protein (Western blotting) expression, and significant disruption of both oxidative phosphorylation and glycolysis (Agilent Seahorse XF Assay). These results provide new insights into the therapeutic potential of JNK inhibition as a targeted strategy for NB. Full article

(This article belongs to the Special Issue The Role of Protein Kinase in Health and Diseases)

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25 pages, 4072 KB

Open AccessArticle

Synergistic Efficacy of Gedatolisib and Darolutamide in Prostate Cancer to Overcome Resistance to Androgen-Targeted Therapy

by Salmaan Khan, Jhomary Molden, Charles Iversrud, Donna Mattonen, Stefano Rossetti and Lance Laing

Int. J. Mol. Sci. 2025, 26(24), 11810; https://doi.org/10.3390/ijms262411810 - 6 Dec 2025

Viewed by 557

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(This article belongs to the Special Issue The Role of Protein Kinase in Health and Diseases)

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31 pages, 5062 KB

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Functional Analysis of the PI3K/AKT/mTOR Pathway Inhibitor, Gedatolisib, Plus Fulvestrant with and Without Palbociclib in Breast Cancer Models

by Aaron Broege, Stefano Rossetti, Adrish Sen, Ann De La Forest, Laura Davis, Megan Seibel, Arul S. Menon, Sydney Stokke, Allison Macaulay, Jhomary Molden and Lance Laing

Int. J. Mol. Sci. 2025, 26(12), 5844; https://doi.org/10.3390/ijms26125844 - 18 Jun 2025

Cited by 5 | Viewed by 3529

Abstract

Treatment with endocrine therapy (ET) in combination with CDK4/6 inhibitors has improved the outcome of patients with hormone receptor (HR)+/HER2- advanced breast cancer (ABC), but most patients eventually experience disease progression. Since the PI3K-AKT-mTOR (PAM), estrogen receptor (ER), and cyclin-dependent kinase (CDK) pathways are interdependent drivers of HR+/HER2- breast cancer (BC), the simultaneous inhibition of these pathways is expected to enhance anti-tumor control. Here we investigated the molecular and cellular effects of gedatolisib, a multi-target kinase inhibitor of the PAM pathway currently being evaluated in Phase 3 clinical trials, combined with fulvestrant and/or palbociclib in BC cell models. We found that the gedatolisib/fulvestrant/palbociclib triplet inhibited BC cell growth significantly more than the single agents or the palbociclib/fulvestrant doublet, both in vitro and vivo. Specifically, the triplet combination counteracted adaptive responses associated with single drug treatment, such as the reactivation of the CDK-RB-E2F pathway after palbociclib treatment, and inhibited multiple cellular functions, such as cell cycle progression, cell survival, protein synthesis, and glucose metabolism. The triplet combination was effective in treatment-naïve BC cell lines as well as in cell lines adapted to palbociclib and/or fulvestrant, regardless of PIK3CA/PTEN genetic alterations. Our findings provide a mechanistic rationale for conducting clinical studies evaluating gedatolisib in combination with CDK4/6 inhibitors and ET in HR+/HER2- ABC. Full article

(This article belongs to the Special Issue The Role of Protein Kinase in Health and Diseases)

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Review

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19 pages, 2393 KB

Open AccessReview

The Role of Protein Kinases in the Management of Oncological Diseases by Acting on Ferroptotic Pathways

by Valentina Folgiero and Matteo Caforio

Int. J. Mol. Sci. 2026, 27(6), 2673; https://doi.org/10.3390/ijms27062673 - 14 Mar 2026

Viewed by 258

Abstract

Ferroptosis is a recently discovered form of cell death, driven by membrane lipid peroxidation with the contribution of intracellular iron. In recent years, many researchers have discovered the involvement of ferroptotic mechanisms in the etiology of various diseases, including several forms of cancer. Different points in the ferroptotic pathway can be crucial for arising or sustained pathologies, given the contribution of numerous molecular mechanisms concerning membrane channels, several proteins, enzymes, and also kinases. The latter, in particular, seem to be very important in the control of ferroptosis in different manners depending on the pathology. Therefore, many articles in recent years have described how the pathways that involve kinases can determine, control, or alter the physiological ferroptotic contribution. Interestingly, in a tumoral context, oncogenes and tumor suppressor activity affect the correct ferroptotic process directly or indirectly promoted by abnormal kinase activity. Expanding the understanding of how kinases contribute to tumorigenesis by altering ferroptosis mechanisms may provide important insights to improve current anticancer therapies. Furthermore, new data have indicated how kinase-dependent ferroptotic activity may influence the efficacy of immunotherapy. Since one of the major obstacles to this promising anticancer therapy concerns the resistance induced by cancer cells, finding new targets, such as kinases, to improve ferroptosis in tumor cells could open an intriguing door to enhancing immunotherapy and overcoming the current obstacle. Full article

(This article belongs to the Special Issue The Role of Protein Kinase in Health and Diseases)

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27 pages, 1739 KB

Open AccessReview

The Link Between Dietary Timing and Exercise Performance Through Adipocyte AMPKα2 Signaling

by Sohyun Kim, Jihyun Baek and Man S. Kim

Int. J. Mol. Sci. 2025, 26(13), 6061; https://doi.org/10.3390/ijms26136061 - 24 Jun 2025

Cited by 1 | Viewed by 2375

Abstract

Emerging evidence suggests that the timing of eating and exercise over the course of the day is paramount to metabolism and physical function. This review highlights seminal studies showing that adipocyte AMPKα2 signaling controls circadian adipose tissue–skeletal muscle communication. Day-restricted feeding has been shown to improve exercise performance via adipocyte-specific activation of AMPKα2, which controls fat–muscle crosstalk in a time-of-day dependent manner. This review also discusses corroborating experimental studies designating mesenchymal stem cells as key cellular mediators, showing that exercise in the afternoon leads to better metabolic effects in humans, and illustrating how incorrect timing of food intake leads to leptin resistance and metabolic dysregulation. Multi-omics strategies have shed light on the molecular mechanisms underlying such effects of time, showing the circadian control of metabolic processes across tissues. These results advance our knowledge of chronometabolism and offer exciting temporal intervention treatments for metabolic diseases, such as time-restricted feeding, timed exercise, and chronopharmacological targeting of AMPK. Fat–muscle crosstalk, physical performance, and metabolic health outcomes can possibly be optimized by synchronizing dietary and exercise timing with endogenous circadian rhythms. Full article

(This article belongs to the Special Issue The Role of Protein Kinase in Health and Diseases)

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21 pages, 1279 KB

Open AccessReview

Metformin in Colorectal Cancer: Epidemiological Evidence, Predictive Biomarkers, and Implications for Prevention and Treatment

by Seokho Myung, Youn Young Park and Man S. Kim

Int. J. Mol. Sci. 2025, 26(13), 6040; https://doi.org/10.3390/ijms26136040 - 24 Jun 2025

Cited by 6 | Viewed by 4559

Abstract

Interest in metformin as a potential anticancer agent for colorectal cancer (CRC) has increased. However, compelling epidemiological links and strong preclinical evidence suggest that metformin has variable efficacy in patients with CRC. This variability highlights the need to identify the patients who are most likely to benefit from effective stratification. We aimed to review the evidence concerning the diverse roles of metformin in CRC prevention and treatment, focusing on identifying and validating the predictive biomarkers essential for selecting patient subgroups that are likely to respond positively. We explored the various molecular pathways through which metformin acts and investigated how these diverse mechanisms might explain the observed differences in patient responses. Epidemiological studies and large meta-analyses have consistently reported reduced CRC incidence and improved survival among patients with diabetes treated with metformin. However, successfully extending these benefits broadly across all patients with CRC or achieving predictable outcomes in advanced disease settings remains a significant challenge. This review consolidates the current knowledge, highlights how different mechanisms interact, critically assesses clinical evidence in light of patient heterogeneity, and advocates for the development and implementation of biomarker-guided personalized therapeutic strategies as key to optimally utilizing the potential of metformin in CRC management. The current challenges and vital future research priorities in this critical area are also outlined. Full article

(This article belongs to the Special Issue The Role of Protein Kinase in Health and Diseases)

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17 pages, 2031 KB

Open AccessReview

Protein Kinase CK2 Inhibition Represents a Pharmacological Chance for the Treatment of Skin Diseases

by Michele Scuruchi, Desirèe Speranza, Giuseppe Bruschetta, Federico Vaccaro, Mariarosaria Galeano, Giovanni Pallio, Mario Vaccaro, Francesco Borgia, Federica Li Pomi, Massimo Collino and Natasha Irrera

Int. J. Mol. Sci. 2025, 26(11), 5404; https://doi.org/10.3390/ijms26115404 - 4 Jun 2025

Viewed by 1998

Abstract

Protein kinase CK2 has emerged as a pivotal regulator of cellular processes involved in skin homeostasis, including cell proliferation, differentiation and inflammatory response regulation. In fact, CK2 activity dysregulation is implicated in the pathogenesis of different skin diseases, such as psoriasis, cancer and inflammatory dermatoses. CK2 overactivation fosters keratinocyte proliferation and pro-inflammatory cytokine production through the STAT3 and Akt pathways in psoriasis, thus contributing to epidermal hyperplasia and inflammation. In the realm of oncology, CK2 overexpression correlates with tumor progression, facilitating cell survival and metastasis in melanoma and non-melanoma skin cancers. Pharmacological inhibition of CK2 has demonstrated therapeutic potential, with CX-4945 (Silmitasertib) as the most studied adenosine triphosphate-competitive inhibitor (ATP-competitive inhibitor). Preclinical models reveal that CK2 inhibitors effectively mitigate pathological features of psoriasis, regulate keratinocyte differentiation, and suppress tumor growth in skin cancers. These inhibitors also potentiate the efficacy of conventional chemotherapeutics and exhibit anti-inflammatory effects in dermatological conditions. Future research will aim to enhance the specificity and delivery of CK2-targeting therapies, including topical formulations, to minimize systemic side effects. Combination therapies integrating CK2 inhibitors with other agents might offer synergistic benefits in managing skin diseases. This review underscores CK2’s critical role in skin and its therapeutic potential as a pharmacological target, advocating for innovative approaches to harness CK2 inhibition in dermatology. Full article

(This article belongs to the Special Issue The Role of Protein Kinase in Health and Diseases)

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