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  1 / 1125 MEDLINE  
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[PMID]:28858528
[Au] Autor:Chen ES; Weng JH; Chen YH; Wang SC; Liu XX; Huang WC; Matsui T; Kawano Y; Liao JH; Lim LH; Bessho Y; Huang KF; Wu WJ; Tsai MD
[Ad] Endereço:Institute of Biological Chemistry, Academia Sinica , Taipei 115, Taiwan.
[Ti] Título:Phospho-Priming Confers Functionally Relevant Specificities for Rad53 Kinase Autophosphorylation.
[So] Source:Biochemistry;56(38):5112-5124, 2017 Sep 26.
[Is] ISSN:1520-4995
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The vast majority of in vitro structural and functional studies of the activation mechanism of protein kinases use the kinase domain alone. Well-demonstrated effects of regulatory domains or allosteric factors are scarce for serine/threonine kinases. Here we use a site-specifically phosphorylated SCD1-FHA1-kinase three-domain construct of the serine/threonine kinase Rad53 to show the effect of phospho-priming, an in vivo regulatory mechanism, on the autophosphorylation intermediate and specificity. Unphosphorylated Rad53 is a flexible monomer in solution but is captured in an asymmetric enzyme:substrate complex in crystal with the two FHA domains separated from each other. Phospho-priming induces formation of a stable dimer via intermolecular pT-FHA binding in solution. Importantly, autophosphorylation of unprimed and phospho-primed Rad53 produced predominantly inactive pS350-Rad53 and active pT354-Rad53, respectively. The latter mechanism was also demonstrated in vivo. Our results show that, while Rad53 can display active conformations under various conditions, simulation of in vivo regulatory conditions confers functionally relevant autophosphorylation.
[Mh] Termos MeSH primário: Proteínas de Ciclo Celular/química
Proteínas de Ciclo Celular/metabolismo
Quinase do Ponto de Checagem 2/química
Quinase do Ponto de Checagem 2/metabolismo
Proteínas de Saccharomyces cerevisiae/química
Proteínas de Saccharomyces cerevisiae/metabolismo
[Mh] Termos MeSH secundário: Proteínas de Ciclo Celular/genética
Quinase do Ponto de Checagem 2/genética
Dano ao DNA
Modelos Moleculares
Ressonância Magnética Nuclear Biomolecular
Fosforilação
Fosfotreonina/metabolismo
Domínios Proteicos
Multimerização Proteica
Proteínas Serina-Treonina Quinases/metabolismo
Proteínas de Saccharomyces cerevisiae/genética
Espalhamento a Baixo Ângulo
Serina/química
Treonina/química
Treonina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cell Cycle Proteins); 0 (Saccharomyces cerevisiae Proteins); 1114-81-4 (Phosphothreonine); 2ZD004190S (Threonine); 452VLY9402 (Serine); EC 2.7.1.- (DUN1 protein, S cerevisiae); EC 2.7.1.11 (Checkpoint Kinase 2); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); EC 2.7.12.1 (RAD53 protein, S cerevisiae)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171010
[Lr] Data última revisão:
171010
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170901
[St] Status:MEDLINE
[do] DOI:10.1021/acs.biochem.7b00689


  2 / 1125 MEDLINE  
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[PMID]:28701415
[Au] Autor:Xia Y; Shang Y; Zhang R; Zhu J
[Ad] Endereço:National Center for Protein Science Shanghai, State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 333 Haike Road, Shanghai 201203,
[Ti] Título:Structure of the PSD-95/MAP1A complex reveals a unique target recognition mode of the MAGUK GK domain.
[So] Source:Biochem J;474(16):2817-2828, 2017 Aug 10.
[Is] ISSN:1470-8728
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The PSD-95 family of membrane-associated guanylate kinases (MAGUKs) are major synaptic scaffold proteins and play crucial roles in the dynamic regulation of dendritic remodelling, which is understood to be the foundation of synaptogenesis and synaptic plasticity. The guanylate kinase (GK) domain of MAGUK family proteins functions as a phosphor-peptide binding module. However, the GK domain of PSD-95 has been found to directly bind to a peptide sequence within the C-terminal region of neuronal-specific microtubule-associated protein 1A (MAP1A), although the detailed molecular mechanism governing this phosphorylation-independent interaction at the atomic level is missing. In the present study, we determine the crystal structure of PSD-95 GK in complex with the MAP1A peptide at 2.6-Å resolution. The complex structure reveals that, unlike a linear and elongated conformation in the phosphor-peptide/GK complexes, the MAP1A peptide adopts a unique conformation with a stretch of hydrophobic residues far from each other in the primary sequence clustering and interacting with the 'hydrophobic site' of PSD-95 GK and a highly conserved aspartic acid of MAP1A (D2117) mimicking the phosphor-serine/threonine in binding to the 'phosphor-site' of PSD-95 GK. We demonstrate that the MAP1A peptide may undergo a conformational transition upon binding to PSD-95 GK. Further structural comparison of known DLG GK-mediated complexes reveals the target recognition specificity and versatility of DLG GKs.
[Mh] Termos MeSH primário: Peptídeos e Proteínas de Sinalização Intracelular/química
Proteínas de Membrana/química
Proteínas Associadas aos Microtúbulos/química
Fosfosserina/química
Fosfotreonina/química
Proteínas Recombinantes de Fusão/química
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Animais
Sítios de Ligação
Clonagem Molecular
Cristalografia por Raios X
Proteína 4 Homóloga a Disks-Large
Escherichia coli/genética
Escherichia coli/metabolismo
Expressão Gênica
Glutationa Transferase/química
Glutationa Transferase/genética
Glutationa Transferase/metabolismo
Células HEK293
Seres Humanos
Interações Hidrofóbicas e Hidrofílicas
Peptídeos e Proteínas de Sinalização Intracelular/genética
Peptídeos e Proteínas de Sinalização Intracelular/metabolismo
Proteínas de Membrana/genética
Proteínas de Membrana/metabolismo
Camundongos
Proteínas Associadas aos Microtúbulos/genética
Proteínas Associadas aos Microtúbulos/metabolismo
Modelos Moleculares
Mimetismo Molecular
Fosfosserina/metabolismo
Fosfotreonina/metabolismo
Ligação Proteica
Domínios e Motivos de Interação entre Proteínas
Estrutura Secundária de Proteína
Ratos
Proteínas Recombinantes de Fusão/genética
Proteínas Recombinantes de Fusão/metabolismo
Alinhamento de Sequência
Homologia de Sequência de Aminoácidos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Disks Large Homolog 4 Protein); 0 (Dlg4 protein, rat); 0 (Intracellular Signaling Peptides and Proteins); 0 (Membrane Proteins); 0 (Microtubule-Associated Proteins); 0 (Mtap1a protein, mouse); 0 (Recombinant Fusion Proteins); 1114-81-4 (Phosphothreonine); 17885-08-4 (Phosphoserine); EC 2.5.1.18 (Glutathione Transferase)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170714
[St] Status:MEDLINE
[do] DOI:10.1042/BCJ20170356


  3 / 1125 MEDLINE  
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[PMID]:28642254
[Au] Autor:Zhu M; Zhang T; Ji W; Silva-Sanchez C; Song WY; Assmann SM; Harmon AC; Chen S
[Ad] Endereço:Department of Biology, Genetics Institute, University of Florida, Gainesville, FL 32610, U.S.A.
[Ti] Título:Redox regulation of a guard cell SNF1-related protein kinase in , an oilseed crop.
[So] Source:Biochem J;474(15):2585-2599, 2017 Jul 17.
[Is] ISSN:1470-8728
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Kinase-mediated phosphorylation is a pivotal regulatory process in stomatal responses to stresses. Through a redox proteomics study, a sucrose non-fermenting 1-related protein kinase (SnRK2.4) was identified to be redox-regulated in guard cells upon abscisic acid treatment. There are six genes encoding SnRK2.4 paralogs in Here, we show that recombinant BnSnRK2.4-1C exhibited autophosphorylation activity and preferentially phosphorylated the N-terminal region of slow anion channel (BnSLAC1-NT) over generic substrates. The activity of BnSnRK2.4-1C requires the presence of manganese (Mn ). Phosphorylation sites of autophosphorylated BnSnRK2.4-1C were mapped, including serine and threonine residues in the activation loop. BnSnRK2.4-1C autophosphorylation activity was inhibited by oxidants such as H O and recovered by active thioredoxin isoforms, indicating redox regulation of BnSnRK2.4-1C. Thiol-specific isotope tagging followed by mass spectrometry analysis revealed specific cysteine residues responsive to oxidant treatments. The activity of BnSnRK2.4-1C is inhibited by 15 min of H O treatment. Taken together, these data indicate that BnSnRK2.4-1C, an SnRK preferentially expressed in guard cells, is redox-regulated with potential roles in guard cell signal transduction.
[Mh] Termos MeSH primário: Brassica napus/citologia
Brassica napus/enzimologia
Produtos Agrícolas/citologia
Produtos Agrícolas/enzimologia
Estômatos de Plantas/citologia
Estômatos de Plantas/enzimologia
Proteínas Serina-Treonina Quinases/metabolismo
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Arabidopsis/efeitos dos fármacos
Arabidopsis/metabolismo
Proteínas de Arabidopsis/metabolismo
Brassica napus/efeitos dos fármacos
Produtos Agrícolas/efeitos dos fármacos
Cisteína/metabolismo
Peróxido de Hidrogênio/farmacologia
Manganês/metabolismo
Oxirredução/efeitos dos fármacos
Fosforilação/efeitos dos fármacos
Fosfosserina/metabolismo
Fosfotreonina/metabolismo
Filogenia
Estômatos de Plantas/efeitos dos fármacos
Proteínas Serina-Treonina Quinases/química
Alinhamento de Sequência
Tiorredoxinas/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Arabidopsis Proteins); 1114-81-4 (Phosphothreonine); 17885-08-4 (Phosphoserine); 42Z2K6ZL8P (Manganese); 52500-60-4 (Thioredoxins); BBX060AN9V (Hydrogen Peroxide); EC 2.7.1.- (SNF1-related protein kinases); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); K848JZ4886 (Cysteine)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170731
[Lr] Data última revisão:
170731
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170624
[St] Status:MEDLINE
[do] DOI:10.1042/BCJ20170070


  4 / 1125 MEDLINE  
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[PMID]:28637792
[Au] Autor:Takata T; Ihara H; Hatano N; Tsuchiya Y; Akaike T; Watanabe Y
[Ad] Endereço:Department of Pharmacology, High Technology Research Center, Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan.
[Ti] Título:Reactive sulfur species inactivate Ca /calmodulin-dependent protein kinase IV via S-polysulfidation of its active-site cysteine residue.
[So] Source:Biochem J;474(15):2547-2562, 2017 Jul 17.
[Is] ISSN:1470-8728
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Reactive sulfur species (RSS) modulate protein functions via S polysulfidation of reactive Cys residues. Here, we report that Ca /calmodulin (CaM)-dependent protein kinase IV (CaMKIV) was reversibly inactivated by RSS via polysulfidation of the active-site Cys residue. CaMKIV is phosphorylated at Thr by its upstream CaMK kinase (CaMKK), resulting in the induction of its full activity. incubation of CaMKIV with the exogenous RSS donors Na S ( = 2-4) resulted in dose-dependent inhibition of the CaMKK-induced phospho-Thr and consequent inactivation of the enzyme activity. Conversely, mutated CaMKIV (C198V) was refractory to the Na S -induced enzyme inhibition. A biotin-polyethylene glycol-conjugated maleimide capture assay revealed that Cys in CaMKIV represents a target for S-polysulfidation. Furthermore, phosho-Thr and CaMKIV activity were inhibited by incubation with cysteine hydropersulfide, a newly identified RSS that is generated from cystine by cystathionine-γ-lyase. In transfected cells expressing CaMKIV, ionomycin-induced CaMKIV phosphorylation at Thr was decreased upon treatment with either Na S or the endoplasmic reticulum (ER) stress inducer thapsigargin, whereas cells expressing mutant CaMKIV (C198V) were resistant to this treatment. In addition, the ionomycin-induced phospho-Thr of endogenous CaMKIV was also inhibited by treatment either with Na S or thapsigargin in Jurkat T lymphocytes. Taken together, these data define a novel signaling function for intracellular RSS in inhibiting CaMKIV activity via S polysulfidation of its Cys during the response to ER stress.
[Mh] Termos MeSH primário: Proteína Quinase Tipo 4 Dependente de Cálcio-Calmodulina/metabolismo
Cisteína/metabolismo
Sulfetos/metabolismo
Enxofre/metabolismo
[Mh] Termos MeSH secundário: Animais
Proteína Quinase Tipo 4 Dependente de Cálcio-Calmodulina/antagonistas & inibidores
Estresse do Retículo Endoplasmático/efeitos dos fármacos
Ativação Enzimática/efeitos dos fármacos
Células HEK293
Seres Humanos
Células Jurkat
Espectrometria de Massas
Proteínas Mutantes/metabolismo
Fosforilação/efeitos dos fármacos
Fosfotreonina/metabolismo
Ratos
Tapsigargina/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Mutant Proteins); 0 (Sulfides); 1114-81-4 (Phosphothreonine); 67526-95-8 (Thapsigargin); 70FD1KFU70 (Sulfur); EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Type 4); K848JZ4886 (Cysteine); YGR27ZW0Y7 (sodium sulfide)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170623
[St] Status:MEDLINE
[do] DOI:10.1042/BCJ20170092


  5 / 1125 MEDLINE  
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[PMID]:28553966
[Au] Autor:Zhang MS; Brunner SF; Huguenin-Dezot N; Liang AD; Schmied WH; Rogerson DT; Chin JW
[Ad] Endereço:Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, England, UK.
[Ti] Título:Biosynthesis and genetic encoding of phosphothreonine through parallel selection and deep sequencing.
[So] Source:Nat Methods;14(7):729-736, 2017 Jul.
[Is] ISSN:1548-7105
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The phosphorylation of threonine residues in proteins regulates diverse processes in eukaryotic cells, and thousands of threonine phosphorylations have been identified. An understanding of how threonine phosphorylation regulates biological function will be accelerated by general methods to biosynthesize defined phosphoproteins. Here we describe a rapid approach for directly discovering aminoacyl-tRNA synthetase-tRNA pairs that selectively incorporate non-natural amino acids into proteins; our method uses parallel positive selections combined with deep sequencing and statistical analysis and enables the direct, scalable discovery of aminoacyl-tRNA synthetase-tRNA pairs with mutually orthogonal substrate specificity. By combining a method to biosynthesize phosphothreonine in cells with this selection approach, we discover a phosphothreonyl-tRNA synthetase-tRNA pair and create an entirely biosynthetic route to incorporating phosphothreonine in proteins. We biosynthesize several phosphoproteins and demonstrate phosphoprotein structure determination and synthetic protein kinase activation.
[Mh] Termos MeSH primário: Escherichia coli/metabolismo
Fosfotreonina/metabolismo
[Mh] Termos MeSH secundário: Aminoacil-tRNA Sintetases/genética
Aminoacil-tRNA Sintetases/metabolismo
Proteínas de Bactérias/genética
Proteínas de Bactérias/metabolismo
Escherichia coli/genética
Engenharia Genética
Modelos Moleculares
Conformação Proteica
Engenharia de Proteínas
Processamento de Proteína Pós-Traducional
RNA de Transferência/genética
RNA de Transferência/metabolismo
Salmonella enterica/metabolismo
Especificidade por Substrato
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bacterial Proteins); 1114-81-4 (Phosphothreonine); 9014-25-9 (RNA, Transfer); EC 6.1.1.- (Amino Acyl-tRNA Synthetases)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170816
[Lr] Data última revisão:
170816
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170530
[St] Status:MEDLINE
[do] DOI:10.1038/nmeth.4302


  6 / 1125 MEDLINE  
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[PMID]:28507061
[Au] Autor:Xia Y; Yang W; Fa M; Li X; Wang Y; Jiang Y; Zheng Y; Lee JH; Li J; Lu Z
[Ad] Endereço:Brain Tumor Center and Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.
[Ti] Título:RNF8 mediates histone H3 ubiquitylation and promotes glycolysis and tumorigenesis.
[So] Source:J Exp Med;214(6):1843-1855, 2017 Jun 05.
[Is] ISSN:1540-9538
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Disassembly of nucleosomes in which genomic DNA is packaged with histone regulates gene expression. However, the mechanisms underlying nucleosome disassembly for gene expression remain elusive. We show here that epidermal growth factor receptor activation results in the binding of the RNF8 forkhead-associated domain to pyruvate kinase M2-phosphorylated histone H3-T11, leading to K48-linked polyubiquitylation of histone H3 at K4 and subsequent proteasome-dependent protein degradation. In addition, H3 polyubiquitylation induces histone dissociation from chromatin, nucleosome disassembly, and binding of RNA polymerase II to and promoter regions for transcription. RNF8-mediated histone H3 polyubiquitylation promotes tumor cell glycolysis and proliferation and brain tumorigenesis. Our findings uncover the role of RNF8-mediated histone H3 polyubiquitylation in the regulation of histone H3 stability and chromatin modification, paving the way to gene expression regulation and tumorigenesis.
[Mh] Termos MeSH primário: Carcinogênese/metabolismo
Proteínas de Ligação a DNA/metabolismo
Glicólise
Histonas/metabolismo
Ubiquitinação
[Mh] Termos MeSH secundário: Carcinogênese/genética
Carcinogênese/patologia
Linhagem Celular Tumoral
Ciclina D1/metabolismo
Proteínas de Ligação a DNA/química
Fator de Crescimento Epidérmico/farmacologia
Regulação da Expressão Gênica
Seres Humanos
Lisina/metabolismo
Modelos Biológicos
Nucleossomos/metabolismo
Fosfotreonina/metabolismo
Regiões Promotoras Genéticas
Domínios Proteicos
Proteólise
Proteínas Proto-Oncogênicas c-myc/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DNA-Binding Proteins); 0 (Histones); 0 (Nucleosomes); 0 (Proto-Oncogene Proteins c-myc); 0 (RNF8 protein, human); 1114-81-4 (Phosphothreonine); 136601-57-5 (Cyclin D1); 62229-50-9 (Epidermal Growth Factor); K3Z4F929H6 (Lysine)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170918
[Lr] Data última revisão:
170918
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170517
[St] Status:MEDLINE
[do] DOI:10.1084/jem.20170015


  7 / 1125 MEDLINE  
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[PMID]:28193222
[Au] Autor:Wang J; Nikhil K; Viccaro K; Chang L; White J; Shah K
[Ad] Endereço:Department of Chemistry and Purdue University Center for Cancer Research, Purdue University, 560 Oval Drive, West Lafayette, IN, 47907, USA.
[Ti] Título:Phosphorylation-dependent regulation of ALDH1A1 by Aurora kinase A: insights on their synergistic relationship in pancreatic cancer.
[So] Source:BMC Biol;15(1):10, 2017 Feb 13.
[Is] ISSN:1741-7007
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Epithelial-to-mesenchymal transition (EMT) and cancer stem cell (CSC) formation are key underlying causes that promote extensive metastasis, drug resistance, and tumor recurrence in highly lethal pancreatic cancer. The mechanisms leading to EMT and CSC phenotypes are not fully understood, which has hindered the development of effective targeted therapies capable of improving treatment outcomes in patients with pancreatic cancer. RESULTS: We show a central role of Aurora kinase A (AURKA) in promoting EMT and CSC phenotypes via ALDH1A1, which was discovered as its direct substrate using an innovative chemical genetic screen. AURKA phosphorylates ALDH1A1 at three critical residues which exert a multifaceted regulation over its level, enzymatic activity, and quaternary structure. While all three phosphorylation sites contribute to its increased stability, T267 phosphorylation primarily regulates ALDH1A1 activity. AURKA-mediated phosphorylation rapidly dissociates tetrameric ALDH1A1 into a highly active monomeric species. ALDH1A1 also reciprocates and prevents AURKA degradation, thereby triggering a positive feedback activation loop which drives highly aggressive phenotypes in cancer. Phospho-resistant ALDH1A1 fully reverses EMT and CSC phenotypes, thus serving as dominant negative, which underscores the clinical significance of the AURKA-ALDH1A1 signaling axis in pancreatic cancer. CONCLUSIONS: While increased levels and activity of ALDH1A1 are hallmarks of CSCs, the underlying molecular mechanism remains unclear. We show the first phosphorylation-dependent regulation of ALDH1A1, which increases its levels and activity via AURKA. Recent global phospho-proteomic screens have revealed increased phosphorylation of ALDH1A1 at the T267 site in human cancers and healthy liver tissues where ALDH1A1 is highly expressed and active, indicating that this regulation is likely crucial both in normal and diseased states. This is also the first study to demonstrate oligomer-dependent activity of ALDH1A1, signifying that targeting its oligomerization state may be an effective therapeutic approach for counteracting its protective functions in cancer. Finally, while AURKA inhibition provides a potent tool to reduce ALDH1A1 levels and activity, the reciprocal loop between them ensures that their concurrent inhibition will be highly synergistic when inhibiting tumorigenesis, chemoresistance, and metastasis in highly aggressive pancreatic cancer and beyond.
[Mh] Termos MeSH primário: Aldeído Desidrogenase/metabolismo
Aurora Quinase A/metabolismo
Neoplasias Pancreáticas/enzimologia
Neoplasias Pancreáticas/patologia
[Mh] Termos MeSH secundário: Linhagem Celular Tumoral
Movimento Celular
Resistência a Medicamentos Antineoplásicos
Estabilidade Enzimática
Transição Epitelial-Mesenquimal
Retroalimentação Fisiológica
Seres Humanos
Invasividade Neoplásica
Fenótipo
Fosforilação
Fosfotreonina/metabolismo
Multimerização Proteica
Transporte Proteico
Proteólise
Frações Subcelulares/enzimologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
1114-81-4 (Phosphothreonine); EC 1.2.1.3 (ALDH1A1 protein, human); EC 1.2.1.3 (Aldehyde Dehydrogenase); EC 2.7.11.1 (Aurora Kinase A)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171016
[Lr] Data última revisão:
171016
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170215
[St] Status:MEDLINE
[do] DOI:10.1186/s12915-016-0335-5


  8 / 1125 MEDLINE  
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[PMID]:27992122
[Au] Autor:Hymel D; Burke TR
[Ad] Endereço:Chemical Biology Laboratory, National Cancer Institute, National Institutes of Health, 1050 Boyles Street, Frederick, MD, 21702, USA.
[Ti] Título:Phosphatase-Stable Phosphoamino Acid Mimetics That Enhance Binding Affinities with the Polo-Box Domain of Polo-like Kinase 1.
[So] Source:ChemMedChem;12(3):202-206, 2017 Feb 03.
[Is] ISSN:1860-7187
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:(2S,3R)-2-Amino-3-methyl-4-phosphonobutanoic acid (Pmab) is a phosphatase-stable analogue of phosphothreonine (pThr), which has been used in a variety of biological contexts. Among these applications are peptidomimetic ligands that bind to the polo-box domain (PBD) of polo-like kinase 1 (Plk1) with affinities approaching that of the corresponding pThr-containing peptides. However, Pmab is not widely used, because there are no direct, high-yield preparations of suitably protected reagent. We have now achieved an efficient synthesis of protected Pmab, as well as variants with different substituents at the 3R center. When incorporated into our peptidomimetic scaffold, these new Pmab analogues exhibit Plk1 PBD-binding affinities that are several-fold higher than Pmab, yet retain good selectivity for Plk1 relative to the PBDs of Plk2 and Plk3. These findings will significantly impact the future development of PBD-binding inhibitors, as well as ligands directed against a broad spectrum of pThr-dependent processes.
[Mh] Termos MeSH primário: Proteínas de Ciclo Celular/metabolismo
Fosfoaminoácidos/química
Proteínas Serina-Treonina Quinases/metabolismo
Proteínas Proto-Oncogênicas/metabolismo
[Mh] Termos MeSH secundário: Sítios de Ligação
Proteínas de Ciclo Celular/química
Cristalografia por Raios X
Simulação de Dinâmica Molecular
Fosfoaminoácidos/metabolismo
Fosfotreonina/química
Isoformas de Proteínas/química
Isoformas de Proteínas/metabolismo
Estrutura Terciária de Proteína
Proteínas Serina-Treonina Quinases/química
Proteínas Proto-Oncogênicas/química
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cell Cycle Proteins); 0 (Phosphoamino Acids); 0 (Protein Isoforms); 0 (Proto-Oncogene Proteins); 1114-81-4 (Phosphothreonine); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); EC 2.7.11.1 (polo-like kinase 1)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:171106
[Lr] Data última revisão:
171106
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161220
[St] Status:MEDLINE
[do] DOI:10.1002/cmdc.201600574


  9 / 1125 MEDLINE  
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[PMID]:27735944
[Au] Autor:Zhuang K; Zhang J; Xiong M; Wang X; Luo X; Han L; Meng Y; Zhang Y; Liao W; Liu S
[Ad] Endereço:Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
[Ti] Título:CDK5 functions as a tumor promoter in human colorectal cancer via modulating the ERK5-AP-1 axis.
[So] Source:Cell Death Dis;7(10):e2415, 2016 Oct 13.
[Is] ISSN:2041-4889
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Abnormal expression of cyclin-dependent kinase 5 (CDK5) has been found in several human cancers, whereas the role of CDK5 in the malignant development of colorectal cancer (CRC) has not been well characterized. Here we investigated the role of CDK5 in CRC and found that its expression was much higher in CRC tissues than that in normal tissues with a higher expression level of CDK5 closely correlating to advanced American Joint Committee on Cancer (AJCC) stage, poor differentiation, increased tumor size and poor prognosis of CRC. Biological function experiments showed that CDK5 regulated CRC cell proliferation and metastasis ability. Whole-genome microarray analysis, co-immunoprecipitation, in vitro kinase assay, western blotting, luciferase reporter assays and electrophoretic mobility shift assay (EMSA) showed that CDK5 could directly phosphorylate ERK5 at threonine (Thr) 732 and finally modulate the oncogenic ERK5-AP-1 axis. Further researches showed that CDK5-ERK5-AP-1 axis could promote progression of CRC carcinogenesis and had a significant correlation in human CRC samples. In summary, this study revealed the functional and mechanistic links between CDK5 and the oncogenic ERK5-AP-1 signaling pathway in the pathogenesis of CRC. These findings suggest that CDK5 has an important role in CRC development and may serve as a potential therapeutic target for CRC.
[Mh] Termos MeSH primário: Neoplasias Colorretais/metabolismo
Neoplasias Colorretais/patologia
Quinase 5 Dependente de Ciclina/metabolismo
Proteína Quinase 7 Ativada por Mitógeno/metabolismo
Transdução de Sinais
Fator de Transcrição AP-1/metabolismo
[Mh] Termos MeSH secundário: Proteínas Adaptadoras de Transdução de Sinal
Carcinogênese/genética
Carcinogênese/patologia
Proteínas de Ciclo Celular
Linhagem Celular Tumoral
Movimento Celular/genética
Proliferação Celular/genética
Neoplasias Colorretais/genética
Progressão da Doença
Regulação para Baixo/genética
Feminino
Perfilação da Expressão Gênica
Regulação Neoplásica da Expressão Gênica
Técnicas de Silenciamento de Genes
Seres Humanos
Masculino
Meia-Idade
Invasividade Neoplásica
Metástase Neoplásica
Fosforilação
Fosfotreonina/metabolismo
Análise de Sobrevida
Regulação para Cima/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adaptor Proteins, Signal Transducing); 0 (CDCA5 protein, human); 0 (Cell Cycle Proteins); 0 (Transcription Factor AP-1); 1114-81-4 (Phosphothreonine); EC 2.7.11.1 (Cyclin-Dependent Kinase 5); EC 2.7.11.22 (CDK5 protein, human); EC 2.7.11.24 (MAPK7 protein, human); EC 2.7.11.24 (Mitogen-Activated Protein Kinase 7)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170731
[Lr] Data última revisão:
170731
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161014
[St] Status:MEDLINE
[do] DOI:10.1038/cddis.2016.333


  10 / 1125 MEDLINE  
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[PMID]:27715385
[Au] Autor:Wild F; Khan MM; Straka T; Rudolf R
[Ad] Endereço:a Interdisciplinary Center for Neurosciences, University of Heidelberg , Heidelberg , Germany.
[Ti] Título:Progress of endocytic CHRN to autophagic degradation is regulated by RAB5-GTPase and T145 phosphorylation of SH3GLB1 at mouse neuromuscular junctions in vivo.
[So] Source:Autophagy;12(12):2300-2310, 2016 Dec.
[Is] ISSN:1554-8635
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Endocytosed nicotinic acetylcholine receptors (CHRN) are degraded via macroautophagy/autophagy during atrophic conditions and are accompanied by the autophagic regulator protein SH3GLB1. The present study addressed the functional role of SH3GLB1 on CHRN trafficking and its implementation. We found an augmented ratio of total SH3GLB1 to threonine-145 phosphorylated SH3GLB1 (SH3GLB1:p-SH3GLB1) under conditions of increased CHRN vesicle numbers. Overexpression of T145 phosphomimetic (T145E) and phosphodeficient (T145A) mutants of SH3GLB1, was found to either slow down or augment the processing of endocytic CHRN vesicles, respectively. Co-expression of the early endosomal orchestrator RAB5 largely rescued the slow processing of endocytic CHRN vesicles induced by T145E. SH3GLB1 phosphomutants did not modulate the expression or colocalization of RAB5 with CHRN vesicles, but instead altered the expression of RAB5 activity regulators. In summary, these findings suggest that SH3GLB1 controls CHRN endocytic trafficking in a phosphorylation- and RAB5-dependent manner at steps upstream of autophagosome formation.
[Mh] Termos MeSH primário: Proteínas Adaptadoras de Transdução de Sinal/metabolismo
Autofagia
Endocitose
Junção Neuromuscular/metabolismo
Receptores Nicotínicos/metabolismo
Proteínas rab5 de Ligação ao GTP/metabolismo
[Mh] Termos MeSH secundário: Animais
Autofagia/efeitos dos fármacos
Cloroquina/farmacologia
Denervação
Endocitose/efeitos dos fármacos
Proteínas de Fluorescência Verde/metabolismo
Camundongos Endogâmicos C57BL
Músculo Esquelético/efeitos dos fármacos
Músculo Esquelético/inervação
Proteínas Mutantes/metabolismo
Junção Neuromuscular/efeitos dos fármacos
Fosforilação/efeitos dos fármacos
Fosfotreonina/metabolismo
Processamento de Proteína Pós-Traducional/efeitos dos fármacos
Nervo Isquiático/efeitos dos fármacos
Nervo Isquiático/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adaptor Proteins, Signal Transducing); 0 (Mutant Proteins); 0 (Receptors, Nicotinic); 0 (Sh3glb1 protein, mouse); 1114-81-4 (Phosphothreonine); 147336-22-9 (Green Fluorescent Proteins); 886U3H6UFF (Chloroquine); EC 3.6.5.2 (rab5 GTP-Binding Proteins)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171113
[Lr] Data última revisão:
171113
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161008
[St] Status:MEDLINE



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