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Protein Kinase in Disease

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 April 2024) | Viewed by 16266

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Dr. Manae Suzuki Kurokawa

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Disease Biomarker Analysis and Molecular Regulation, Graduate School of Medicine, St Marianna University, Miyamae Ku, 2-16-1 Sugao, Kawasaki 2168511, Kanagawa, Japan
Interests: protein kinases; phosphorylation; cancers; inflammatory diseases; protein kinase inhibitors; anticancer drugs
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Dear Colleagues,

Protein kinases are enzymes that transfer ATP-γ-phosphate to the hydroxy groups of serine, threonine, and tyrosine residues of substrate proteins. Through phosphorylation of substrate proteins, protein kinases regulate their biological activity, cellular location, and interaction with other proteins to conduct signal transduction for cell proliferation, differentiation, and metabolism. The fine tuning of protein phosphorylation is crucial for orchestrating protein networks, which are essential for vital functions.

A total of 518 putative protein kinases have been identified in the human genome. They are divided into serine/threonine kinases and tyrosine kinases. The former group is further divided into seven subgroups (AGC, CAMK, CK1, CMGC, RGC, STE, and TKL), while the latter group is divided into two subgroups (receptor type and non-receptor type). Abnormality of protein kinases due to chromosomal mutation, translocation and deletion, aberrant splicing, and protein overexpression and loss of function is involved in developmental anomalies and various diseases such as cancers, inflammatory diseases, and metabolic disorders (e.g., diabetes mellitus). It is also related to the occurrence of cardiovascular diseases, neuronal degeneration, immune dysregulation, renal diseases, and sense organ disorders. Therapeutic strategies targeting these protein kinases are being explored. This has already led to the discovery of more than 40 protein kinase inhibitors as anticancer drugs. Further analysis of protein kinases associated with diseases and the development of novel protein kinase inhibitors may help to overcome intractable diseases.

Dr. Manae Suzuki Kurokawa
Guest Editor

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Keywords

protein kinases
phosphorylation
cancers
inflammatory diseases
protein kinase inhibitors
anticancer drugs

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Related Special Issue

Protein Kinase in Disease, 2nd Edition in International Journal of Molecular Sciences

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Research

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17 pages, 3028 KiB

Open AccessArticle

Structure-Based De Novo Design for the Discovery of Miniprotein Inhibitors Targeting Oncogenic Mutant BRAF

by Jae Min Ham, Myeongbin Kim, Taeho Kim, Seong Eon Ryu and Hwangseo Park

Int. J. Mol. Sci. 2024, 25(10), 5535; https://doi.org/10.3390/ijms25105535 - 19 May 2024

Viewed by 1182

Abstract

Being a component of the Ras/Raf/MEK/ERK signaling pathway crucial for cellular responses, the VRAF murine sarcoma viral oncogene homologue B1 (BRAF) kinase has emerged as a promising target for anticancer drug discovery due to oncogenic mutations that lead to pathway hyperactivation. Despite the discovery of several small-molecule BRAF kinase inhibitors targeting oncogenic mutants, their clinical utility has been limited by challenges such as off-target effects and suboptimal pharmacological properties. This study focuses on identifying miniprotein inhibitors for the oncogenic V600E mutant BRAF, leveraging their potential as versatile drug candidates. Using a structure-based de novo design approach based on binding affinity to V600E mutant BRAF and hydration energy, 39 candidate miniprotein inhibitors comprising three helices and 69 amino acids were generated from the substructure of the endogenous ligand protein (14-3-3). Through in vitro binding and kinase inhibition assays, two miniproteins (63 and 76) were discovered as novel inhibitors of V600E mutant BRAF with low-micromolar activity, with miniprotein 76 demonstrating a specific impediment to MEK1 phosphorylation in mammalian cells. These findings highlight miniprotein 76 as a potential lead compound for developing new cancer therapeutics, and the structural features contributing to its biochemical potency against V600E mutant BRAF are discussed in detail. Full article

(This article belongs to the Special Issue Protein Kinase in Disease)

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16 pages, 4380 KiB

Open AccessArticle

Structural Models for a Series of Allosteric Inhibitors of IGF1R Kinase

by Jyoti Verma and Harish Vashisth

Int. J. Mol. Sci. 2024, 25(10), 5368; https://doi.org/10.3390/ijms25105368 - 14 May 2024

Viewed by 867

Abstract

The allosteric inhibition of insulin-like growth factor receptor 1 kinase (IGF1RK) is a potential strategy to overcome selectivity barriers for targeting receptor tyrosine kinases. We constructed structural models of a series of 12 indole-butyl-amine derivatives that have been reported as allosteric inhibitors of IGF1RK. We further studied the dynamics and interactions of each inhibitor in the allosteric pocket via all-atom explicit-solvent molecular dynamics (MD) simulations. We discovered that a bulky carbonyl substitution at the R1 indole ring is structurally unfavorable for inhibitor binding in the IGF1RK allosteric pocket. Moreover, we found that the most potent derivative (termed C11) acquires a distinct conformation: forming an allosteric pocket channel with better shape complementarity and interactions with the receptor. In addition to a hydrogen-bonding interaction with V1063, the cyano derivative C11 forms a stable hydrogen bond with M1156, which is responsible for its unique binding conformation in the allosteric pocket. Our findings show that the positioning of chemical substituents with different pharmacophore features at the R1 indole ring influences molecular interactions and binding conformations of indole-butyl-amine derivatives and, hence, dramatically affects their potencies. Our results provide a structural framework for the design of allosteric inhibitors with improved affinities and specificities against IGF1RK. Full article

(This article belongs to the Special Issue Protein Kinase in Disease)

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16 pages, 6404 KiB

Open AccessArticle

Regulation of Cell Cycle Progression through RB Phosphorylation by Nilotinib and AT-9283 in Human Melanoma A375P Cells

by Trang Minh Pham, Mahmoud Ahmed, Trang Huyen Lai, Md Entaz Bahar, Jin Seok Hwang, Rizi Firman Maulidi, Quang Nhat Ngo and Deok Ryong Kim

Int. J. Mol. Sci. 2024, 25(5), 2956; https://doi.org/10.3390/ijms25052956 - 3 Mar 2024

Cited by 1 | Viewed by 1844

Abstract

BCR-ABL tyrosine kinase inhibitors are commonly employed for the treatment of chronic myeloid leukemia, yet their impact on human malignant melanoma remains uncertain. In this study, we delved into the underlying mechanisms of specific BCR-ABL tyrosine kinase inhibitors (imatinib, nilotinib, ZM-306416, and AT-9283) in human melanoma A375P cells. We first evaluated the influence of these inhibitors on cell growth using cell proliferation and wound-healing assays. Subsequently, we scrutinized cell cycle regulation in drug-treated A375P cells using flow cytometry and Western blot assays. Notably, imatinib, nilotinib, ZM-306416, and AT-9283 significantly reduced cell proliferation and migration in A375P cells. In particular, nilotinib and AT-9283 impeded the G1/S transition of the cell cycle by down-regulating cell cycle-associated proteins, including cyclin E, cyclin A, and CDK2. Moreover, these inhibitors reduced RB phosphorylation, subsequently inhibiting E2F transcriptional activity. Consequently, the expression of the E2F target genes (CCNA2, CCNE1, POLA1, and TK-1) was markedly suppressed in nilotinib and AT9283-treated A375P cells. In summary, our findings suggest that BCR-ABL tyrosine kinase inhibitors may regulate the G1-to-S transition in human melanoma A375P cells by modulating the RB-E2F complex. Full article

(This article belongs to the Special Issue Protein Kinase in Disease)

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14 pages, 5994 KiB

Open AccessArticle

Suppressing Src-Mediated EGFR Signaling by Sustained Calcium Supply Targeting Triple-Negative Breast Cancer

by Keun-Yeong Jeong, Seon Young Park, Min Hee Park and Hwan Mook Kim

Int. J. Mol. Sci. 2023, 24(17), 13291; https://doi.org/10.3390/ijms241713291 - 27 Aug 2023

Cited by 1 | Viewed by 1117

Abstract

Src is emerging as a promising target in triple-negative breast cancer (TNBC) treatment because it activates survival signaling linked to the epidermal growth factor receptor. In this study, the effect of calcium supply on Src degradation was investigated to confirm underlying mechanisms and anticancer effects targeting TNBC. MDA-MB-231 cells, the TNBC cell line, were used. Calcium supply was feasible through lactate calcium salt (CaLac), and the applicable calcium concentration was decided by changes in the viability with different doses of CaLac. Expression of signaling molecules mediated by calcium-dependent Src degradation was observed by Western blot analysis and immunocytochemistry, and the recovery of the signaling molecules was confirmed following calpeptin treatment. The anticancer effect was investigated in the xenograft animal model. Significant suppression of Src was induced by calcium supply, followed by a successive decrease in the expression of epithelial growth factor receptor, RAS, extracellular signal-regulated kinase, and nuclear factor kappa B. Then, the suppression of cyclooxygenase-2 contributed to a significant deactivation of the prostaglandin E2 receptors. These results suggest that calcium supply has the potential to reduce the risk of TNBC. However, as this study is at an early stage to determine clinical applicability, close consideration is needed. Full article

(This article belongs to the Special Issue Protein Kinase in Disease)

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15 pages, 3845 KiB

Open AccessArticle

Inhibition of ITK Signaling Causes Amelioration in Sepsis-Associated Neuroinflammation and Depression-like State in Mice

by Mohammad M. Algahtani, Samiyah Alshehri, Sana S. Alqarni, Sheikh F. Ahmad, Naif O. Al-Harbi, Saleh A. Alqarni, Ali S. Alfardan, Khalid E. Ibrahim, Sabry M. Attia and Ahmed Nadeem

Int. J. Mol. Sci. 2023, 24(9), 8101; https://doi.org/10.3390/ijms24098101 - 30 Apr 2023

Cited by 6 | Viewed by 2216

Abstract

Sepsis affects millions of people worldwide and is associated with multiorgan dysfunction that is a major cause of increased morbidity and mortality. Sepsis is associated with several morbidities, such as lung, liver, and central nervous system (CNS) dysfunction. Sepsis-associated CNS dysfunction usually leads to several mental problems including depression. IL-17A is one of the crucial cytokines that is expressed and secreted by Th17 cells. Th17 cells are reported to be involved in the pathogenesis of depression and anxiety in humans and animals. One of the protein tyrosine kinases that plays a key role in controlling the development/differentiation of Th17 cells is ITK. However, the role of ITK in sepsis-associated neuroinflammation and depression-like symptoms in mice has not been investigated earlier. Therefore, this study investigated the efficacy of the ITK inhibitor, BMS 509744, in sepsis-linked neuroinflammation (ITK, IL-17A, NFkB, iNOS, MPO, lipid peroxides, IL-6, MCP-1, IL-17A) and a battery of depression-like behavioral tests, such as sucrose preference, tail suspension, and the marble burying test. Further, the effect of the ITK inhibitor on anti-inflammatory signaling (Foxp3, IL-10, Nrf2, HO-1, SOD-2) was assessed in the CNS. Our data show that sepsis causes increased ITK protein expression, IL-17A signaling, and neuroinflammatory mediators in the CNS that are associated with a depression-like state in mice. ITK inhibitor-treated mice with sepsis show attenuated IL-17A signaling, which is associated with the upregulation of IL-10/Nrf2 signaling and the amelioration of depression-like symptoms in mice. Our data show, for the first time, that the ITK inhibition strategy may counteract sepsis-mediated depression through a reduction in IL-17A signaling in the CNS. Full article

(This article belongs to the Special Issue Protein Kinase in Disease)

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15 pages, 3115 KiB

Open AccessArticle

Combined BCL-2 and PI3K/AKT Pathway Inhibition in KMT2A-Rearranged Acute B-Lymphoblastic Leukemia Cells

by Clemens Holz, Sandra Lange, Anett Sekora, Gudrun Knuebel, Saskia Krohn, Hugo Murua Escobar, Christian Junghanss and Anna Richter

Int. J. Mol. Sci. 2023, 24(2), 1359; https://doi.org/10.3390/ijms24021359 - 10 Jan 2023

Cited by 2 | Viewed by 2886

Abstract

Numerous hematologic neoplasms, including acute B-lymphoblastic leukemia (B-ALL), are characterized by overexpression of anti-apoptotic BCL-2 family proteins. Despite the high clinical efficacy of the specific BCL-2 inhibitor venetoclax in acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL), dose limitation and resistance argue for the early exploration of rational combination strategies. Recent data indicated that BCL-2 inhibition in B-ALL with KMT2A rearrangements is a promising intervention option; however, combinatorial approaches have not been in focus so far. The PI3K/AKT pathway has emerged as a possible target structure due to multiple interactions with the apoptosis cascade as well as relevant dysregulation in B-ALL. Herein, we demonstrate for the first time that combined BCL-2 and PI3K/AKT inhibition has synergistic anti-proliferative effects on B-ALL cell lines. Of note, all tested combinations (venetoclax + PI3K inhibitors idelalisib or BKM-120, as well as AKT inhibitors MK-2206 or perifosine) achieved comparable anti-leukemic effects. In a detailed analysis of apoptotic processes, among the PI3K/AKT inhibitors only perifosine resulted in an increased rate of apoptotic cells. Furthermore, the combination of venetoclax and perifosine synergistically enhanced the activity of the intrinsic apoptosis pathway. Subsequent gene expression studies identified the pro-apoptotic gene BBC3 as a possible player in synergistic action. All combinatorial approaches additionally modulated extrinsic apoptosis pathway genes. The present study provides rational combination strategies involving selective BCL-2 and PI3K/AKT inhibition in B-ALL cell lines. Furthermore, we identified a potential mechanistic background of the synergistic activity of combined venetoclax and perifosine application. Full article

(This article belongs to the Special Issue Protein Kinase in Disease)

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27 pages, 5638 KiB

Open AccessArticle

Highly Conserved Interaction Profiles between Clinically Relevant Mutants of the Cytomegalovirus CDK-like Kinase pUL97 and Human Cyclins: Functional Significance of Cyclin H

by Martin Schütz, Regina Müller, Eileen Socher, Christina Wangen, Florian Full, Emanuel Wyler, Diana Wong, Myriam Scherer, Thomas Stamminger, Sunwen Chou, William D. Rawlinson, Stuart T. Hamilton, Heinrich Sticht and Manfred Marschall

Int. J. Mol. Sci. 2022, 23(19), 11814; https://doi.org/10.3390/ijms231911814 - 5 Oct 2022

Cited by 8 | Viewed by 2018

Abstract

The complex host interaction network of human cytomegalovirus (HCMV) involves the regulatory protein kinase pUL97, which represents a viral cyclin-dependent kinase (CDK) ortholog. pUL97 interacts with the three human cyclin types T1, H, and B1, whereby the binding region of cyclin T1 and the pUL97 oligomerization region were both assigned to amino acids 231-280. We further addressed the question of whether HCMVs harboring mutations in ORF-UL97, i.e., short deletions or resistance-conferring point mutations, are affected in the interaction with human cyclins and viral replication. To this end, clinically relevant UL97 drug-resistance-conferring mutants were analyzed by whole-genome sequencing and used for genetic marker transfer experiments. The recombinant HCMVs indicated conservation of pUL97–cyclin interaction, since all viral UL97 point mutants continued to interact with the analyzed cyclin types and exerted wild-type-like replication fitness. In comparison, recombinant HCMVs UL97 Δ231-280 and also the smaller deletion Δ236-275, but not Δ241-270, lost interaction with cyclins T1 and H, showed impaired replication efficiency, and also exhibited reduced kinase activity. Moreover, a cellular knock-out of cyclins B1 or T1 did not alter HCMV replication phenotypes or pUL97 kinase activity, possibly indicating alternative, compensatory pUL97–cyclin interactions. In contrast, however, cyclin H knock-out, similar to virus deletion mutants in the pUL97–cyclin H binding region, exhibited strong defective phenotypes of HCMV replication, as supported by reduced pUL97 kinase activity in a cyclin H-dependent coexpression setting. Thus, cyclin H proved to be a very relevant determinant of pUL97 kinase activity and viral replication efficiency. As a conclusion, the results provide evidence for the functional importance of pUL97–cyclin interaction. High selective pressure on the formation of pUL97–cyclin complexes was identified by the use of clinically relevant mutants. Full article

(This article belongs to the Special Issue Protein Kinase in Disease)

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Review

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13 pages, 3411 KiB

Open AccessReview

Gaining Insights into Key Structural Hotspots within the Allosteric Binding Pockets of Protein Kinases

by Swapnil P. Bhujbal, Joonhong Jun, Haebeen Park, Jihyun Moon, Kyungbae Min and Jung-Mi Hah

Int. J. Mol. Sci. 2024, 25(9), 4725; https://doi.org/10.3390/ijms25094725 - 26 Apr 2024

Viewed by 1181

Abstract

Protein kinases are essential regulators of cell function and represent one of the largest and most diverse protein families. They are particularly influential in signal transduction and coordinating complex processes like the cell cycle. Out of the 518 human protein kinases identified, 478 are part of a single superfamily sharing catalytic domains that are related in sequence. The dysregulation of protein kinases due to certain mutations has been associated with various diseases, including cancer. Although most of the protein kinase inhibitors identified as type I or type II primarily target the ATP-binding pockets of kinases, the structural and sequential resemblances among these pockets pose a significant challenge for selective inhibition. Therefore, targeting allosteric pockets that are beside highly conserved ATP pockets has emerged as a promising strategy to prevail current limitations, such as poor selectivity and drug resistance. In this article, we compared the binding pockets of various protein kinases for which allosteric (type III) inhibitors have already been developed. Additionally, understanding the structure and shape of existing ligands could aid in identifying key interaction sites within the allosteric pockets of kinases. This comprehensive review aims to facilitate the design of more effective and selective allosteric inhibitors. Full article

(This article belongs to the Special Issue Protein Kinase in Disease)

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13 pages, 1275 KiB

Open AccessReview

Influential Serum Kinases (Non-sFlt-1) and Phosphatases in Preeclampsia—Systemic Review and Metanalysis

by Karla Cecilia Marrufo-Gallegos, Jose Rafael Villafán-Bernal, Salvador Espino-y-Sosa, Guadalupe Estrada-Gutierrez, Iris Paola Guzmán-Guzmán, Raigam Jafet Martinez-Portilla and Johnatan Torres-Torres

Int. J. Mol. Sci. 2023, 24(16), 12842; https://doi.org/10.3390/ijms241612842 - 16 Aug 2023

Viewed by 1600

Abstract

The early identification of women with an increased risk of preeclampsia (PE) is desirable, but apart from soluble fms-like tyrosine kinase-1 (sFlt-1), few biomarkers have previously been identified as relevant for predicting preeclampsia. Since kinases and phosphatases regulate critical biological processes and previous evidence suggests a potential role of these molecules in preeclampsia, we performed this systematic review and metanalysis. The objective was to determine if there are kinases and phosphatases whose serum levels are different between women with and without PE, being relevant biomarkers of PE. We followed the recommendations of Cochrane and the Preferred Reported Items for Systematic Reviews and Metanalysis (PRISMA) to perform this study. The MESH terms preeclampsia, kinases, phosphatases, angiopoietins, soluble tyrosine protein kinase receptor (sTIE2), and cellular-mesenchymal-epithelial transition factor (c-MET) were combined to find relevant articles in the PubMed, PROSPERO, and Cochrane databases. Then, a qualitative and quantitative analysis was performed in R Studio software. From 580 abstracts identified, 37 were included in the final analysis, which comprised 24,211 pregnant women (2879 with PE and 21,332 women without PE [HP]. The pooled analysis showed that serum creatine kinase (CK) (SMD: 2.43, CI 95% 0.25–4.62) was significantly higher in PE, whereas sTIE2 and anti-angiogenic factor soluble c-Met (sMet)were significantly lower in PE than in HP (SMD: −0.23, CI95% −0.37 to −0.09; and SMD:0.24, CI95% 0.01–0.47, respectively). Adenosine monophosphate-activated protein kinase (AMPK), angiopoietin-1 (ANG-1), angiopoietin-2 (ANG-2), the ratio angiopoietin-1/angiopoietin-2, acid phosphatase, and alkaline phosphatase were not different between women with PE and HP. In summary CK, sTIE2, and c-MET are relevant biomarkers of PE. It is desirable to incorporate them into current models for PE prediction to evaluate their utility as biomarkers. Full article

(This article belongs to the Special Issue Protein Kinase in Disease)

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