Kinases and phosphatases最新文献_第2页

The Yin and Yang of IκB Kinases in Cancer 癌症中 IκB 激酶的阴与阳

Kinases and phosphatases Pub Date : 2023-12-31 DOI: 10.3390/kinasesphosphatases2010002

Abdalla M. Abdrabou

引用次数: 0

The CK2/ECE1c Partnership: An Unveiled Pathway to Aggressiveness in Cancer CK2/ECE1c伙伴关系：揭示癌症侵袭性的途径

Kinases and phosphatases Pub Date : 2023-12-19 DOI: 10.3390/kinasesphosphatases2010001

Karla Villalobos-Nova, M. A. Toro, Pablo Pérez-Moreno, Ignacio Niechi, Julio C. Tapia

{"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":null,"pages":null},"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}

引用次数: 0

Discovery and Exploration of Protein Kinase CK2 Binding Sites Using CK2α′Cys336Ser as an Exquisite Crystallographic Tool 以 CK2α′Cys336Ser 为精密结晶工具发现和探索蛋白激酶 CK2 结合位点

Kinases and phosphatases Pub Date : 2023-11-25 DOI: 10.3390/kinasesphosphatases1040018

Christian Werner, D. Lindenblatt, Kaido Viht, A. Uri, K. Niefind

{"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":null,"pages":null},"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}

引用次数: 0

CK2 Chemical Probes: Past, Present, and Future CK2化学探针:过去，现在和未来

Kinases and phosphatases Pub Date : 2023-11-01 DOI: 10.3390/kinasesphosphatases1040017

Han Wee Ong, David H. Drewry, Alison D. Axtman

引用次数: 0

Interaction Networks Explain Holoenzyme Allostery in Protein Kinase A 相互作用网络解释蛋白激酶A全酶变构

Kinases and phosphatases Pub Date : 2023-10-31 DOI: 10.3390/kinasesphosphatases1040016

Colin L. Welsh, Abigail E. Conklin, Lalima K. Madan

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Exploring Protein Kinase CK2 Substrate Recognition and the Dynamic Response of Substrate Phosphorylation to Kinase Modulation 探索蛋白激酶CK2底物识别和底物磷酸化对激酶调节的动态响应

Kinases and phosphatases Pub Date : 2023-10-07 DOI: 10.3390/kinasesphosphatases1040015

Luca Cesaro, Angelica Maria Zuliani, Valentina Bosello Travain, Mauro Salvi

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Receptor Tyrosine Kinase KIT: Mutation-Induced Conformational Shift Promotes Alternative Allosteric Pockets 受体酪氨酸激酶KIT:突变诱导的构象转移促进了可变的变构口袋

Kinases and phosphatases Pub Date : 2023-09-25 DOI: 10.3390/kinasesphosphatases1040014

Julie Ledoux, Marina Botnari, Luba Tchertanov

{"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":null,"pages":null},"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}

引用次数: 0

Overview of Capillary Electrophoresis Analysis of Alkaline Phosphatase (ALP) with Emphasis on Post-Translational Modifications (PTMs) 碱性磷酸酶(ALP)毛细管电泳分析综述及翻译后修饰(PTMs)研究进展

Kinases and phosphatases Pub Date : 2023-09-15 DOI: 10.3390/kinasesphosphatases1030013

Thanih Balbaied, Eric Moore

引用次数: 0

Phosphorylation of Ack1 by the Receptor Tyrosine Kinase Mer. 受体酪氨酸激酶Mer对Ack1的磷酸化作用。

Kinases and phosphatases Pub Date : 2023-09-01 DOI: 10.3390/kinasesphosphatases1030011

Samantha Y Hayashi, Barbara P Craddock, W Todd Miller

{"title":"Phosphorylation of Ack1 by the Receptor Tyrosine Kinase Mer.","authors":"Samantha Y Hayashi, Barbara P Craddock, W Todd Miller","doi":"10.3390/kinasesphosphatases1030011","DOIUrl":"https://doi.org/10.3390/kinasesphosphatases1030011","url":null,"abstract":"<p><p>Ack1 is a nonreceptor tyrosine kinase that is associated with cellular proliferation and survival. The receptor tyrosine kinase Mer, a member of the TAM family of receptors, has previously been reported to be an upstream activator of Ack1 kinase. The mechanism linking the two kinases, however, has not been investigated. We confirmed that Ack1 and Mer interact by co-immunoprecipitation experiments and found that Mer expression led to increased Ack1 activity. The effect on Ack1 was dependent on the kinase activity of Mer, whereas mutation of the Mer C-terminal tyrosines Y867 and Y924 did not significantly decrease the ability of Mer to activate Ack1. Ack1 possesses a Mig6 Homology Region (MHR) that contains adjacent regulatory tyrosines (Y859 and Y860). Using synthetic peptides, we showed that Mer preferentially binds and phosphorylates the MHR sequence containing phosphorylated pY860, as compared to the pY859 sequence. This suggested the possibility of sequential phosphorylation within the MHR of Ack1, as has been observed previously for other kinases. In cells co-expressing Mer and Ack1 MHR mutants, the Y859F mutant had higher activity than the Y860F mutant, consistent with this model. The interaction between Mer and Ack1 could play a role in immune cell signaling in normal physiology and could also contribute to the hyperactivation of Ack1 in prostate cancer and other tumors.</p>","PeriodicalId":74042,"journal":{"name":"Kinases and phosphatases","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10473914/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10149329","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

From Kinases to Diseases: Investigating the Role of AMPK in Human Pathologies 从激酶到疾病:研究AMPK在人类病理中的作用

Kinases and phosphatases Pub Date : 2023-08-01 DOI: 10.3390/kinasesphosphatases1030012

V. Rey, Isaac Tamargo-Gómez

{"title":"From Kinases to Diseases: Investigating the Role of AMPK in Human Pathologies","authors":"V. Rey, Isaac Tamargo-Gómez","doi":"10.3390/kinasesphosphatases1030012","DOIUrl":"https://doi.org/10.3390/kinasesphosphatases1030012","url":null,"abstract":"Adenosine Monophosphate-Activated Protein Kinase (AMPK) is the major conserved regulator of cellular metabolism in eukaryotic cells, from yeast to mammals. Given its pivotal role, it is not surprising that alterations in its function may contribute to the pathogenesis of numerous human diseases. Indeed, AMPK has become a promising therapeutic target for several pathologies. In this context, significant efforts have been dedicated to discovering new pharmacological agents capable of activating AMPK based on next-generation sequencing (NGS) technology and personalized medicine. Thanks to computational methodologies and high-throughput screening, the identification of small molecules and compounds with the potential to directly activate AMPK or modulate its intricate signaling network has become viable. However, the most widely used drug to activate AMPK in human patients is still metformin, which has shown promising results in the treatment of various diseases, such as type II diabetes, atherosclerosis, Alzheimer’s disease, Huntington’s disease, and several types of cancer. In this review, we present a comprehensive analysis of the involvement of AMPK in human pathology, emphasizing its significant potential as a therapeutic target.","PeriodicalId":74042,"journal":{"name":"Kinases and phosphatases","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90827204","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}

引用次数: 2