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":"5 3","pages":""},"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":"120 ","pages":""},"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。
{"title":"p38- and ERK-MAPK Signalling Modulate Developmental Neurotoxicity of Nickel and Vanadium in the Caenorhabditis elegans Model","authors":"O. Ijomone, Annie Weishaupt, Vivien Michaelis, O. Ijomone, J. Bornhorst","doi":"10.3390/kinasesphosphatases2010003","DOIUrl":"https://doi.org/10.3390/kinasesphosphatases2010003","url":null,"abstract":"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.","PeriodicalId":74042,"journal":{"name":"Kinases and phosphatases","volume":"66 9","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139386165","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 : 2023-12-31DOI: 10.3390/kinasesphosphatases2010002
Abdalla M. Abdrabou
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.
{"title":"The Yin and Yang of IκB Kinases in Cancer","authors":"Abdalla M. Abdrabou","doi":"10.3390/kinasesphosphatases2010002","DOIUrl":"https://doi.org/10.3390/kinasesphosphatases2010002","url":null,"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 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.","PeriodicalId":74042,"journal":{"name":"Kinases and phosphatases","volume":"5 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139135908","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 : 2023-12-19DOI: 10.3390/kinasesphosphatases2010001
Karla Villalobos-Nova, M. A. Toro, Pablo Pérez-Moreno, Ignacio Niechi, Julio C. Tapia
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.
{"title":"The CK2/ECE1c Partnership: An Unveiled Pathway to Aggressiveness in Cancer","authors":"Karla Villalobos-Nova, M. A. Toro, Pablo Pérez-Moreno, Ignacio Niechi, Julio C. Tapia","doi":"10.3390/kinasesphosphatases2010001","DOIUrl":"https://doi.org/10.3390/kinasesphosphatases2010001","url":null,"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. 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.","PeriodicalId":74042,"journal":{"name":"Kinases and phosphatases","volume":"117 15","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138959636","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 : 2023-11-25DOI: 10.3390/kinasesphosphatases1040018
Christian Werner, D. Lindenblatt, Kaido Viht, A. Uri, K. Niefind
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.
{"title":"Discovery and Exploration of Protein Kinase CK2 Binding Sites Using CK2α′Cys336Ser as an Exquisite Crystallographic Tool","authors":"Christian Werner, D. Lindenblatt, Kaido Viht, A. Uri, K. Niefind","doi":"10.3390/kinasesphosphatases1040018","DOIUrl":"https://doi.org/10.3390/kinasesphosphatases1040018","url":null,"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 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.","PeriodicalId":74042,"journal":{"name":"Kinases and phosphatases","volume":"25 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139237585","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 : 2023-11-01DOI: 10.3390/kinasesphosphatases1040017
Han Wee Ong, David H. Drewry, Alison D. Axtman
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.
{"title":"CK2 Chemical Probes: Past, Present, and Future","authors":"Han Wee Ong, David H. Drewry, Alison D. Axtman","doi":"10.3390/kinasesphosphatases1040017","DOIUrl":"https://doi.org/10.3390/kinasesphosphatases1040017","url":null,"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 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.","PeriodicalId":74042,"journal":{"name":"Kinases and phosphatases","volume":"287 3","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135321185","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 : 2023-10-31DOI: 10.3390/kinasesphosphatases1040016
Colin L. Welsh, Abigail E. Conklin, Lalima K. Madan
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.
{"title":"Interaction Networks Explain Holoenzyme Allostery in Protein Kinase A","authors":"Colin L. Welsh, Abigail E. Conklin, Lalima K. Madan","doi":"10.3390/kinasesphosphatases1040016","DOIUrl":"https://doi.org/10.3390/kinasesphosphatases1040016","url":null,"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 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.","PeriodicalId":74042,"journal":{"name":"Kinases and phosphatases","volume":"206 ","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135872463","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 : 2023-10-07DOI: 10.3390/kinasesphosphatases1040015
Luca Cesaro, Angelica Maria Zuliani, Valentina Bosello Travain, Mauro Salvi
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.
{"title":"Exploring Protein Kinase CK2 Substrate Recognition and the Dynamic Response of Substrate Phosphorylation to Kinase Modulation","authors":"Luca Cesaro, Angelica Maria Zuliani, Valentina Bosello Travain, Mauro Salvi","doi":"10.3390/kinasesphosphatases1040015","DOIUrl":"https://doi.org/10.3390/kinasesphosphatases1040015","url":null,"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. 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.","PeriodicalId":74042,"journal":{"name":"Kinases and phosphatases","volume":"47 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135301082","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 : 2023-09-25DOI: 10.3390/kinasesphosphatases1040014
Julie Ledoux, Marina Botnari, Luba Tchertanov
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.
{"title":"Receptor Tyrosine Kinase KIT: Mutation-Induced Conformational Shift Promotes Alternative Allosteric Pockets","authors":"Julie Ledoux, Marina Botnari, Luba Tchertanov","doi":"10.3390/kinasesphosphatases1040014","DOIUrl":"https://doi.org/10.3390/kinasesphosphatases1040014","url":null,"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 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.","PeriodicalId":74042,"journal":{"name":"Kinases and phosphatases","volume":"66 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135863455","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}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：