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Protein Kinases: Function, Substrates, and Implication in Diseases

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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 (31 January 2021) | Viewed by 51249

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Dr. Lubos Cipak

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Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, 84505 Bratislava, Slovakia
Interests: maintenance of genome stability; post-translational modification; protein kinase; splicing; helicase
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Protein kinases represent an important family of enzymes involved in the regulation of many cellular processes. They phosphorylate proteins, and in turn, regulate their biological activities. As phosphorylation is a most frequent reversible post-translational modification, it has to be dynamically regulated. When defining the impact of phosphorylation on protein activities, it is clear that the presence or absence of phosphate groups change the conformation of the protein, and thus modify its activities. From that view, it has become clear that protein kinases play specific regulatory roles throughout the cell, and their defects may result in the development of various diseases.

For this Special Issue, we look forward to receiving review articles as well as original research and methodological manuscripts related to understanding the biological functions of protein kinases, with a special focus on the dynamic nature of their regulatory activities.

Dr. Lubos Cipak
Guest Editor

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Keywords

protein kinases
kinase networks
phosphorylation
protein kinase targets
phosphoproteomics
disease-related protein kinase mutations

Published Papers (13 papers)

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Editorial

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2 pages, 174 KiB

Open AccessEditorial

Protein Kinases: Function, Substrates, and Implication in Diseases

by Lubos Cipak

Int. J. Mol. Sci. 2022, 23(7), 3560; https://doi.org/10.3390/ijms23073560 - 24 Mar 2022

Cited by 1 | Viewed by 1761

Abstract

Protein kinases are important enzymes, involved in the regulation of various cellular processes [...] Full article

(This article belongs to the Special Issue Protein Kinases: Function, Substrates, and Implication in Diseases)

Research

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14 pages, 2120 KiB

Open AccessArticle

Label-Free Quantitative Phosphoproteomics of the Fission Yeast Schizosaccharomyces pombe Using Strong Anion Exchange- and Porous Graphitic Carbon-Based Fractionation Strategies

by Barbara Sivakova, Jan Jurcik, Veronika Lukacova, Tomas Selicky, Ingrid Cipakova, Peter Barath and Lubos Cipak

Int. J. Mol. Sci. 2021, 22(4), 1747; https://doi.org/10.3390/ijms22041747 - 9 Feb 2021

Cited by 6 | Viewed by 2609

Abstract

The phosphorylation of proteins modulates various functions of proteins and plays an important role in the regulation of cell signaling. In recent years, label-free quantitative (LFQ) phosphoproteomics has become a powerful tool to analyze the phosphorylation of proteins within complex samples. Despite the great progress, the studies of protein phosphorylation are still limited in throughput, robustness, and reproducibility, hampering analyses that involve multiple perturbations, such as those needed to follow the dynamics of phosphoproteomes. To address these challenges, we introduce here the LFQ phosphoproteomics workflow that is based on Fe-IMAC phosphopeptide enrichment followed by strong anion exchange (SAX) and porous graphitic carbon (PGC) fractionation strategies. We applied this workflow to analyze the whole-cell phosphoproteome of the fission yeast Schizosaccharomyces pombe. Using this strategy, we identified 8353 phosphosites from which 1274 were newly identified. This provides a significant addition to the S. pombe phosphoproteome. The results of our study highlight that combining of PGC and SAX fractionation strategies substantially increases the robustness and specificity of LFQ phosphoproteomics. Overall, the presented LFQ phosphoproteomics workflow opens the door for studies that would get better insight into the complexity of the protein kinase functions of the fission yeast S. pombe. Full article

(This article belongs to the Special Issue Protein Kinases: Function, Substrates, and Implication in Diseases)

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20 pages, 6182 KiB

Open AccessArticle

Photoswitchable Azo- and Diazocine-Functionalized Derivatives of the VEGFR-2 Inhibitor Axitinib

by Linda Heintze, Dorian Schmidt, Theo Rodat, Lydia Witt, Julia Ewert, Malte Kriegs, Rainer Herges and Christian Peifer

Int. J. Mol. Sci. 2020, 21(23), 8961; https://doi.org/10.3390/ijms21238961 - 25 Nov 2020

Cited by 25 | Viewed by 4247

Abstract

In this study, we aimed at the application of the concept of photopharmacology to the approved vascular endothelial growth factor receptor (VEGFR)-2 kinase inhibitor axitinib. In a previous study, we found out that the photoisomerization of axitinib’s stilbene-like double bond is unidirectional in aqueous solution due to a competing irreversible [2+2]-cycloaddition. Therefore, we next set out to azologize axitinib by means of incorporating azobenzenes as well as diazocine moieties as photoresponsive elements. Conceptually, diazocines (bridged azobenzenes) show favorable photoswitching properties compared to standard azobenzenes because the thermodynamically stable Z-isomer usually is bioinactive, and back isomerization from the bioactive E-isomer occurs thermally. Here, we report on the development of different sulfur–diazocines and carbon–diazocines attached to the axitinib pharmacophore that allow switching the VEGFR-2 activity reversibly. For the best sulfur–diazocine, we could verify in a VEGFR-2 kinase assay that the Z-isomer is biologically inactive (IC₅₀ >> 10,000 nM), while significant VEGFR-2 inhibition can be observed after irradiation with blue light (405 nm), resulting in an IC₅₀ value of 214 nM. In summary, we could successfully develop reversibly photoswitchable kinase inhibitors that exhibit more than 40-fold differences in biological activities upon irradiation. Moreover, we demonstrate the potential advantage of diazocine photoswitches over standard azobenzenes. Full article

(This article belongs to the Special Issue Protein Kinases: Function, Substrates, and Implication in Diseases)

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Graphical abstract

17 pages, 2382 KiB

Open AccessArticle

A Screen for PKN3 Substrates Reveals an Activating Phosphorylation of ARHGAP18

by Michal Dibus, Jan Brábek and Daniel Rösel

Int. J. Mol. Sci. 2020, 21(20), 7769; https://doi.org/10.3390/ijms21207769 - 20 Oct 2020

Cited by 4 | Viewed by 2900

Abstract

Protein kinase N3 (PKN3) is a serine/threonine kinase implicated in tumor progression of multiple cancer types, however, its substrates and effector proteins still remain largely understudied. In the present work we aimed to identify novel PKN3 substrates in a phosphoproteomic screen using analog sensitive PKN3. Among the identified putative substrates we selected ARHGAP18, a protein from RhoGAP family, for validation of the screen and further study. We confirmed that PKN3 can phosphorylate ARHGAP18 in vitro and we also characterized the interaction of the two proteins, which is mediated via the N-terminal part of ARHGAP18. We present strong evidence that PKN3-ARHGAP18 interaction is increased upon ARHGAP18 phosphorylation and that the phosphorylation of ARHGAP18 by PKN3 enhances its GAP domain activity and contributes to negative regulation of active RhoA. Taken together, we identified new set of potential PKN3 substrates and revealed a new negative feedback regulatory mechanism of Rho signaling mediated by PKN3-induced ARHGAP18 activation. Full article

(This article belongs to the Special Issue Protein Kinases: Function, Substrates, and Implication in Diseases)

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15 pages, 1867 KiB

Open AccessArticle

by Katarzyna Szoltysek, Carmela Ciardullo, Peixun Zhou, Anna Walaszczyk, Elaine Willmore, Vikki Rand, Scott Marshall, Andy Hall, Christine J. Harrison, Jeyanthy Eswaran and Meera Soundararajan

Int. J. Mol. Sci. 2020, 21(20), 7663; https://doi.org/10.3390/ijms21207663 - 16 Oct 2020

Cited by 9 | Viewed by 3097

Abstract

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the Western World and it is characterized by a marked degree of clinical heterogeneity. An impaired balance between pro- and anti-apoptotic stimuli determines chemorefractoriness and outcome. The low proliferation rate of CLL cells indicates that one of the primary mechanisms involved in disease development may be an apoptotic failure. Here, we study the clinical and functional significance of DRAK2, a novel stress response kinase that plays a critical role in apoptosis, T-cell biology, and B-cell activation in CLL. We have analyzed CLL patient samples and showed that low expression levels of DRAK2 were significantly associated with unfavorable outcome in our CLL cohort. DRAK2 expression levels showed a positive correlation with the expression of DAPK1, and TGFBR1. Consistent with clinical data, the downregulation of DRAK2 in MEC-1 CLL cells strongly increased cell viability and proliferation. Further, our transcriptome data from MEC-1 cells highlighted MAPK, NF-κB, and Akt and as critical signaling hubs upon DRAK2 knockdown. Taken together, our results indicate DRAK2 as a novel marker of CLL survival that plays key regulatory roles in CLL prognosis. Full article

(This article belongs to the Special Issue Protein Kinases: Function, Substrates, and Implication in Diseases)

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19 pages, 3634 KiB

Open AccessArticle

Synergistic Interactions of 5-Fluorouracil with Inhibitors of Protein Kinase CK2 Correlate with p38 MAPK Activation and FAK Inhibition in the Triple-Negative Breast Cancer Cell Line

by Patrycja Wińska, Olena Karatsai, Monika Staniszewska, Mirosława Koronkiewicz, Konrad Chojnacki and Maria Jolanta Rędowicz

Int. J. Mol. Sci. 2020, 21(17), 6234; https://doi.org/10.3390/ijms21176234 - 28 Aug 2020

Cited by 11 | Viewed by 2880

Abstract

Background: The combination effect of 5-fluorouracil (5-FU) with either CX-4945 or a new inhibitor of protein kinase CK2, namely 14B (4,5,6,7-tetrabromo-1-(3-bromopropyl)-2-methyl-1H-benzimidazole), on the viability of MCF-7 and triple-negative MDA-MB-231 breast cancer cell lines was studied. Methods: Combination index (CI) values were determined using an MTT-based assay and the Chou-Talalay model. The effect of the tested drug combinations on pro-apoptotic properties and cell cycle progression was examined using flow cytometry. The activation of FAK, p38 MAPK, and ERK1/2 kinases and the expression of selected pro-apoptotic markers in MDA-MB-231 cell line after the combined treatment were evaluated by the western blot method. Confocal microscopy was used to examine actin network in MDA-MB-231. Results: Our results showed that a synergistic effect (CI < 1) occurred in MDA-MB-231 after treatment with both combinations of 5-FU with 14B or CX-4945, whereas the combination of 5-FU and 14B evoked an antagonistic effect in MCF-7. We conclude that the synergistic interactions (CI < 1) observed for both the combinations of 5-FU and 14B or CX-4945 in MDA-MB-231 correlated with an activation of p38 MAPK, inhibition of FAK, increased expression of apoptogenic markers, prolongation of S-phase of cell cycle, and destabilization of actin network. Conclusions: The obtained results support the recent observation that CK2 inhibitors can improve 5-FU-based anticancer therapy and FAK kinase can be an attractive molecular target in breast cancer therapy. Full article

(This article belongs to the Special Issue Protein Kinases: Function, Substrates, and Implication in Diseases)

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Review

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17 pages, 1116 KiB

Open AccessReview

Targeting Protein Kinases in Blood Cancer: Focusing on CK1α and CK2

by Zaira Spinello, Anna Fregnani, Laura Quotti Tubi, Livio Trentin, Francesco Piazza and Sabrina Manni

Int. J. Mol. Sci. 2021, 22(7), 3716; https://doi.org/10.3390/ijms22073716 - 2 Apr 2021

Cited by 22 | Viewed by 3658

Abstract

Disturbance of protein kinase activity may result in dramatic consequences that often lead to cancer development and progression. In tumors of blood origin, both tyrosine kinases and serine/threonine kinases are altered by different types of mutations, critically regulating cancer hallmarks. CK1α and CK2 are highly conserved, ubiquitously expressed and constitutively active pleiotropic kinases, which participate in multiple biological processes. The involvement of these kinases in solid and blood cancers is well documented. CK1α and CK2 are overactive in multiple myeloma, leukemias and lymphomas. Intriguingly, they are not required to the same degree for the viability of normal cells, corroborating the idea of “druggable” kinases. Different to other kinases, mutations on the gene encoding CK1α and CK2 are rare or not reported. Actually, these two kinases are outside the paradigm of oncogene addiction, since cancer cells’ dependency on these proteins resembles the phenomenon of “non-oncogene” addiction. In this review, we will summarize the general features of CK1α and CK2 and the most relevant oncogenic and stress-related signaling nodes, regulated by kinase phosphorylation, that may lead to tumor progression. Finally, we will report the current data, which support the positioning of these two kinases in the therapeutic scene of hematological cancers. Full article

(This article belongs to the Special Issue Protein Kinases: Function, Substrates, and Implication in Diseases)

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8 pages, 541 KiB

Open AccessReview

Nemo-Like Kinase in Development and Diseases: Insights from Mouse Studies

by Renée Daams and Ramin Massoumi

Int. J. Mol. Sci. 2020, 21(23), 9203; https://doi.org/10.3390/ijms21239203 - 2 Dec 2020

Cited by 11 | Viewed by 2548

Abstract

The Wnt signalling pathway is a central communication cascade between cells to orchestrate polarity and fate during development and adult tissue homeostasis in various organisms. This pathway can be regulated by different signalling molecules in several steps. One of the coordinators in this pathway is Nemo-like kinase (NLK), which is an atypical proline-directed serine/threonine mitogen-activated protein (MAP) kinase. Very recently, NLK was established as an essential regulator in different cellular processes and abnormal NLK expression was highlighted to affect the development and progression of various diseases. In this review, we focused on the recent discoveries by using NLK-deficient mice, which show a phenotype in the development and function of organs such as the lung, heart and skeleton. Furthermore, NLK could conduct the function and differentiation of cells from the immune system, in addition to regulating neurodegenerative diseases, such as Huntington’s disease and spinocerebellar ataxias. Overall, generations of NLK-deficient mice have taught us valuable lessons about the role of this kinase in certain diseases and development. Full article

(This article belongs to the Special Issue Protein Kinases: Function, Substrates, and Implication in Diseases)

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19 pages, 887 KiB

Open AccessReview

Targeting Casein Kinase 1 (CK1) in Hematological Cancers

by Pavlína Janovská, Emmanuel Normant, Hari Miskin and Vítězslav Bryja

Int. J. Mol. Sci. 2020, 21(23), 9026; https://doi.org/10.3390/ijms21239026 - 27 Nov 2020

Cited by 43 | Viewed by 6432

Abstract

The casein kinase 1 enzymes (CK1) form a family of serine/threonine kinases with seven CK1 isoforms identified in humans. The most important substrates of CK1 kinases are proteins that act in the regulatory nodes essential for tumorigenesis of hematological malignancies. Among those, the most important are the functions of CK1s in the regulation of Wnt pathways, cell proliferation, apoptosis and autophagy. In this review we summarize the recent developments in the understanding of biology and therapeutic potential of the inhibition of CK1 isoforms in the pathogenesis of chronic lymphocytic leukemia (CLL), other non-Hodgkin lymphomas (NHL), myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) and multiple myeloma (MM). CK1δ/ε inhibitors block CLL development in preclinical models via inhibition of WNT-5A/ROR1-driven non-canonical Wnt pathway. While no selective CK1 inhibitors have reached clinical stage to date, one dual PI3Kδ and CK1ε inhibitor, umbralisib, is currently in clinical trials for CLL and NHL patients. In MDS, AML and MM, inhibition of CK1α, acting via activation of p53 pathway, showed promising preclinical activities and the first CK1α inhibitor has now entered the clinical trials. Full article

(This article belongs to the Special Issue Protein Kinases: Function, Substrates, and Implication in Diseases)

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16 pages, 2290 KiB

Open AccessReview

The 14-3-3 Proteins as Important Allosteric Regulators of Protein Kinases

by Veronika Obsilova and Tomas Obsil

Int. J. Mol. Sci. 2020, 21(22), 8824; https://doi.org/10.3390/ijms21228824 - 21 Nov 2020

Cited by 38 | Viewed by 4776

Abstract

Phosphorylation by kinases governs many key cellular and extracellular processes, such as transcription, cell cycle progression, differentiation, secretion and apoptosis. Unsurprisingly, tight and precise kinase regulation is a prerequisite for normal cell functioning, whereas kinase dysregulation often leads to disease. Moreover, the functions of many kinases are regulated through protein–protein interactions, which in turn are mediated by phosphorylated motifs and often involve associations with the scaffolding and chaperon protein 14-3-3. Therefore, the aim of this review article is to provide an overview of the state of the art on 14-3-3-mediated kinase regulation, focusing on the most recent mechanistic insights into these important protein–protein interactions and discussing in detail both their structural aspects and functional consequences. Full article

(This article belongs to the Special Issue Protein Kinases: Function, Substrates, and Implication in Diseases)

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18 pages, 580 KiB

Open AccessReview

The Role of RIPK1 and RIPK3 in Cardiovascular Disease

by Elise DeRoo, Ting Zhou and Bo Liu

Int. J. Mol. Sci. 2020, 21(21), 8174; https://doi.org/10.3390/ijms21218174 - 31 Oct 2020

Cited by 23 | Viewed by 6332

Abstract

Cardiovascular diseases, including peripheral arterial and venous disease, myocardial infarction, and stroke, are the number one cause of death worldwide annually. In the last 20 years, the role of necroptosis, a newly identified form of regulated necrotic cell death, in cardiovascular disease has come to light. Specifically, the damaging role of two kinase proteins pivotal in the necroptosis pathway, Receptor Interacting Protein Kinase 1 (RIPK1) and Receptor Interacting Protein Kinase 3 (RIPK3), in cardiovascular disease has become a subject of great interest and importance. In this review, we provide an overview of the current evidence supporting a pathologic role of RIPK1 and RIPK3 in cardiovascular disease. Moreover, we highlight the evidence behind the efficacy of targeted RIPK1 and RIPK3 inhibitors in the prevention and treatment of cardiovascular disease. Full article

(This article belongs to the Special Issue Protein Kinases: Function, Substrates, and Implication in Diseases)

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28 pages, 6045 KiB

Open AccessReview

Advances in Understanding TKS4 and TKS5: Molecular Scaffolds Regulating Cellular Processes from Podosome and Invadopodium Formation to Differentiation and Tissue Homeostasis

by Gyöngyi Kudlik, Tamás Takács, László Radnai, Anita Kurilla, Bálint Szeder, Kitti Koprivanacz, Balázs L. Merő, László Buday and Virag Vas

Int. J. Mol. Sci. 2020, 21(21), 8117; https://doi.org/10.3390/ijms21218117 - 30 Oct 2020

Cited by 15 | Viewed by 4448

Abstract

Scaffold proteins are typically thought of as multi-domain “bridging molecules.” They serve as crucial regulators of key signaling events by simultaneously binding multiple participants involved in specific signaling pathways. In the case of epidermal growth factor (EGF)-epidermal growth factor receptor (EGFR) binding, the activated EGFR contacts cytosolic SRC tyrosine-kinase, which then becomes activated. This process leads to the phosphorylation of SRC-substrates, including the tyrosine kinase substrates (TKS) scaffold proteins. The TKS proteins serve as a platform for the recruitment of key players in EGFR signal transduction, promoting cell spreading and migration. The TKS4 and the TKS5 scaffold proteins are tyrosine kinase substrates with four or five SH3 domains, respectively. Their structural features allow them to recruit and bind a variety of signaling proteins and to anchor them to the cytoplasmic surface of the cell membrane. Until recently, TKS4 and TKS5 had been recognized for their involvement in cellular motility, reactive oxygen species-dependent processes, and embryonic development, among others. However, a number of novel functions have been discovered for these molecules in recent years. In this review, we attempt to cover the diverse nature of the TKS molecules by discussing their structure, regulation by SRC kinase, relevant signaling pathways, and interaction partners, as well as their involvement in cellular processes, including migration, invasion, differentiation, and adipose tissue and bone homeostasis. We also describe related pathologies and the established mouse models. Full article

(This article belongs to the Special Issue Protein Kinases: Function, Substrates, and Implication in Diseases)

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19 pages, 1150 KiB

Open AccessReview

Phosphoproteomics Meets Chemical Genetics: Approaches for Global Mapping and Deciphering the Phosphoproteome

by Jan Jurcik, Barbara Sivakova, Ingrid Cipakova, Tomas Selicky, Erika Stupenova, Matus Jurcik, Michaela Osadska, Peter Barath and Lubos Cipak

Int. J. Mol. Sci. 2020, 21(20), 7637; https://doi.org/10.3390/ijms21207637 - 15 Oct 2020

Cited by 5 | Viewed by 4070

Abstract

Protein kinases are important enzymes involved in the regulation of various cellular processes. To function properly, each protein kinase phosphorylates only a limited number of proteins among the thousands present in the cell. This provides a rapid and dynamic regulatory mechanism that controls biological functions of the proteins. Despite the importance of protein kinases, most of their substrates remain unknown. Recently, the advances in the fields of protein engineering, chemical genetics, and mass spectrometry have boosted studies on identification of bona fide substrates of protein kinases. Among the various methods in protein kinase specific substrate identification, genetically engineered protein kinases and quantitative phosphoproteomics have become promising tools. Herein, we review the current advances in the field of chemical genetics in analog-sensitive protein kinase mutants and highlight selected strategies for identifying protein kinase substrates and studying the dynamic nature of protein phosphorylation. Full article

(This article belongs to the Special Issue Protein Kinases: Function, Substrates, and Implication in Diseases)

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