Pub Date : 2023-07-03DOI: 10.3390/kinasesphosphatases1030010
A. Hemmerlin
The recycling of metabolic products is a major way to reduce the energy cost of de novo biosynthesis. The salvage pathways involved not only regain a metabolic product but also generate additional molecules that might serve specific physiological, developmental and/or defensive functions. The isoprenoid pathway is a perfect example of a fine-regulated biosynthetic pathway, by virtue of the large number of molecules with different functions that must be synthesized simultaneously. Additionally, isoprenoid salvage pathways have been characterized. Thus, to produce isoprenoid precursors such as farnesyl diphosphate or phytyl diphosphate, short-chain isoprenols recovered from end-chain metabolites are phosphorylated. In the first instance, the so-called FPP-salvage machinery recycles farnesyl diphosphate from proteolyzed farnesylated proteins. In a second example, phytyl diphosphate is recycled from degraded chlorophyll, to be used for the biosynthesis of vitamin E. Both compounds are recovered as alcohols and require two phosphorylation events to be reactivated and reintegrated into the isoprenoid biosynthetic pathway. This review covers current knowledge of isoprenol biosynthesis, metabolism and function, as well as potential benefits of recycling pathways for plants, with a particular focus on stress responses.
{"title":"Phosphorylation of Metabolites Involved in Salvage Pathways for Isoprenoid Biosynthesis in Plants","authors":"A. Hemmerlin","doi":"10.3390/kinasesphosphatases1030010","DOIUrl":"https://doi.org/10.3390/kinasesphosphatases1030010","url":null,"abstract":"The recycling of metabolic products is a major way to reduce the energy cost of de novo biosynthesis. The salvage pathways involved not only regain a metabolic product but also generate additional molecules that might serve specific physiological, developmental and/or defensive functions. The isoprenoid pathway is a perfect example of a fine-regulated biosynthetic pathway, by virtue of the large number of molecules with different functions that must be synthesized simultaneously. Additionally, isoprenoid salvage pathways have been characterized. Thus, to produce isoprenoid precursors such as farnesyl diphosphate or phytyl diphosphate, short-chain isoprenols recovered from end-chain metabolites are phosphorylated. In the first instance, the so-called FPP-salvage machinery recycles farnesyl diphosphate from proteolyzed farnesylated proteins. In a second example, phytyl diphosphate is recycled from degraded chlorophyll, to be used for the biosynthesis of vitamin E. Both compounds are recovered as alcohols and require two phosphorylation events to be reactivated and reintegrated into the isoprenoid biosynthetic pathway. This review covers current knowledge of isoprenol biosynthesis, metabolism and function, as well as potential benefits of recycling pathways for plants, with a particular focus on stress responses.","PeriodicalId":74042,"journal":{"name":"Kinases and phosphatases","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76970799","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 : 2023-06-16DOI: 10.3390/kinasesphosphatases1020009
Camila Paz Quezada Meza, M. Ruzzene
Protein kinase CK2 is a Ser/Thr protein kinase that phosphorylates hundreds of substrates mainly related to survival and proliferation pathways. It has long been considered an anti-cancer drug target. However, during the recent COVID-19 pandemic, CK2 inhibitors have been repurposed as anti-SARS-CoV-2 drugs. This was based on the initial finding of CK2 among the proteins of the host cell that interact with the viral proteins and modulate the infection. Since then, several studies have deepened our understanding of the CK2/COVID-19 connection, and we deem it is time to review all the findings. Interestingly, other coronaviruses cross-talk with CK2 as well, with similarities and differences compared to the SARS-CoV-2 case. Therefore, we believe that the analysis of the effects obtained by targeting CK2 in case of coronavirus infections, both at the molecular and phenomenological level, will help in extrapolating information that could be useful not only for COVID-19 (whose pandemic emergency is hopefully turning off) but also for other infections.
{"title":"Protein Kinase CK2 and SARS-CoV-2: An Expected Interplay Story","authors":"Camila Paz Quezada Meza, M. Ruzzene","doi":"10.3390/kinasesphosphatases1020009","DOIUrl":"https://doi.org/10.3390/kinasesphosphatases1020009","url":null,"abstract":"Protein kinase CK2 is a Ser/Thr protein kinase that phosphorylates hundreds of substrates mainly related to survival and proliferation pathways. It has long been considered an anti-cancer drug target. However, during the recent COVID-19 pandemic, CK2 inhibitors have been repurposed as anti-SARS-CoV-2 drugs. This was based on the initial finding of CK2 among the proteins of the host cell that interact with the viral proteins and modulate the infection. Since then, several studies have deepened our understanding of the CK2/COVID-19 connection, and we deem it is time to review all the findings. Interestingly, other coronaviruses cross-talk with CK2 as well, with similarities and differences compared to the SARS-CoV-2 case. Therefore, we believe that the analysis of the effects obtained by targeting CK2 in case of coronavirus infections, both at the molecular and phenomenological level, will help in extrapolating information that could be useful not only for COVID-19 (whose pandemic emergency is hopefully turning off) but also for other infections.","PeriodicalId":74042,"journal":{"name":"Kinases and phosphatases","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79496037","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 goal of drug discovery is to uncover new molecules with specific chemical properties that can be used to cure diseases. With the accessibility of machine learning techniques, the approach used in this search has become a significant component in computer science in recent years. To meet the Precision Medicine Initiative’s goals and the additional obstacles that they have created, it is vital to develop strong, consistent, and repeatable computational approaches. Predictive models based on machine learning are becoming increasingly crucial in preclinical investigations. In discovering novel pharmaceuticals, this step substantially reduces expenses and research times. The human kinome contains various kinase enzymes that play vital roles through catalyzing protein phosphorylation. Interestingly, the dysregulation of kinases causes various human diseases, viz., cancer, cardiovascular disease, and several neuro-degenerative disorders. Thus, inhibitors of specific kinases can treat those diseases through blocking their activity as well as restoring normal cellular signaling. This review article discusses recent advancements in computational drug design algorithms through machine learning and deep learning and the computational drug design of kinase enzymes. Analyzing the current state-of-the-art in this sector will offer us a sense of where cheminformatics may evolve in the near future and the limitations and beneficial outcomes it has produced. The approaches utilized to model molecular data, the biological problems addressed, and the machine learning algorithms employed for drug discovery in recent years will be the emphasis of this review.
{"title":"Recent Advancements in Computational Drug Design Algorithms through Machine Learning and Optimization","authors":"Soham Choudhuri, Manas Yendluri, Sudip Poddar, Aimin Li, Koushik Mallick, Saurav Mallik, B. Ghosh","doi":"10.3390/kinasesphosphatases1020008","DOIUrl":"https://doi.org/10.3390/kinasesphosphatases1020008","url":null,"abstract":"The goal of drug discovery is to uncover new molecules with specific chemical properties that can be used to cure diseases. With the accessibility of machine learning techniques, the approach used in this search has become a significant component in computer science in recent years. To meet the Precision Medicine Initiative’s goals and the additional obstacles that they have created, it is vital to develop strong, consistent, and repeatable computational approaches. Predictive models based on machine learning are becoming increasingly crucial in preclinical investigations. In discovering novel pharmaceuticals, this step substantially reduces expenses and research times. The human kinome contains various kinase enzymes that play vital roles through catalyzing protein phosphorylation. Interestingly, the dysregulation of kinases causes various human diseases, viz., cancer, cardiovascular disease, and several neuro-degenerative disorders. Thus, inhibitors of specific kinases can treat those diseases through blocking their activity as well as restoring normal cellular signaling. This review article discusses recent advancements in computational drug design algorithms through machine learning and deep learning and the computational drug design of kinase enzymes. Analyzing the current state-of-the-art in this sector will offer us a sense of where cheminformatics may evolve in the near future and the limitations and beneficial outcomes it has produced. The approaches utilized to model molecular data, the biological problems addressed, and the machine learning algorithms employed for drug discovery in recent years will be the emphasis of this review.","PeriodicalId":74042,"journal":{"name":"Kinases and phosphatases","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72436002","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 : 2023-04-21DOI: 10.3390/kinasesphosphatases1020007
A. Nair, Bhaskar Saha
Ras, a GTP-GDP binary switch protein, transduces signals from diverse receptors to regulate various signaling networks. Three Ras genes encode for protein isoforms, namely, Harvey Ras (H-Ras), Kirsten Ras (K-Ras, with two splice variants, K-Ras4A and K-Ras4B), and Neuroblastoma Ras (N-Ras). The isoforms undergo a series of post-translational modifications that enable their membrane attachment and biological activity. The activation of Ras isoforms is tightly regulated, and any dysregulation affects cellular processes, such as cell division, apoptosis, differentiation, cell migration, etc. The Ras gene is highly prone to mutation, and ~30% of cancers carry somatic mutations in Ras, whereas germline mutations clinically manifest as various rasopathies. In addition to regulation by the Guanine nucleotide exchange factors and the GTPase activation proteins, Ras signaling, and localization are also regulated by phosphorylation-dephosphorylation, ubiquitination, nitrosylation, and acetylation. Herein, we review the regulation of Ras signaling and localization by various regulatory enzymes in depth and assess the current status of Ras drug discovery targeting these regulatory enzymes.
{"title":"Regulation of Ras-GTPase Signaling and Localization by Post-Translational Modifications","authors":"A. Nair, Bhaskar Saha","doi":"10.3390/kinasesphosphatases1020007","DOIUrl":"https://doi.org/10.3390/kinasesphosphatases1020007","url":null,"abstract":"Ras, a GTP-GDP binary switch protein, transduces signals from diverse receptors to regulate various signaling networks. Three Ras genes encode for protein isoforms, namely, Harvey Ras (H-Ras), Kirsten Ras (K-Ras, with two splice variants, K-Ras4A and K-Ras4B), and Neuroblastoma Ras (N-Ras). The isoforms undergo a series of post-translational modifications that enable their membrane attachment and biological activity. The activation of Ras isoforms is tightly regulated, and any dysregulation affects cellular processes, such as cell division, apoptosis, differentiation, cell migration, etc. The Ras gene is highly prone to mutation, and ~30% of cancers carry somatic mutations in Ras, whereas germline mutations clinically manifest as various rasopathies. In addition to regulation by the Guanine nucleotide exchange factors and the GTPase activation proteins, Ras signaling, and localization are also regulated by phosphorylation-dephosphorylation, ubiquitination, nitrosylation, and acetylation. Herein, we review the regulation of Ras signaling and localization by various regulatory enzymes in depth and assess the current status of Ras drug discovery targeting these regulatory enzymes.","PeriodicalId":74042,"journal":{"name":"Kinases and phosphatases","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80318743","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 : 2023-02-23DOI: 10.3390/kinasesphosphatases1010006
T. Montagnoli, D. R. D. de OLIVEIRA, C. A. Fraga
Cerebral cavernous malformations (CCM) are developmental venous dysplasias which present as abnormally dilated blood vessels occurring mainly in the brain. Alterations in vascular biology originate from somatic mutations in genes regulating angiogenesis and endothelial-to-mesenchymal transition. Vascular lesions may occur at any time and develop silently, remaining asymptomatic for years. However, symptomatic disease is often debilitating, and patients are prone to develop drug-resistant epilepsy and hemorrhages. There is no cure, and surgical treatment is recommended only for superficial lesions on cortical areas. The study of lesion biology led to the identification of different pathways related to disease onset and progression, of which RhoA/Rho-associated protein kinase (ROCK) shows activation in different subsets of patients. This work will explore the current knowledge about the involvement of ROCK in the many aspects of CCM disease, including isoform-specific actions, and delineate the recent development of ROCK inhibitors for CNS-targeted diseases.
{"title":"Therapeutic Perspectives on ROCK Inhibition for Cerebral Cavernous Malformations","authors":"T. Montagnoli, D. R. D. de OLIVEIRA, C. A. Fraga","doi":"10.3390/kinasesphosphatases1010006","DOIUrl":"https://doi.org/10.3390/kinasesphosphatases1010006","url":null,"abstract":"Cerebral cavernous malformations (CCM) are developmental venous dysplasias which present as abnormally dilated blood vessels occurring mainly in the brain. Alterations in vascular biology originate from somatic mutations in genes regulating angiogenesis and endothelial-to-mesenchymal transition. Vascular lesions may occur at any time and develop silently, remaining asymptomatic for years. However, symptomatic disease is often debilitating, and patients are prone to develop drug-resistant epilepsy and hemorrhages. There is no cure, and surgical treatment is recommended only for superficial lesions on cortical areas. The study of lesion biology led to the identification of different pathways related to disease onset and progression, of which RhoA/Rho-associated protein kinase (ROCK) shows activation in different subsets of patients. This work will explore the current knowledge about the involvement of ROCK in the many aspects of CCM disease, including isoform-specific actions, and delineate the recent development of ROCK inhibitors for CNS-targeted diseases.","PeriodicalId":74042,"journal":{"name":"Kinases and phosphatases","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81412960","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 : 2023-02-15DOI: 10.3390/kinasesphosphatases1010005
Julie Ledoux, L. Tchertanov
The kinase insert domain (KID) of RTK KIT is a key recruitment region for downstream signalling proteins (DSPs). KID, as a multisite phosphorylation region, provides alternative recognition sites for DSPs and activates them by binding a phosphotyrosine (pY) to their SH2 domains. Significant steric, biochemical, and biophysical requirements must be fulfilled by each pair of interacting proteins as the adaptation of their configurations is mandatory for the selective activation of DSPs. The accurate 3D atomistic models obtained by modelling and molecular dynamics (MD) simulations of phosphorylated KID (p-KID) have been delivered to describe KID INTERACTOME. By taking phosphorylated KIDpY721 and the N-terminal SH2 domain of phosphatidylinositol 3-kinase (PI3K), a physiological partner of KID, we showed the two proteins are intrinsically disordered. Using 3D models of both proteins, we probe alternative orientations of KIDpY721 relative to the SH2 binding pocket using automatic docking (HADDOCK) and intuitive user-guided docking. This modelling yields to two possible models of the functionally related non-covalent complex KIDpY721/SH2, where one can be regarded as the first precursor to probe PI3K activation via KIT KID. We suggest that such generation of a KID/SH2 complex is best suited for future studies of the post-transduction effects of RTK KIT.
{"title":"Site-Specific Phosphorylation of RTK KIT Kinase Insert Domain: Interactome Landscape Perspectives","authors":"Julie Ledoux, L. Tchertanov","doi":"10.3390/kinasesphosphatases1010005","DOIUrl":"https://doi.org/10.3390/kinasesphosphatases1010005","url":null,"abstract":"The kinase insert domain (KID) of RTK KIT is a key recruitment region for downstream signalling proteins (DSPs). KID, as a multisite phosphorylation region, provides alternative recognition sites for DSPs and activates them by binding a phosphotyrosine (pY) to their SH2 domains. Significant steric, biochemical, and biophysical requirements must be fulfilled by each pair of interacting proteins as the adaptation of their configurations is mandatory for the selective activation of DSPs. The accurate 3D atomistic models obtained by modelling and molecular dynamics (MD) simulations of phosphorylated KID (p-KID) have been delivered to describe KID INTERACTOME. By taking phosphorylated KIDpY721 and the N-terminal SH2 domain of phosphatidylinositol 3-kinase (PI3K), a physiological partner of KID, we showed the two proteins are intrinsically disordered. Using 3D models of both proteins, we probe alternative orientations of KIDpY721 relative to the SH2 binding pocket using automatic docking (HADDOCK) and intuitive user-guided docking. This modelling yields to two possible models of the functionally related non-covalent complex KIDpY721/SH2, where one can be regarded as the first precursor to probe PI3K activation via KIT KID. We suggest that such generation of a KID/SH2 complex is best suited for future studies of the post-transduction effects of RTK KIT.","PeriodicalId":74042,"journal":{"name":"Kinases and phosphatases","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82132111","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 : 2023-01-23DOI: 10.3390/kinasesphosphatases1010004
P. Weerawarna, Timothy I. Richardson
LYN proto-oncogene, Src family tyrosine kinase (Lyn) is a tyrosine kinase that belongs to the Src family (SFK). It is expressed as two isoforms in humans, LynA and LynB. Like other SFKs, Lyn consists of five protein domains, an N-terminal SH4 domain followed by a unique domain, the SH3 and SH2 domains, and a catalytic SH1 domain. The autophosphorylation of Tyr397 activates the protein, while the phosphorylation of the C-terminal inhibitory Tyr508 by C-terminal Src kinase (Csk) or Csk homologous kinase (Chk) inhibits the catalytic activity. The interaction of the SH2 domain with the phosphorylated Tyr508 stabilizes a compact, self-inhibited state. The interaction of the SH3 domain with a linker between the SH2 and catalytic domains further stabilizes this inactive conformation. The two critical structural features of the catalytic domain are a conserved DFG moiety and the αC helix, which can adopt in or out conformations. In the active state, both the DFG moiety and αC helix adopt in conformations, while in the inactive state, they adopt out conformations. Lyn has well-established functions in various hematopoietic cell types and more recent studies have revealed its roles in non-hematopoietic cells. At the molecular level, these functions are mainly exerted by phosphorylating specific tyrosine residues in immunoreceptor tyrosine-based inhibitory motifs (ITIMs) and immunoreceptor tyrosine-based activator motifs (ITAMs) associated with cell surface receptors. The phosphorylation of ITAMs by Lyn can initiate either activating or inhibitory (ITAMi) cell signaling depending on the receptor, targeting mode (crosslinking or monovalent targeting), and the cellular context. The phosphorylation of ITIMs by Lyn initiates inhibitory cell signaling via the recruitment of phosphatases to the ITIM-bearing receptor. The role of Lyn in cancer and autoimmune diseases has been extensively discussed in the literature. The involvement of Lyn in neurodegenerative diseases has been described more recently and, as such, it is now an emerging target for the treatment of neurodegenerative diseases.
{"title":"Lyn Kinase Structure, Regulation, and Involvement in Neurodegenerative Diseases: A Mini Review","authors":"P. Weerawarna, Timothy I. Richardson","doi":"10.3390/kinasesphosphatases1010004","DOIUrl":"https://doi.org/10.3390/kinasesphosphatases1010004","url":null,"abstract":"LYN proto-oncogene, Src family tyrosine kinase (Lyn) is a tyrosine kinase that belongs to the Src family (SFK). It is expressed as two isoforms in humans, LynA and LynB. Like other SFKs, Lyn consists of five protein domains, an N-terminal SH4 domain followed by a unique domain, the SH3 and SH2 domains, and a catalytic SH1 domain. The autophosphorylation of Tyr397 activates the protein, while the phosphorylation of the C-terminal inhibitory Tyr508 by C-terminal Src kinase (Csk) or Csk homologous kinase (Chk) inhibits the catalytic activity. The interaction of the SH2 domain with the phosphorylated Tyr508 stabilizes a compact, self-inhibited state. The interaction of the SH3 domain with a linker between the SH2 and catalytic domains further stabilizes this inactive conformation. The two critical structural features of the catalytic domain are a conserved DFG moiety and the αC helix, which can adopt in or out conformations. In the active state, both the DFG moiety and αC helix adopt in conformations, while in the inactive state, they adopt out conformations. Lyn has well-established functions in various hematopoietic cell types and more recent studies have revealed its roles in non-hematopoietic cells. At the molecular level, these functions are mainly exerted by phosphorylating specific tyrosine residues in immunoreceptor tyrosine-based inhibitory motifs (ITIMs) and immunoreceptor tyrosine-based activator motifs (ITAMs) associated with cell surface receptors. The phosphorylation of ITAMs by Lyn can initiate either activating or inhibitory (ITAMi) cell signaling depending on the receptor, targeting mode (crosslinking or monovalent targeting), and the cellular context. The phosphorylation of ITIMs by Lyn initiates inhibitory cell signaling via the recruitment of phosphatases to the ITIM-bearing receptor. The role of Lyn in cancer and autoimmune diseases has been extensively discussed in the literature. The involvement of Lyn in neurodegenerative diseases has been described more recently and, as such, it is now an emerging target for the treatment of neurodegenerative diseases.","PeriodicalId":74042,"journal":{"name":"Kinases and phosphatases","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76690023","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 : 2022-12-22DOI: 10.3390/kinasesphosphatases1010003
Susumu Tanaka, Y. Honda, Misa Sawachika, Kensuke Futani, N. Yoshida, T. Kodama
Serine/threonine-protein kinase 16 (STK16) is a novel member of the Numb-associated family of protein kinases with an atypical kinase domain. In this study, we aimed to investigate the involvement of STK16 in sleep–wake mechanisms. We confirmed the expression of Stk16 in the murine hypothalamus, the sleep–wake center, and found considerable changes in STK16 protein levels in the anterior hypothalamus during the light–dark cycle. We found that the coexistence of the potassium channel tetramerization domain containing 17 (KCTD17), an STK16 interactor, caused STK16 degradation. In contrast, the proteasome inhibitor MG132 inhibited the degradation of STK16. In addition, polyubiquitinated STK16 was observed, suggesting that KCTD17 acts as an adapter for E3 ligase to recognize STK16 as a substrate, leading to STK16 degradation via the ubiquitin–proteasome system. The vast changes in STK16 in the anterior hypothalamus, a mammalian sleep center, as well as the reported sleep abnormalities in the ubiquitin B knockout mice and the Drosophila with the inhibition of the KCTD17 homolog or its E3 ligase cullin-3, suggest that STK16 plays a major role in sleep–wake regulation.
{"title":"Degradation of STK16 via KCTD17 with Ubiquitin–Proteasome System in Relation to Sleep–Wake Cycle","authors":"Susumu Tanaka, Y. Honda, Misa Sawachika, Kensuke Futani, N. Yoshida, T. Kodama","doi":"10.3390/kinasesphosphatases1010003","DOIUrl":"https://doi.org/10.3390/kinasesphosphatases1010003","url":null,"abstract":"Serine/threonine-protein kinase 16 (STK16) is a novel member of the Numb-associated family of protein kinases with an atypical kinase domain. In this study, we aimed to investigate the involvement of STK16 in sleep–wake mechanisms. We confirmed the expression of Stk16 in the murine hypothalamus, the sleep–wake center, and found considerable changes in STK16 protein levels in the anterior hypothalamus during the light–dark cycle. We found that the coexistence of the potassium channel tetramerization domain containing 17 (KCTD17), an STK16 interactor, caused STK16 degradation. In contrast, the proteasome inhibitor MG132 inhibited the degradation of STK16. In addition, polyubiquitinated STK16 was observed, suggesting that KCTD17 acts as an adapter for E3 ligase to recognize STK16 as a substrate, leading to STK16 degradation via the ubiquitin–proteasome system. The vast changes in STK16 in the anterior hypothalamus, a mammalian sleep center, as well as the reported sleep abnormalities in the ubiquitin B knockout mice and the Drosophila with the inhibition of the KCTD17 homolog or its E3 ligase cullin-3, suggest that STK16 plays a major role in sleep–wake regulation.","PeriodicalId":74042,"journal":{"name":"Kinases and phosphatases","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77704274","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 : 2022-11-21DOI: 10.3390/kinasesphosphatases1010002
Hajar Yaakoub, S. Mina, A. Marot, N. Papon, A. Calenda, J. Bouchara
Scedosporium species are opportunistic filamentous fungi found in human-impacted areas. Clinically relevant species, such as S. apiospermum, rank as the second most frequent colonizers of the airways of patients with cystic fibrosis (CF), which are characterized by persistent oxidative stress. This raises the question of how Scedosporium species abate conditions imposed in hostile environments. Since the High Osmolarity Glycerol (HOG) pathway plays a central role in fungal adaptation to stress, we aimed to pheno-profile the involvement of the pathway in response to stress in S. apiospermum using Western blot. We show for the first time that a wide range of stress distinctively activates the HOG pathway in S. apiospermum, including oxidants (H2O2, menadione, cumene hydroperoxide, diamide, paraquat, and honokiol), osmotic agents (sorbitol and KCl), cell-wall stress agents (caffeine, calcofluor white, and Congo Red), heavy metals (cadmium and arsenite), fungicides (fludioxonil and iprodione), antifungals (voriconazole and amphotericin B), and acid stress (pH 4). We suggest that the function of the HOG pathway as a general stress regulator is also conserved in S. apiospermum.
{"title":"A Stress Hub in Scedosporium apiospermum: The High Osmolarity Glycerol (HOG) Pathway","authors":"Hajar Yaakoub, S. Mina, A. Marot, N. Papon, A. Calenda, J. Bouchara","doi":"10.3390/kinasesphosphatases1010002","DOIUrl":"https://doi.org/10.3390/kinasesphosphatases1010002","url":null,"abstract":"Scedosporium species are opportunistic filamentous fungi found in human-impacted areas. Clinically relevant species, such as S. apiospermum, rank as the second most frequent colonizers of the airways of patients with cystic fibrosis (CF), which are characterized by persistent oxidative stress. This raises the question of how Scedosporium species abate conditions imposed in hostile environments. Since the High Osmolarity Glycerol (HOG) pathway plays a central role in fungal adaptation to stress, we aimed to pheno-profile the involvement of the pathway in response to stress in S. apiospermum using Western blot. We show for the first time that a wide range of stress distinctively activates the HOG pathway in S. apiospermum, including oxidants (H2O2, menadione, cumene hydroperoxide, diamide, paraquat, and honokiol), osmotic agents (sorbitol and KCl), cell-wall stress agents (caffeine, calcofluor white, and Congo Red), heavy metals (cadmium and arsenite), fungicides (fludioxonil and iprodione), antifungals (voriconazole and amphotericin B), and acid stress (pH 4). We suggest that the function of the HOG pathway as a general stress regulator is also conserved in S. apiospermum.","PeriodicalId":74042,"journal":{"name":"Kinases and phosphatases","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90392291","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 : 2022-10-12DOI: 10.3390/kinasesphosphatases1010001
M. Salvi
On behalf of all the Editorial Board members and the MDPI staff, I’m pleased to announce the publishing of the inaugural issue of the Kinases and Phosphatases journal [...]
我很高兴地代表所有编辑委员会成员和MDPI的工作人员宣布，激酶和磷酸酶杂志的创刊号已经出版[…]
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