Journal Description
Kinases and Phosphatases
Kinases and Phosphatases
is an international, peer-reviewed, open access journal on every aspect of post-translational modifications in all biological systems, from bacteria to humans, covering a wide range of disciplines, including biochemistry, molecular biology, structural biology, cell biology, medicinal chemistry, pharmacology, cellular pathology, and clinical disciplines, and is published quarterly online by MDPI.
- Open Access— free for readers, with article processing charges (APC) paid by authors or their institutions.
- Rapid Publication: first decisions in 16 days; acceptance to publication in 5.8 days (median values for MDPI journals in the second half of 2023).
- Recognition of Reviewers: APC discount vouchers, optional signed peer review, and reviewer names published annually in the journal.
Latest Articles
Protein Phosphorylation Nexus of Cyanobacterial Adaptation and Metabolism
Kinases Phosphatases 2024, 2(2), 209-223; https://doi.org/10.3390/kinasesphosphatases2020013 - 20 Jun 2024
Abstract
►
Show Figures
Protein phosphorylation serves as a fundamental regulatory mechanism to modulate cellular responses to environmental stimuli and plays a crucial role in orchestrating adaptation and metabolic homeostasis in various diverse organisms. In cyanobacteria, an ancient phylum of significant ecological and biotechnological relevance, protein phosphorylation
[...] Read more.
Protein phosphorylation serves as a fundamental regulatory mechanism to modulate cellular responses to environmental stimuli and plays a crucial role in orchestrating adaptation and metabolic homeostasis in various diverse organisms. In cyanobacteria, an ancient phylum of significant ecological and biotechnological relevance, protein phosphorylation emerges as a central regulatory axis mediating adaptive responses that are essential for survival and growth. This exhaustive review thoroughly explores the complex terrain of protein phosphorylation in cyanobacterial adaptation and metabolism, illustrating its diverse forms and functional implications. Commencing with an overview of cyanobacterial physiology and the historical trajectory of protein phosphorylation research in prokaryotes, this review navigates through the complex mechanisms of two-component sensory systems and their interplay with protein phosphorylation. Furthermore, it investigates the different feeding modes of cyanobacteria and highlights the complex interplay between photoautotrophy, environmental variables, and susceptibility to photo-inhibition. The significant elucidation of the regulatory role of protein phosphorylation in coordinating light harvesting with the acquisition of inorganic nutrients underscores its fundamental importance in the cyanobacterial physiology. This review highlights its novelty by synthesizing existing knowledge and proposing future research trajectories, thereby contributing to the deeper elucidation of cyanobacterial adaptation and metabolic regulation through protein phosphorylation.
Full article
Open AccessArticle
Insights into the Regulation of the Mitochondrial Inheritance and Trafficking Adaptor Protein Mmr1 in Saccharomyces cerevisiae
by
Nourah Nayef, Lakhan Ekal, Ewald H. Hettema and Kathryn R. Ayscough
Kinases Phosphatases 2024, 2(2), 190-208; https://doi.org/10.3390/kinasesphosphatases2020012 - 18 Jun 2024
Abstract
►▼
Show Figures
Mitochondria are organelles involved in cellular energetics in all eukaryotes, and changes in their dynamics, fission, fusion, or localization can lead to cell defects and disease in humans. Budding yeast, Saccharomyces cerevisiae, has been shown to be an effective model organism in
[...] Read more.
Mitochondria are organelles involved in cellular energetics in all eukaryotes, and changes in their dynamics, fission, fusion, or localization can lead to cell defects and disease in humans. Budding yeast, Saccharomyces cerevisiae, has been shown to be an effective model organism in elucidating mechanisms underpinning these mitochondrial processes. In the work presented here, a genetic screen was performed to identify overexpressing kinases, phosphatases, and ubiquitin ligases, which resulted in mitochondrial defects. A total of 33 overexpressed genes showed mitochondrial phenotypes but without severe growth defects. These included a subset that affected the timing of mitochondrial inheritance and were the focus of further study. Using cell and biochemical approaches, the roles of the PAK-family kinase Cla4 and the E3-ubiquitin ligases Dma1 and Dma2 were investigated. Previous studies have indicated the roles of kinase Cla4 and ligases Dma1 and Dma2 in triggering the degradation of trafficking adaptors in the bud, which leads to disruption of the interaction with the transporting class V myosin, Myo2. Here, we map a key interface between Cla4 and the mitochondrial adaptor Mmr1 necessary for phosphorylation and identify a region of Mmr1 required for its degradation via Dma1 and Dma2. Together, our data provide insights into key regulatory regions of Mmr1 responsible for its function in mitochondrial inheritance.
Full article
Figure 1
Open AccessReview
NT157 as an Anticancer Drug Candidate That Targets Kinase- and Phosphatase-Mediated Signaling
by
Keli Lima and João Agostinho Machado-Neto
Kinases Phosphatases 2024, 2(2), 179-189; https://doi.org/10.3390/kinasesphosphatases2020011 - 29 May 2024
Abstract
►▼
Show Figures
Cancer, characterized by uncontrolled cell growth and metastasis, represents a significant challenge to public health. The IGF1/IGF1R axis plays a pivotal role in tumor proliferation and survival, presenting an attractive target for intervention. NT157, a small molecule tyrphostin, has emerged as a promising
[...] Read more.
Cancer, characterized by uncontrolled cell growth and metastasis, represents a significant challenge to public health. The IGF1/IGF1R axis plays a pivotal role in tumor proliferation and survival, presenting an attractive target for intervention. NT157, a small molecule tyrphostin, has emerged as a promising inhibitor of this axis, displaying potent antineoplastic effects across various cancer types. This review synthesizes the literature on NT157’s mechanism of action and its impact on cellular processes in experimental cancer models. Initially identified for inducing the serine phosphorylation of IRS1 and IRS2, leading to their degradation and inhibiting the IGF1R signaling cascade, subsequent studies revealed additional targets of NT157, including STAT3, STAT5, and AXL, suggesting a multifaceted mechanism. Experimental evidence demonstrates that NT157 effectively suppresses tumor growth, metastasis, and angiogenesis in diverse cancer models. Additionally, NT157 enhances chemotherapy efficacy in combination therapy. Moreover, NT157 impacts not only tumor cells but also the tumor microenvironment, modulating inflammation and immune responses by targeting cancer-associated fibroblasts, myeloid cells, and immune cells, creating a suppressive milieu hindering tumor progression and metastasis. In conclusion, NT157 exhibits remarkable versatility in targeting multiple oncogenic pathways and hallmarks of cancer, underscoring its potential as a promising therapeutic agent.
Full article
Figure 1
Open AccessReview
Exogenous and Endogenous Molecules Potentially Proficient to Modulate Mitophagy in Cardiac Disorders
by
Moeka Nakashima, Naoko Suga and Satoru Matsuda
Kinases Phosphatases 2024, 2(2), 166-178; https://doi.org/10.3390/kinasesphosphatases2020010 - 23 May 2024
Abstract
It has been proposed that procedures which upregulate mitochondrial biogenesis and autophagy by replacing damaged mitochondria with healthy ones may prevent the development of several heart diseases. A member of serine and threonine kinases, adenosine monophosphate-activated protein kinase (AMPK), could play essential roles
[...] Read more.
It has been proposed that procedures which upregulate mitochondrial biogenesis and autophagy by replacing damaged mitochondria with healthy ones may prevent the development of several heart diseases. A member of serine and threonine kinases, adenosine monophosphate-activated protein kinase (AMPK), could play essential roles in the autophagy and/or mitophagy. AMPK is widely distributed in various cells, which might play diverse regulatory roles in different tissues and/or organs. In fact, changes in the kinase function of AMPK due to alteration of activity have been linked with diverse pathologies including cardiac disorders. AMPK can regulate mitochondrial biogenesis via peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) signaling and also improve oxidative mitochondrial metabolism through inhibition of mechanistic/mammalian target of rapamycin (mTOR) pathway, which may also modulate the autophagy/mitophagy through autophagy activating kinase 1 (ULK1) and/or transforming growth factor beta (TGF-β) signaling. Therefore, the modulation of AMPK in autophagy/mitophagy pathway might probably be thought as a therapeutic tactic for several cardiac disorders. As kinases are amongst the most controllable proteins, in general, the design of small molecules targeting kinases might be an eye-catching avenue to modulate cardiac function. Some analyses of the molecular biology underlying mitophagy suggest that nutraceuticals and/or drugs including specific AMPK modulator as well as physical exercise and/or dietary restriction that could modulate AMPK may be useful against several heart diseases. These observations may virtually be limited to preclinical studies. Come to think of these, however, it is speculated that some nutraceutical regimens might have positive potential for managing some of cardiac disorders.
Full article
(This article belongs to the Special Issue Human Protein Kinases: Development of Small-Molecule Therapies)
►▼
Show Figures
Figure 1
Open AccessReview
Cancer Stem Cell Metastatic Checkpoints and Glycosylation Patterns: Implications for Therapeutic Strategies
by
Sara Sadat Aghamiri and Rada Amin
Kinases Phosphatases 2024, 2(2), 151-165; https://doi.org/10.3390/kinasesphosphatases2020009 - 22 Apr 2024
Abstract
Cancer stem cells (CSCs), found within tumors, are powerful drivers of disease recurrence and metastasis. Their abilities to self-renew and maintain stem-like properties make treatment difficult, as their heterogeneity and metastatic properties can lead to resistance and limit the effectiveness of standard therapies.
[...] Read more.
Cancer stem cells (CSCs), found within tumors, are powerful drivers of disease recurrence and metastasis. Their abilities to self-renew and maintain stem-like properties make treatment difficult, as their heterogeneity and metastatic properties can lead to resistance and limit the effectiveness of standard therapies. Given their significance, CSCs are typically isolated based on combinations of markers, which often indicate heterogeneous populations of CSCs. The lack of consensus in cell characterization poses challenges in defining and targeting these cells for effective therapeutic interventions. In this review, we suggest five promising molecules—ABCB5, CD26, CD66c, uPAR, and Trop-2—chosen specifically for their distinct distribution within cancer types and clinical relevance. These markers, expressed at the cell surface of CSCs, could significantly enhance the specificity of cancer stemness characterization. This review focuses on describing their pivotal roles as biomarker checkpoints for metastasis. Additionally, this review outlines existing literature on glycosylation modifications, which present intriguing epitopes aimed at modulating the stability and function of these markers. Finally, we summarize several promising in vivo and clinical trial approaches targeting the mentioned surface markers, offering potential solutions to overcome the therapeutic resistance of CSCs and addressing current gaps in treatment strategies.
Full article
Open AccessArticle
Short-Chain Fatty Acids Suppress mTOR Signaling in Colon Cancer Cells via Long Non-Coding RNA RMST
by
Jiuhui Wang, Yande Guo, Xiangwei Fang, Yuanqin Zhang and Daotai Nie
Kinases Phosphatases 2024, 2(2), 136-150; https://doi.org/10.3390/kinasesphosphatases2020008 - 1 Apr 2024
Abstract
Short-chain fatty acids (SCFAs), derived from fermentation of dietary fibers and resistant starch by the microbiota in the colon, exert multiple effects on colonic functions, including tumor suppressing activities. Our previous studies found that SCFAs induced autophagy in colon cancer cells via downregulating
[...] Read more.
Short-chain fatty acids (SCFAs), derived from fermentation of dietary fibers and resistant starch by the microbiota in the colon, exert multiple effects on colonic functions, including tumor suppressing activities. Our previous studies found that SCFAs induced autophagy in colon cancer cells via downregulating mTOR signaling, but the mechanism involved in mTOR suppression still needs to be defined. In this study, we identified rhabdomyosarcoma 2 associated transcript (RMST), a long non-coding RNA, as a key mediator for SCFAs to suppress mTOR activation in colon cancer cells. RMST could be significantly induced by SCFAs in a time- and dose-dependent manner. RMST, by itself, was sufficient to suppress mTOR signaling and augment autophagosome formation. Depletion of RMST, through siRNA or CRISPR knockdown, reduced the abilities of SCFAs to suppress mTOR activation or to induce autophagic responses. RMST increased the expression level of TSC2, a negative regulator of the mTOR signaling pathway. Our data delineate a novel RMST/TSC2 cellular pathway, enlisted by SCFAs, to modulate mTOR activities in colon cancer cells.
Full article
(This article belongs to the Special Issue The PI3K Pathway in Human Disease from the Bench to the Clinic: There and Back Again)
►▼
Show Figures
Figure 1
Open AccessReview
CK2 Inhibitors Targeting Inside and Outside the Catalytic Box
by
Sophie Day-Riley, Rebekah M. West, Paul D. Brear, Marko Hyvönen and David R. Spring
Kinases Phosphatases 2024, 2(2), 110-135; https://doi.org/10.3390/kinasesphosphatases2020007 - 26 Mar 2024
Abstract
CK2 is a protein kinase that plays an important role in numerous cellular pathways involved in cell growth, differentiation, proliferation, and death. Consequently, upregulation of CK2 is implicated in many disease types, in particular cancer. As such, CK2 has gained significant attention as
[...] Read more.
CK2 is a protein kinase that plays an important role in numerous cellular pathways involved in cell growth, differentiation, proliferation, and death. Consequently, upregulation of CK2 is implicated in many disease types, in particular cancer. As such, CK2 has gained significant attention as a potential therapeutic target in cancer, and over 40 chemical probes targeting CK2 have been developed in the past decade. In this review, we highlighted several chemical probes that target sites outside the conventional ATP-binding site. These chemical probes belong to different classes of molecules, from small molecules to peptides, and possess different mechanisms of action. Many of the chemical probes discussed in this review could serve as promising new candidates for drugs selectively targeting CK2.
Full article
(This article belongs to the Special Issue Past, Present and Future of Protein Kinase CK2 Research)
►▼
Show Figures
Figure 1
Open AccessReview
The Importance of Kinases in Retinal Degenerative Diseases
by
Paulo F. Santos, António Francisco Ambrósio and Hélène Léger
Kinases Phosphatases 2024, 2(1), 93-109; https://doi.org/10.3390/kinasesphosphatases2010006 - 25 Feb 2024
Abstract
►▼
Show Figures
Kinases play crucial roles in the pathophysiology of retinal degenerative diseases. These diseases, such as diabetic retinopathy, age-related macular degeneration, glaucoma, and retinitis pigmentosa, are characterized by progressive degeneration of retinal cells, including photoreceptors, ganglion cells, vascular cells, and retinal pigment epithelium, among
[...] Read more.
Kinases play crucial roles in the pathophysiology of retinal degenerative diseases. These diseases, such as diabetic retinopathy, age-related macular degeneration, glaucoma, and retinitis pigmentosa, are characterized by progressive degeneration of retinal cells, including photoreceptors, ganglion cells, vascular cells, and retinal pigment epithelium, among others. The involvement of kinases in cell survival and apoptosis, immune responses and inflammation regulation, mitochondrial functions and mitophagy, autophagy, and proteostasis is crucial for maintaining cellular homeostasis and responding to various stressors. This review highlights the importance of studying kinases to better understand their functions and, regulation permitting, enable the identification of novel molecular players or potential drug targets and, consequently, the development of more effective and precise treatments to slow or halt the progression of retinal degenerative diseases.
Full article
Figure 1
Open AccessReview
Transglutaminase2: An Enduring Enzyme in Diabetes and Age-Related Metabolic Diseases
by
Neera Yadav and Sun-Yeou Kim
Kinases Phosphatases 2024, 2(1), 67-92; https://doi.org/10.3390/kinasesphosphatases2010005 - 21 Feb 2024
Abstract
►▼
Show Figures
Tissue transglutaminase2 (TG2) has emerged as a key enigmatic protein in the development of various metabolic and age-related diseases. It catalyzes covalent cross-linking of countless proteins and provides strength to the extracellular matrix and resistance to proteolytic degradation via different pathways, including NF-kβ,
[...] Read more.
Tissue transglutaminase2 (TG2) has emerged as a key enigmatic protein in the development of various metabolic and age-related diseases. It catalyzes covalent cross-linking of countless proteins and provides strength to the extracellular matrix and resistance to proteolytic degradation via different pathways, including NF-kβ, TGF-β and PI3K/Akt as the major signaling pathways. The etiology of diabetes and associated diseases has been found to be linked to unbalanced TG2 activity that may not only result in impaired or delayed wound healing in diabetics but also worsen degenerative and metabolic disease conditions. TG2 is usually overexpressed in diabetes, fibrosis, cancer, and neurodegenerative disorders. These TG2-linked diseases are usually associated with prolonged activation of inflammatory pathways. Therefore, reducing the inflammatory mechanisms and improving tissue remodeling appear to be the main treatment strategies to exterminate TG2-linked diseases. The present review aims to deliver a detailed overview of the existing understanding of TG2 in diabetes and associated diseases’ progression, as well as treatment strategies to regulate TG2 tightly and its potential clinical applications. Our research endorses the notion that TG2 can serve as an effective early-stage diagnostic biomarker for metabolic diseases and a therapeutic target for the development of potential drug.
Full article
Figure 1
Open AccessReview
Scoping Pleiotropy of CK2 in Musculoskeletal Disorders for a Novel Targeting Approach
by
Venu Pandit, Kailey DeGeorge and Anja Nohe
Kinases Phosphatases 2024, 2(1), 43-66; https://doi.org/10.3390/kinasesphosphatases2010004 - 31 Jan 2024
Abstract
Protein kinase CK2 (CK2) influences one-fifth of the cellular phosphoproteome. It regulates almost all cellular pathways and is thus a critical switch between biological processes within a cell. Inhibition of CK2 reverses oncogene addiction of tumor and alters tumor microenvironment. The success of
[...] Read more.
Protein kinase CK2 (CK2) influences one-fifth of the cellular phosphoproteome. It regulates almost all cellular pathways and is thus a critical switch between biological processes within a cell. Inhibition of CK2 reverses oncogene addiction of tumor and alters tumor microenvironment. The success of this strategy and its clinical translation opens new opportunities. Targeting CK2 in musculoskeletal disorders is promising. Clinical manifestations of these disorders include dysfunctional inflammation, dysregulated cell differentiation, and senescence. Processes regulated by CK2 include all of these. Its emerging role in senescence also indicates its function’s centrality in cellular metabolism. This review summarizes considerations for targeting CK2 in musculoskeletal disorders. We have discussed the implications of CK2-regulated processes in musculoskeletal disorders.
Full article
(This article belongs to the Special Issue Past, Present and Future of Protein Kinase CK2 Research)
►▼
Show Figures
Figure 1
Open AccessArticle
p38- and ERK-MAPK Signalling Modulate Developmental Neurotoxicity of Nickel and Vanadium in the Caenorhabditis elegans Model
by
Omamuyovwi M. Ijomone, Ann-Kathrin Weishaupt, Vivien Michaelis, Olayemi K. Ijomone and Julia Bornhorst
Kinases Phosphatases 2024, 2(1), 28-42; https://doi.org/10.3390/kinasesphosphatases2010003 - 4 Jan 2024
Abstract
►▼
Show Figures
Nickel (Ni) and vanadium (V) are characteristic heavy metal constituents of many crude oil blends in Sub-Saharan Africa, and we have previously demonstrated their neurotoxic impact. However, molecular mechanisms driving Ni and V neurotoxicity are still being elucidated. The p38- and ERKs-MAPK pathways,
[...] Read more.
Nickel (Ni) and vanadium (V) are characteristic heavy metal constituents of many crude oil blends in Sub-Saharan Africa, and we have previously demonstrated their neurotoxic impact. However, molecular mechanisms driving Ni and V neurotoxicity are still being elucidated. The p38- and ERKs-MAPK pathways, which are mostly known for their involvement in human immune and inflammatory signalling, have been shown to influence an array of neurodevelopmental processes. In the present study, we attempt to elucidate the role of p38- and ERK-MAPK in neurotoxicity after early life exposures to Ni and V using the Caenorhabditis elegans model. Synchronized larvae stage-1 (L1) worms were treated with varying concentrations of Ni and V singly or in combination for 1 h. Our results show Ni induces lethality in C. elegans even at very low concentrations, while much higher V concentrations are required to induce lethality. Furthermore, we identified that loss-of-function of pmk-1 and pmk-3, which are both homologous to human p38-α (MAPK14), is differentially affected by Ni and V exposures. Also, all exposure scenarios triggered significant developmental delays in both wild-type and mutant strains. We also see increased mitochondrial-derived reactive oxygen species following Ni and V exposures in wild-type worms with differential responses in the mutant strains. Additionally, we observed alterations in dopamine and serotonin levels after metal exposures, particularly in the pmk-1 strain. In conclusion, both Ni and V induce lethality, developmental delays, and mitochondrial-derived ROS in worms, with V requiring a much higher concentration. Further, the results suggest the p38- and ERK-MAPK signalling pathways may modulate Ni and V neurodevelopmental toxicity, potentially affecting mitochondrial health, metal bioavailability, and neurotransmitter levels.
Full article
Figure 1
Open AccessReview
The Yin and Yang of IκB Kinases in Cancer
by
Abdalla M. Abdrabou
Kinases Phosphatases 2024, 2(1), 9-27; https://doi.org/10.3390/kinasesphosphatases2010002 - 31 Dec 2023
Abstract
IκB kinases (IKKs), specifically IKKα and IKKβ, have long been recognized for their pivotal role in the NF-κB pathway, orchestrating immune and inflammatory responses. However, recent years have unveiled their dual role in cancer, where they can act as both promoters and suppressors
[...] Read more.
IκB kinases (IKKs), specifically IKKα and IKKβ, have long been recognized for their pivotal role in the NF-κB pathway, orchestrating immune and inflammatory responses. However, recent years have unveiled their dual role in cancer, where they can act as both promoters and suppressors of tumorigenesis. In addition, the interplay with pathways such as the MAPK and PI3K pathways underscores the complexity of IKK regulation and its multifaceted role in both inflammation and cancer. By exploring the molecular underpinnings of these processes, we can better comprehend the complex interplay between IKKs, tumor development, immune responses, and the development of more effective therapeutics. Ultimately, this review explores the dual role of IκB kinases in cancer, focusing on the impact of phosphorylation events and crosstalk with other signaling pathways, shedding light on their intricate regulation and multifaceted functions in both inflammation and cancer.
Full article
(This article belongs to the Special Issue Human Protein Kinases: Development of Small-Molecule Therapies)
►▼
Show Figures
Figure 1
Open AccessBrief Report
The CK2/ECE1c Partnership: An Unveiled Pathway to Aggressiveness in Cancer
by
Karla Villalobos-Nova, María de los Ángeles Toro, Pablo Pérez-Moreno, Ignacio Niechi and Julio C. Tapia
Kinases Phosphatases 2024, 2(1), 1-8; https://doi.org/10.3390/kinasesphosphatases2010001 - 19 Dec 2023
Abstract
The endothelin-1 (ET1) peptide has a pathological role in the activation of proliferation, survival and invasiveness pathways in different cancers. ET1’s effects rely on its activation by the endothelin-converting enzyme-1 (ECE1), which is expressed as four isoforms, differing only in their cytoplasmic N-terminuses.
[...] Read more.
The endothelin-1 (ET1) peptide has a pathological role in the activation of proliferation, survival and invasiveness pathways in different cancers. ET1’s effects rely on its activation by the endothelin-converting enzyme-1 (ECE1), which is expressed as four isoforms, differing only in their cytoplasmic N-terminuses. We already demonstrated in colorectal cancer, glioblastoma, and preliminarily lung cancer, that the isoform ECE1c heightens aggressiveness by promoting cancer stem cell traits. This is achieved through a non-canonical ET1-independent mechanism of enhancement of ECE1c’s stability upon CK2-dependent phosphorylation at S18 and S20. Here, a K6 residue is presumably responsible for ECE1c ubiquitination as its mutation to R impairs proteasomal degradation. However, how phosphorylation enhances ECE1c’s stability and how this translates into aggressiveness are still open questions. In this brief report, by swapping residues to either phospho-mimetic or phospho-resistant amino acids, we propose that the N-terminus may also be phosphorylated at Y5 and/or T9 by an unknown kinase(s). In addition, N-terminus phosphorylation may lead to a blockage of K6 ubiquitination, increasing ECE1c’s stability and presumably activating the Wnt/β-catenin signaling pathway. Thus, a novel CK2/ECE1c partnership may be emerging to promote aggressiveness and thus become a biomarker of poor prognosis and a potential therapeutic target for several cancers.
Full article
(This article belongs to the Special Issue Past, Present and Future of Protein Kinase CK2 Research)
►▼
Show Figures
Graphical abstract
Open AccessArticle
Discovery and Exploration of Protein Kinase CK2 Binding Sites Using CK2α′Cys336Ser as an Exquisite Crystallographic Tool
by
Christian Werner, Dirk Lindenblatt, Kaido Viht, Asko Uri and Karsten Niefind
Kinases Phosphatases 2023, 1(4), 306-322; https://doi.org/10.3390/kinasesphosphatases1040018 - 25 Nov 2023
Cited by 1
Abstract
The structural knowledge about protein kinase CK2 is dominated by crystal structures of human CK2α, the catalytic subunit of human CK2, and the product of the CSNK2A1 gene. In contrast, far fewer structures of CK2α′, its paralogous isoform and the product of the
[...] Read more.
The structural knowledge about protein kinase CK2 is dominated by crystal structures of human CK2α, the catalytic subunit of human CK2, and the product of the CSNK2A1 gene. In contrast, far fewer structures of CK2α′, its paralogous isoform and the product of the CSNK2A2 gene, have been published. However, according to a PDB survey, CK2α′ is the superior alternative for crystallographic studies because of the inherent potential of the single mutant CK2α′Cys336Ser to provide crystal structures with atomic resolution. In particular, a triclinic crystal form of CK2α′Cys336Ser is a robust tool to determine high-quality enzyme-ligand complex structures via soaking. In this work, further high-resolution CK2α′Cys336Ser structures in complex with selected ligands emphasizing this trend are described. In one of these structures, the “N-terminal segment site”, a small-molecule binding region never found in any eukaryotic protein kinase and holding the potential for the development of highly selective substrate-competitive CK2 inhibitors, was discovered. In order to also address the binding site for the non-catalytic subunit CK2β, which is inaccessible in these triclinic CK2α′Cys336Ser crystals for small molecules, a reliable path to a promising monoclinic crystal form of CK2α′Cys336Ser is presented. In summary, the quality of CK2α′Cys336Ser as an exquisite crystallographic tool is solidified.
Full article
(This article belongs to the Special Issue Past, Present and Future of Protein Kinase CK2 Research)
►▼
Show Figures
Figure 1
Open AccessReview
CK2 Chemical Probes: Past, Present, and Future
by
Han Wee Ong, David H. Drewry and Alison D. Axtman
Kinases Phosphatases 2023, 1(4), 288-305; https://doi.org/10.3390/kinasesphosphatases1040017 - 1 Nov 2023
Cited by 1
Abstract
Protein kinase casein kinase 2 (CK2/CSNK2) is a pleiotropic kinase involved in many cellular processes and, accordingly, has been identified as a potential target for therapeutic intervention for multiple indications. Significant research effort has been invested into identifying CK2 inhibitors as potential drug
[...] Read more.
Protein kinase casein kinase 2 (CK2/CSNK2) is a pleiotropic kinase involved in many cellular processes and, accordingly, has been identified as a potential target for therapeutic intervention for multiple indications. Significant research effort has been invested into identifying CK2 inhibitors as potential drug candidates and potent and selective CK2 chemical probes to interrogate CK2 function. Here, we review the small molecule inhibitors reported for CK2 and discuss various orthosteric, allosteric, and bivalent inhibitors of CK2. We focus on the pyrazolo[1,5-a]pyrimidines and naphthyridines, two chemotypes that have been extensively explored for chemical probe development. We highlight the uptake and demonstrated utility of the pyrazolo[1,5-a]pyrimidine chemical probe SGC-CK2-1 by the scientific community in cellular studies. Finally, we propose criteria for an ideal in vivo chemical probe for investigating CK2 function in a living organism. While no compound currently meets these metrics, we discuss ongoing and future directions in the development of in vivo chemical probes for CK2.
Full article
(This article belongs to the Special Issue Past, Present and Future of Protein Kinase CK2 Research)
►▼
Show Figures
Figure 1
Open AccessReview
Interaction Networks Explain Holoenzyme Allostery in Protein Kinase A
by
Colin L. Welsh, Abigail E. Conklin and Lalima K. Madan
Kinases Phosphatases 2023, 1(4), 265-287; https://doi.org/10.3390/kinasesphosphatases1040016 - 31 Oct 2023
Abstract
Protein kinase A (PKA) signaling exemplifies phosphorylation-based signaling as we understand it today. Its catalytic-subunit structure and dynamics continue to advance our understanding of kinase mechanics as the first protein kinase catalytic domain to be identified, sequenced, cloned, and structurally detailed. The PKA
[...] Read more.
Protein kinase A (PKA) signaling exemplifies phosphorylation-based signaling as we understand it today. Its catalytic-subunit structure and dynamics continue to advance our understanding of kinase mechanics as the first protein kinase catalytic domain to be identified, sequenced, cloned, and structurally detailed. The PKA holoenzyme elaborates on the role of its regulatory subunits and maintains our understanding of cAMP-dependent cellular signaling. The activation of PKA holoenzymes by cAMP is an example of specialized protein allostery, emphasizing the relevance of protein binding interfaces, unstructured regions, isoform diversity, and dynamics-based allostery. This review provides the most up-to-date overview of PKA structure and function, including a description of the catalytic and regulatory subunits’ structures. In addition, the structure, activation, and allostery of holoenzymes are covered.
Full article
(This article belongs to the Special Issue Human Protein Kinases: Development of Small-Molecule Therapies)
►▼
Show Figures
Figure 1
Open AccessReview
Exploring Protein Kinase CK2 Substrate Recognition and the Dynamic Response of Substrate Phosphorylation to Kinase Modulation
by
Luca Cesaro, Angelica Maria Zuliani, Valentina Bosello Travain and Mauro Salvi
Kinases Phosphatases 2023, 1(4), 251-264; https://doi.org/10.3390/kinasesphosphatases1040015 - 7 Oct 2023
Abstract
Protein kinase CK2 (formerly known as casein kinase 2 or II), a ubiquitous and constitutively active enzyme, is widely recognized as one of the most pleiotropic serine/threonine kinases. It plays a critical role in numerous signaling pathways, with hundreds of bona fide substrates.
[...] Read more.
Protein kinase CK2 (formerly known as casein kinase 2 or II), a ubiquitous and constitutively active enzyme, is widely recognized as one of the most pleiotropic serine/threonine kinases. It plays a critical role in numerous signaling pathways, with hundreds of bona fide substrates. However, despite considerable research efforts, our understanding of the entire CK2 substratome and its functional associations with the majority of these substrates is far from being completely deciphered. In this context, we aim to provide an overview of how CK2 recognizes its substrates. We will discuss the pros and cons of the existing methods to manipulate CK2 activity in cells, as well as exploring the dynamic response of substrate phosphorylation to CK2 modulation.
Full article
(This article belongs to the Special Issue Past, Present and Future of Protein Kinase CK2 Research)
►▼
Show Figures
Figure 1
Open AccessArticle
Receptor Tyrosine Kinase KIT: Mutation-Induced Conformational Shift Promotes Alternative Allosteric Pockets
by
Julie Ledoux, Marina Botnari and Luba Tchertanov
Kinases Phosphatases 2023, 1(4), 220-250; https://doi.org/10.3390/kinasesphosphatases1040014 - 25 Sep 2023
Abstract
Receptor tyrosine kinase (RTK) KIT is key regulator of cellular signalling, and its deregulation contributes to the development and progression of many serious diseases. Several mutations lead to the constitutive activation of the cytoplasmic domain of KIT, causing the aberrant intracellular signalling observed
[...] Read more.
Receptor tyrosine kinase (RTK) KIT is key regulator of cellular signalling, and its deregulation contributes to the development and progression of many serious diseases. Several mutations lead to the constitutive activation of the cytoplasmic domain of KIT, causing the aberrant intracellular signalling observed in malignant tumours. Elucidating the molecular basis of mutation-induced effects at the atomistic level is absolutely required. We report the first dynamic 3D model (DYNASOME) of the full-length cytoplasmic domain of the oncogenic mutant KITD816V generated through unbiased long-timescale MD simulations under conditions mimicking the natural environment of KIT. The comparison of the structural and dynamical properties of multidomain KITD816V with those of wild type KIT (KITWT) allowed us to evaluate the impact of the D816V mutation on each protein domain, including multifunctional well-ordered and intrinsically disordered (ID) regions. The two proteins were compared in terms of free energy landscape and intramolecular coupling. The increased intrinsic disorder and gain of coupling within each domain and between distant domains in KITD816V demonstrate its inherent self-regulated constitutive activation. The search for pockets revealed novel allosteric pockets (POCKETOME) in each protein, KITD816V and KITWT. These pockets open an avenue for the development of new highly selective allosteric modulators specific to KITD816V.
Full article
(This article belongs to the Special Issue Regulation of Protein Kinase Activities and Associated Protein Structure Prediction Applied to Drug Discovery)
►▼
Show Figures
Figure 1
Open AccessReview
Overview of Capillary Electrophoresis Analysis of Alkaline Phosphatase (ALP) with Emphasis on Post-Translational Modifications (PTMs)
by
Thanih Balbaied and Eric Moore
Kinases Phosphatases 2023, 1(3), 206-219; https://doi.org/10.3390/kinasesphosphatases1030013 - 15 Sep 2023
Abstract
►▼
Show Figures
Alkaline phosphatase is a vital enzyme used in separation studies and as a biomarker for liver, bone, and certain cancer conditions. Its stability and specific properties enable insights into enzyme behavior, aiding in the development of detection methods with broader applications in various
[...] Read more.
Alkaline phosphatase is a vital enzyme used in separation studies and as a biomarker for liver, bone, and certain cancer conditions. Its stability and specific properties enable insights into enzyme behavior, aiding in the development of detection methods with broader applications in various scientific fields. Alkaline phosphatase has four main isoenzymes: GCAP, IAP, PLAP, and TNAP, each with distinct roles. TNAP is found in the liver, kidney, and bones, playing a role in bone mineralization. The functions of the other isoenzymes are not fully known. Separation techniques like electrophoresis and chromatography are valuable for studying enzymes and proteins, revealing insights into their structure and function in pharmaceutical research and PTM studies. The main goal of this review paper is to thoroughly evaluate how capillary electrophoresis is applied to analyze alkaline phosphatase. It seeks to investigate the latest advancements in capillary electrophoresis and how they can improve the sensitivity, selectivity, and efficiency of alkaline phosphatase analysis.
Full article
Figure 1
Open AccessReview
From Kinases to Diseases: Investigating the Role of AMPK in Human Pathologies
by
Verónica Rey and Isaac Tamargo-Gómez
Kinases Phosphatases 2023, 1(3), 181-205; https://doi.org/10.3390/kinasesphosphatases1030012 - 1 Aug 2023
Cited by 4
Abstract
►▼
Show Figures
Adenosine Monophosphate-Activated Protein Kinase (AMPK) is the major conserved regulator of cellular metabolism in eukaryotic cells, from yeast to mammals. Given its pivotal role, it is not surprising that alterations in its function may contribute to the pathogenesis of numerous human diseases. Indeed,
[...] Read more.
Adenosine Monophosphate-Activated Protein Kinase (AMPK) is the major conserved regulator of cellular metabolism in eukaryotic cells, from yeast to mammals. Given its pivotal role, it is not surprising that alterations in its function may contribute to the pathogenesis of numerous human diseases. Indeed, AMPK has become a promising therapeutic target for several pathologies. In this context, significant efforts have been dedicated to discovering new pharmacological agents capable of activating AMPK based on next-generation sequencing (NGS) technology and personalized medicine. Thanks to computational methodologies and high-throughput screening, the identification of small molecules and compounds with the potential to directly activate AMPK or modulate its intricate signaling network has become viable. However, the most widely used drug to activate AMPK in human patients is still metformin, which has shown promising results in the treatment of various diseases, such as type II diabetes, atherosclerosis, Alzheimer’s disease, Huntington’s disease, and several types of cancer. In this review, we present a comprehensive analysis of the involvement of AMPK in human pathology, emphasizing its significant potential as a therapeutic target.
Full article
Figure 1
Highly Accessed Articles
Latest Books
E-Mail Alert
News
Topics
Conferences
Special Issues
Special Issue in
Kinases and Phosphatases
Human Protein Kinases: Development of Small-Molecule Therapies
Guest Editor: Alison D. AxtmanDeadline: 30 July 2024
Special Issue in
Kinases and Phosphatases
The Role of Kinases in Ocular Diseases
Guest Editor: Paulo SantosDeadline: 30 September 2024
Special Issue in
Kinases and Phosphatases
Inhibitors for Alkaline Phosphatase
Guest Editor: Hussain RazaDeadline: 31 October 2024