Pub Date : 2024-07-25DOI: 10.3390/kinasesphosphatases2030015
R. Valverde, Jennifer Lowe
Copper is an essential heavy metal for diverse biological functions but toxic in excess. Consequently, a tightly regulated protein system is required to ensure adequate intracellular levels. In recent decades, several studies have explored the role of Cu+-ATPases in copper transport and homeostasis, revealing that these proteins are subject to kinase-mediated phosphorylation that significantly impacts their function. Techniques such as phosphoproteomic screening, site-directed mutagenesis, and artificial neural network tools demonstrated the regulatory effect of phosphorylation on these ATPases. Different protein kinases regulate Cu+-ATPases, modulating the active copper transport by affecting specific steps of the catalytic cycle, long-range intramolecular crosstalks, protein trafficking, gene expression, and protein stability. Therefore, the regulatory phosphorylation of Cu+-ATPases by kinases ultimately influences the intracellular copper distribution. This study aims to present a review of the scientific literature on the regulation of Cu+-ATPases by kinase-mediated phosphorylation as a crucial mechanism for copper homeostasis. This regulation offers new perspectives for developing therapies for disorders related to copper metabolism, such as Wilson and Menkes diseases, as well as cancer, diabetes mellitus, Parkinson’s, and Alzheimer’s diseases. These findings emphasize the need to further comprehend the signaling pathways involving protein kinases in the context of copper regulation.
{"title":"Protein Kinases in Copper Homeostasis: A Review on Cu+-ATPase Modulation","authors":"R. Valverde, Jennifer Lowe","doi":"10.3390/kinasesphosphatases2030015","DOIUrl":"https://doi.org/10.3390/kinasesphosphatases2030015","url":null,"abstract":"Copper is an essential heavy metal for diverse biological functions but toxic in excess. Consequently, a tightly regulated protein system is required to ensure adequate intracellular levels. In recent decades, several studies have explored the role of Cu+-ATPases in copper transport and homeostasis, revealing that these proteins are subject to kinase-mediated phosphorylation that significantly impacts their function. Techniques such as phosphoproteomic screening, site-directed mutagenesis, and artificial neural network tools demonstrated the regulatory effect of phosphorylation on these ATPases. Different protein kinases regulate Cu+-ATPases, modulating the active copper transport by affecting specific steps of the catalytic cycle, long-range intramolecular crosstalks, protein trafficking, gene expression, and protein stability. Therefore, the regulatory phosphorylation of Cu+-ATPases by kinases ultimately influences the intracellular copper distribution. This study aims to present a review of the scientific literature on the regulation of Cu+-ATPases by kinase-mediated phosphorylation as a crucial mechanism for copper homeostasis. This regulation offers new perspectives for developing therapies for disorders related to copper metabolism, such as Wilson and Menkes diseases, as well as cancer, diabetes mellitus, Parkinson’s, and Alzheimer’s diseases. These findings emphasize the need to further comprehend the signaling pathways involving protein kinases in the context of copper regulation.","PeriodicalId":74042,"journal":{"name":"Kinases and phosphatases","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141805455","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The phosphorylation state of 20 types of intracellular proteins in the presence of the protein phosphatase 1 (PP1)- and PP2A-specific Ser/Thr phosphatase inhibitor calyculin A or the Tyr phosphatase inhibitor pervanadate was visualized by Phos-tag SDS-PAGE followed by immunoblotting. All blots showed a Phos-tag pattern indicating increased phosphorylation in the presence of one or both phosphatase inhibitors. The increase in phosphorylation stoichiometry per protein tends to be greater for Ser/Thr phosphatase inhibition than for Tyr phosphatase inhibition. This is consistent with the fact that the number of Ser/Thr kinase genes in the human genome is greater than that of Tyr kinases and with the fact that the phospho-Ser/phospho-Thr ratio in the actual human phosphoproteome is far greater than that of phospho-Tyr ratio. This suggests that cellular proteins are routinely and randomly phosphorylated by different kinases with no biological significance, simply depending on the frequency of substrate encounters. Phosphatase is responsible for routinely removing these unwanted phosphate groups systematically and maintaining the dynamic equilibrium of physiological protein phosphorylation. Phos-tag SDS-PAGE visualized that the kinase reaction involves many incidental phosphorylation and that phosphatases play broader roles besides being strict counterparts to kinases.
{"title":"Dynamic Equilibrium of Protein Phosphorylation by Kinases and Phosphatases Visualized by Phos-Tag SDS-PAGE","authors":"Emiko Kinoshita-Kikuta, Kento Nishikawa, Kento Hiraishi, Kaku Shimoji, Kenichi Nagase, Eiji Kinoshita","doi":"10.3390/kinasesphosphatases2030014","DOIUrl":"https://doi.org/10.3390/kinasesphosphatases2030014","url":null,"abstract":"The phosphorylation state of 20 types of intracellular proteins in the presence of the protein phosphatase 1 (PP1)- and PP2A-specific Ser/Thr phosphatase inhibitor calyculin A or the Tyr phosphatase inhibitor pervanadate was visualized by Phos-tag SDS-PAGE followed by immunoblotting. All blots showed a Phos-tag pattern indicating increased phosphorylation in the presence of one or both phosphatase inhibitors. The increase in phosphorylation stoichiometry per protein tends to be greater for Ser/Thr phosphatase inhibition than for Tyr phosphatase inhibition. This is consistent with the fact that the number of Ser/Thr kinase genes in the human genome is greater than that of Tyr kinases and with the fact that the phospho-Ser/phospho-Thr ratio in the actual human phosphoproteome is far greater than that of phospho-Tyr ratio. This suggests that cellular proteins are routinely and randomly phosphorylated by different kinases with no biological significance, simply depending on the frequency of substrate encounters. Phosphatase is responsible for routinely removing these unwanted phosphate groups systematically and maintaining the dynamic equilibrium of physiological protein phosphorylation. Phos-tag SDS-PAGE visualized that the kinase reaction involves many incidental phosphorylation and that phosphatases play broader roles besides being strict counterparts to kinases.","PeriodicalId":74042,"journal":{"name":"Kinases and phosphatases","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141821889","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-23DOI: 10.3390/kinasesphosphatases2020010
Moeka Nakashima, Naoko Suga, Satoru Matsuda
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.
{"title":"Exogenous and Endogenous Molecules Potentially Proficient to Modulate Mitophagy in Cardiac Disorders","authors":"Moeka Nakashima, Naoko Suga, Satoru Matsuda","doi":"10.3390/kinasesphosphatases2020010","DOIUrl":"https://doi.org/10.3390/kinasesphosphatases2020010","url":null,"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 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.","PeriodicalId":74042,"journal":{"name":"Kinases and phosphatases","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141105426","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-22DOI: 10.3390/kinasesphosphatases2020009
S. Aghamiri, Rada Amin
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.
{"title":"Cancer Stem Cell Metastatic Checkpoints and Glycosylation Patterns: Implications for Therapeutic Strategies","authors":"S. Aghamiri, Rada Amin","doi":"10.3390/kinasesphosphatases2020009","DOIUrl":"https://doi.org/10.3390/kinasesphosphatases2020009","url":null,"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. 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.","PeriodicalId":74042,"journal":{"name":"Kinases and phosphatases","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140676263","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-01DOI: 10.3390/kinasesphosphatases2020008
Jiuhui Wang, Yande Guo, Xiangwei Fang, Yuanqin Zhang, D. Nie
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.
{"title":"Short-Chain Fatty Acids Suppress mTOR Signaling in Colon Cancer Cells via Long Non-Coding RNA RMST","authors":"Jiuhui Wang, Yande Guo, Xiangwei Fang, Yuanqin Zhang, D. Nie","doi":"10.3390/kinasesphosphatases2020008","DOIUrl":"https://doi.org/10.3390/kinasesphosphatases2020008","url":null,"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 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.","PeriodicalId":74042,"journal":{"name":"Kinases and phosphatases","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140771714","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-26DOI: 10.3390/kinasesphosphatases2020007
Sophie Day-Riley, Rebekah M. West, P. Brear, M. Hyvönen, D. Spring
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.
{"title":"CK2 Inhibitors Targeting Inside and Outside the Catalytic Box","authors":"Sophie Day-Riley, Rebekah M. West, P. Brear, M. Hyvönen, D. Spring","doi":"10.3390/kinasesphosphatases2020007","DOIUrl":"https://doi.org/10.3390/kinasesphosphatases2020007","url":null,"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 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.","PeriodicalId":74042,"journal":{"name":"Kinases and phosphatases","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140378420","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-25DOI: 10.3390/kinasesphosphatases2010006
P. F. Santos, António Francisco Ambrósio, Hélène Léger
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.
{"title":"The Importance of Kinases in Retinal Degenerative Diseases","authors":"P. F. Santos, António Francisco Ambrósio, Hélène Léger","doi":"10.3390/kinasesphosphatases2010006","DOIUrl":"https://doi.org/10.3390/kinasesphosphatases2010006","url":null,"abstract":"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.","PeriodicalId":74042,"journal":{"name":"Kinases and phosphatases","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140432543","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-21DOI: 10.3390/kinasesphosphatases2010005
Neera Yadav, Sun-Yeou Kim
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.
{"title":"Transglutaminase2: An Enduring Enzyme in Diabetes and Age-Related Metabolic Diseases","authors":"Neera Yadav, Sun-Yeou Kim","doi":"10.3390/kinasesphosphatases2010005","DOIUrl":"https://doi.org/10.3390/kinasesphosphatases2010005","url":null,"abstract":"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.","PeriodicalId":74042,"journal":{"name":"Kinases and phosphatases","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140445230","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-31DOI: 10.3390/kinasesphosphatases2010004
Venu Pandit, Kailey DeGeorge, Anja Nohe
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.
{"title":"Scoping Pleiotropy of CK2 in Musculoskeletal Disorders for a Novel Targeting Approach","authors":"Venu Pandit, Kailey DeGeorge, Anja Nohe","doi":"10.3390/kinasesphosphatases2010004","DOIUrl":"https://doi.org/10.3390/kinasesphosphatases2010004","url":null,"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 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.","PeriodicalId":74042,"journal":{"name":"Kinases and phosphatases","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140478809","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-04DOI: 10.3390/kinasesphosphatases2010003
O. Ijomone, Annie Weishaupt, Vivien Michaelis, O. Ijomone, J. Bornhorst
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.
镍（Ni）和钒（V）是撒哈拉以南非洲地区许多原油混合物的特征性重金属成分，我们之前已经证明了它们对神经的毒性影响。然而，驱动镍和钒神经毒性的分子机制仍有待阐明。p38- 和 ERKs-MAPK 通路因参与人类免疫和炎症信号传导而广为人知，但它们已被证明会影响一系列神经发育过程。在本研究中，我们试图利用秀丽隐杆线虫模型来阐明 p38- 和 ERK-MAPK 在早期暴露于镍和钒后的神经毒性中的作用。我们的研究结果表明，即使在很低的浓度下，镍也会诱导 elegans 死亡，而诱导死亡所需的 V 浓度则要高得多。此外，我们还发现 pmk-1 和 pmk-3（均与人类 p38-α (MAPK14)同源）的功能缺失会受到镍和钒暴露的不同影响。此外，所有暴露情况都会导致野生型和突变型菌株出现明显的发育迟缓。我们还发现，野生型蠕虫暴露于镍和钒后，线粒体衍生的活性氧增加，而突变株的反应则不同。此外，我们还观察到金属暴露后多巴胺和血清素水平的变化，尤其是在 pmk-1 株系中。总之，镍和钒都会诱导蠕虫致死、发育迟缓和线粒体衍生的 ROS，其中钒需要更高的浓度。此外，研究结果表明，p38 和 ERK-MAPK 信号通路可能会调节 Ni 和 V 的神经发育毒性，从而可能影响线粒体健康、金属生物利用率和神经递质水平。
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