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[PMID]:27777073
[Au] Autor:Hau AM; Leivo MZ; Gilder AS; Hu JJ; Gonias SL; Hansel DE
[Ad] Endereço:Departments of Pathology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, United States.
[Ti] Título:mTORC2 activation is regulated by the urokinase receptor (uPAR) in bladder cancer.
[So] Source:Cell Signal;29:96-106, 2017 01.
[Is] ISSN:1873-3913
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Mammalian target of rapamycin complex 2 (mTORC2) has been identified as a major regulator of bladder cancer cell migration and invasion. Upstream pathways that mediate mTORC2 activation remain poorly defined. Urokinase-type plasminogen activator receptor (uPAR) is a GPI-anchored membrane protein and known activator of cell-signaling. We identified increased uPAR expression in 94% of invasive human bladder cancers and in 54-71% of non-invasive bladder cancers, depending on grade. Normal urothelium was uPAR-immunonegative. Analysis of publicly available datasets identified uPAR gene amplification or mRNA upregulation in a subset of bladder cancer patients with reduced overall survival. Using biochemical approaches, we showed that uPAR activates mTORC2 in bladder cancer cells. Highly invasive bladder cancer cell lines, including T24, J82 and UM-UC-3 cells, showed increased uPAR mRNA expression and protein levels compared with the less aggressive cell lines, UROtsa and RT4. uPAR gene-silencing significantly reduced phosphorylation of Serine-473 in Akt, an mTORC2 target. uPAR gene-silencing also reduced bladder cancer cell migration and Matrigel invasion. S473 phosphorylation was observed by immunohistochemistry in human bladder cancers only when the tumors expressed high levels of uPAR. S473 phosphorylation was not controlled by uPAR in bladder cancer cell lines that are PTEN-negative; however, this result probably did not reflect altered mTORC2 regulation. Instead, PTEN deficiency de-repressed alternative kinases that phosphorylate S473. Our results suggest that uPAR and mTORC2 are components of a single cell-signaling pathway. Targeting uPAR or mTORC2 may be beneficial in patients with bladder cancer.
[Mh] Termos MeSH primário: Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo
Receptores de Ativador de Plasminogênio Tipo Uroquinase/metabolismo
Neoplasias da Bexiga Urinária/metabolismo
Neoplasias da Bexiga Urinária/patologia
[Mh] Termos MeSH secundário: Adulto
Idoso
Idoso de 80 Anos ou mais
Linhagem Celular Tumoral
Movimento Celular
Feminino
Regulação Neoplásica da Expressão Gênica
Seres Humanos
Masculino
Meia-Idade
Gradação de Tumores
Invasividade Neoplásica
Fosforilação
Fosfosserina/metabolismo
Prognóstico
Proteínas Proto-Oncogênicas c-akt/metabolismo
Regulação para Cima
Neoplasias da Bexiga Urinária/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Receptors, Urokinase Plasminogen Activator); 17885-08-4 (Phosphoserine); EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:180124
[Lr] Data última revisão:
180124
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161107
[St] Status:MEDLINE


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[PMID]:28465465
[Au] Autor:Stutz A; Kolbe CC; Stahl R; Horvath GL; Franklin BS; van Ray O; Brinkschulte R; Geyer M; Meissner F; Latz E
[Ad] Endereço:Institute of Innate Immunity, University Hospital, University of Bonn, 53127 Bonn, Germany.
[Ti] Título:NLRP3 inflammasome assembly is regulated by phosphorylation of the pyrin domain.
[So] Source:J Exp Med;214(6):1725-1736, 2017 Jun 05.
[Is] ISSN:1540-9538
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:NLRP3 is a cytosolic pattern recognition receptor that senses microbes and endogenous danger signals. Upon activation, NLRP3 forms an inflammasome with the adapter ASC, resulting in caspase-1 activation, release of proinflammatory cytokines and cell death. How NLRP3 activation is regulated by transcriptional and posttranslational mechanisms to prevent aberrant activation remains incompletely understood. Here, we identify three conserved phosphorylation sites in NLRP3 and demonstrate that NLRP3 activation is controlled by phosphorylation of its pyrin domain (PYD). Phosphomimetic residues in NLRP3 PYD abrogate inflammasome activation and structural modeling indicates that phosphorylation of the PYD regulates charge-charge interaction between two PYDs that are essential for NLRP3 activation. Phosphatase 2A (PP2A) inhibition or knock-down drastically reduces NLRP3 activation, showing that PP2A can license inflammasome assembly via dephosphorylating NLRP3 PYD. These results propose that the balance between kinases and phosphatases acting on the NLRP3 PYD is critical for NLRP3 activation.
[Mh] Termos MeSH primário: Inflamassomos/metabolismo
Proteína 3 que Contém Domínio de Pirina da Família NLR/química
Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo
Pirina/química
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Animais
Células HEK293
Seres Humanos
Camundongos
Modelos Biológicos
Modelos Moleculares
Fosforilação
Fosfosserina/metabolismo
Ligação Proteica
Domínios Proteicos
Proteína Fosfatase 2/metabolismo
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Inflammasomes); 0 (NLR Family, Pyrin Domain-Containing 3 Protein); 0 (Nlrp3 protein, mouse); 0 (Pyrin); 17885-08-4 (Phosphoserine); EC 3.1.3.16 (Protein Phosphatase 2)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171205
[Lr] Data última revisão:
171205
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170504
[St] Status:MEDLINE
[do] DOI:10.1084/jem.20160933


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[PMID]:28864417
[Au] Autor:Shen LT; Chou HE; Kato M
[Ad] Endereço:School of Integrative and Global Majors, University of Tsukuba, Tsukuba, Japan; Department of Experimental Pathology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
[Ti] Título:TIF1ß is phosphorylated at serine 473 in colorectal tumor cells through p38 mitogen-activated protein kinase as an oxidative defense mechanism.
[So] Source:Biochem Biophys Res Commun;492(3):310-315, 2017 Oct 21.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:TIF1ß is a pleiotropic regulator of a diverse range of cellular processes such as DNA repair or gene repression in stem cells. This functional switch depends on phosphorylation at serine residue 473 and multiple pathways exist to accomplish this. However, the effects of exogenous reactive oxygen species (ROS) generated by bacterial flora and dietary metabolites in the colonic lumen or chemotherapy on TIF1ß have not been determined. We report here that exposure of colorectal cancer (CRC) cell lines DLD-1 and HCT116 to hydrogen peroxide specifically induces TIF1ß Ser473 phosphorylation. Hydrogen peroxide also induces primarily p38 MAPK and some p42/44 MAPK phosphorylation. Chemical inhibition of p38 MAPK and p42/44 MAPK reduced phosphorylation of TIF1ß serine 473 and increased CRC cell death upon peroxide exposure. Taken together, this suggests that it is primarily peroxide-induced p38 MAPK that mediates Ser473 phosphorylation and activation of TIF1ß to enable more efficient DNA repair to assist in tumor cell survival against exogenous ROS.
[Mh] Termos MeSH primário: Neoplasias Colorretais/metabolismo
Neoplasias Colorretais/patologia
Estresse Oxidativo
Fosfosserina/metabolismo
Proteínas Repressoras/química
Proteínas Repressoras/metabolismo
Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
[Mh] Termos MeSH secundário: Morte Celular/efeitos dos fármacos
Células Cultivadas
Relação Dose-Resposta a Droga
Células HCT116
Células HEK293
Seres Humanos
Peróxido de Hidrogênio/farmacologia
Estresse Oxidativo/efeitos dos fármacos
Fosforilação/efeitos dos fármacos
RNA Interferente Pequeno/farmacologia
Proteínas Repressoras/antagonistas & inibidores
Relação Estrutura-Atividade
Proteína 28 com Motivo Tripartido
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (RNA, Small Interfering); 0 (Repressor Proteins); 17885-08-4 (Phosphoserine); BBX060AN9V (Hydrogen Peroxide); EC 2.3.2.27 (TRIM28 protein, human); EC 2.3.2.27 (Tripartite Motif-Containing Protein 28); EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170903
[St] Status:MEDLINE


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[PMID]:28843494
[Au] Autor:Masselink W; Masaki M; Sieiro D; Marcelle C; Currie PD
[Ad] Endereço:Australian Regenerative Medicine Institute, Level 1, Building 75, Monash University, Wellington Road, Clayton, VIC 3800, Australia; Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Campus-Vienna-Biocenter 1, 1030 Vienna, Austria.
[Ti] Título:Phosphorylation of Lbx1 controls lateral myoblast migration into the limb.
[So] Source:Dev Biol;430(2):302-309, 2017 10 15.
[Is] ISSN:1095-564X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The migration of limb myogenic precursors from limb level somites to their ultimate site of differentiation in the limb is a paradigmatic example of a set of dynamic and orchestrated migratory cell behaviours. The homeobox containing transcription factor ladybird homeobox 1 (Lbx1) is a central regulator of limb myoblast migration, null mutations of Lbx1 result in severe disruptions to limb muscle formation, particularly in the distal region of the limb in mice (Gross et al., 2000). As such Lbx1 has been hypothesized to control lateral migration of myoblasts into the distal limb anlage. It acts as a core regulator of the limb myoblast migration machinery, controlled by Pax3. A secondary role for Lbx1 in the differentiation and commitment of limb musculature has also been proposed (Brohmann et al., 2000; Uchiyama et al., 2000). Here we show that lateral migration, but not differentiation or commitment of limb myoblasts, is controlled by the phosphorylation of three adjacent serine residues of LBX1. Electroporation of limb level somites in the chick embryo with a dephosphomimetic form of Lbx1 results in a specific defect in the lateral migration of limb myoblasts. Although the initial delamination and migration of myoblasts is unaffected, migration into the distal limb bud is severely disrupted. Interestingly, myoblasts undergo normal differentiation independent of their migratory status, suggesting that the differentiation potential of hypaxial muscle is not regulated by the phosphorylation state of LBX1. Furthermore, we show that FGF8 and ERK mediated signal transduction, both critical regulators of the developing limb bud, have the capacity to induce the phosphorylation of LBX1 at these residues. Overall, this suggests a mechanism whereby the phosphorylation of LBX1, potentially through FGF8 and ERK signalling, controls the lateral migration of myoblasts into the distal limb bud.
[Mh] Termos MeSH primário: Extremidades/embriologia
Mioblastos/citologia
Fatores de Transcrição/fisiologia
Proteínas de Peixe-Zebra/fisiologia
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Animais
Movimento Celular
Células Cultivadas
Embrião de Galinha
MAP Quinases Reguladas por Sinal Extracelular/fisiologia
Fator 8 de Crescimento de Fibroblasto/fisiologia
Seres Humanos
Camundongos
Mutação
Fosforilação/efeitos dos fármacos
Fosfosserina/metabolismo
Processamento de Proteína Pós-Traducional/efeitos dos fármacos
Proteínas Recombinantes/genética
Proteínas Recombinantes/metabolismo
Alinhamento de Sequência
Homologia de Sequência de Aminoácidos
Somitos/citologia
Especificidade da Espécie
Fatores de Transcrição/genética
Peixe-Zebra/genética
Proteínas de Peixe-Zebra/genética
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Lbx1 protein, zebrafish); 0 (Recombinant Proteins); 0 (Transcription Factors); 0 (Zebrafish Proteins); 148997-75-5 (Fibroblast Growth Factor 8); 17885-08-4 (Phosphoserine); EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171111
[Lr] Data última revisão:
171111
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170828
[St] Status:MEDLINE


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[PMID]:28807902
[Au] Autor:Li Y; Wang C; Cai W; Sengupta S; Zavortink M; Deng H; Girton J; Johansen J; Johansen KM
[Ad] Endereço:Roy J. Carver Department of Biochemistry, Biophysics, and Molecular Biology, Iowa State University, Ames, Iowa 50011, USA.
[Ti] Título:H2Av facilitates H3S10 phosphorylation but is not required for heat shock-induced chromatin decondensation or transcriptional elongation.
[So] Source:Development;144(18):3232-3240, 2017 09 15.
[Is] ISSN:1477-9129
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:A model has been proposed in which JIL-1 kinase-mediated H3S10 and H2Av phosphorylation is required for transcriptional elongation and heat shock-induced chromatin decondensation. However, here we show that although H3S10 phosphorylation is indeed compromised in the null mutant, chromatin decondensation at heat shock loci is unaffected in the absence of JIL-1 as well as of H2Av and that there is no discernable decrease in the elongating form of RNA polymerase II in either mutant. Furthermore, mRNA for the major heat shock protein Hsp70 is transcribed at robust levels in both and null mutants. Using a different chromatin remodeling paradigm that is JIL-1 dependent, we provide evidence that ectopic tethering of JIL-1 and subsequent H3S10 phosphorylation recruits PARP-1 to the remodeling site independently of H2Av phosphorylation. These data strongly suggest that H2Av or H3S10 phosphorylation by JIL-1 is not required for chromatin decondensation or transcriptional elongation in .
[Mh] Termos MeSH primário: Cromatina/metabolismo
Proteínas de Drosophila/metabolismo
Drosophila melanogaster/metabolismo
Histonas/metabolismo
Fosfosserina/metabolismo
Elongação da Transcrição Genética
[Mh] Termos MeSH secundário: Animais
Eucromatina/metabolismo
Proteínas de Fluorescência Verde/metabolismo
Resposta ao Choque Térmico/genética
Immunoblotting
Imuno-Histoquímica
Óperon Lac/genética
Mutação/genética
Fosforilação
Poli(ADP-Ribose) Polimerases/metabolismo
Cromossomos Politênicos/metabolismo
Proteínas Serina-Treonina Quinases/metabolismo
Transgenes
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Chromatin); 0 (Drosophila Proteins); 0 (Euchromatin); 0 (H2AV protein, Drosophila); 0 (Histones); 147336-22-9 (Green Fluorescent Proteins); 17885-08-4 (Phosphoserine); EC 2.4.2.30 (Poly(ADP-ribose) Polymerases); EC 2.7.11.1 (JIL-1 protein, Drosophila); EC 2.7.11.1 (Protein-Serine-Threonine Kinases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171126
[Lr] Data última revisão:
171126
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170816
[St] Status:MEDLINE
[do] DOI:10.1242/dev.151134


  6 / 2960 MEDLINE  
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[PMID]:28754590
[Au] Autor:Song KH; Bae SJ; Chang J; Park JH; Jo I; Cho KW; Cho DH
[Ad] Endereço:Division of Endocrinology and Metabolism, Department of Internal Medicine, Konkuk University School of Medicine, 120-1, Neungdong-ro, Hwayang-dong, Gwangjin-gu, Seoul 05030, South Korea.
[Ti] Título:Telmisartan mitigates hyperglycemia-induced vascular inflammation by increasing GSK3ß-Ser phosphorylation in endothelial cells and mouse aortas.
[So] Source:Biochem Biophys Res Commun;491(4):903-911, 2017 Sep 30.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Telmisartan, an angiotensin II type 1 receptor blocker (ARB), attenuates hyperglycemia-aggravated vascular inflammation by decreasing IκB kinase ß (IKKß) expression in endothelial cells. Because glycogen synthase 3ß (GSK3ß) is involved in inflammatory process by regulating nuclear factor-κB (NF-κB) activity, we investigated whether GSK3ß mediates telmisartan-ameliorated vascular inflammation in hyperglycemia-treated endothelial cells and high-fat diet (HFD)-fed mice. Telmisartan remarkably induced GSK3ß-Ser phosphorylation in hyperglycemia-treated endothelial cells that accompanied a decrease in hyperglycemia-induced NF-κB p65-Ser phosphorylation, vascular cell adhesion molecule-1 (VCAM-1) expression, and THP-1 monocyte adhesion. Ectopic expression of GSK3ß-S9A, a constitutively active mutant of GSK3ß, significantly restored complete telmisartan-inhibited NF-κB p65-Ser phosphorylation, VCAM-1 expression, and THP-1 monocyte adhesion. In addition, it reversed telmisartan-repressed IKKß expression. Among the ARB, including losartan and fimasartan, only telmisartan increased GSK3ß-Ser phosphorylation, and telmisartan-induced GSK3ß-Ser phosphorylation remained unchanged by pretreatment with GW9662, a specific and irreversible peroxisome proliferator-activated receptor γ (PPARγ) antagonist. Finally, in the aortas of HFD-fed mice, telmisartan treatment significantly attenuated HFD-induced upregulation of NF-κB p65-Ser phosphorylation, VCAM-1 expression, and IKKß expression and downregulation of GSK3ß-Ser phosphorylation. Taken together, our findings demonstrated that telmisartan ameliorates hyperglycemia-exacerbated vascular inflammation, at least in part, by inducing GSK3ß-Ser phosphorylation, which consequently inhibits IKKß expression, NF-κB p65-Ser phosphorylation, and VCAM-1 expression in a PPARγ-independent manner.
[Mh] Termos MeSH primário: Aorta/efeitos dos fármacos
Benzimidazóis/farmacologia
Benzoatos/farmacologia
Células Endoteliais/efeitos dos fármacos
Glicogênio Sintase Quinase 3 beta/metabolismo
Hiperglicemia/tratamento farmacológico
Inflamação/tratamento farmacológico
Fosfosserina/metabolismo
Vasculite/tratamento farmacológico
[Mh] Termos MeSH secundário: Animais
Aorta/metabolismo
Benzimidazóis/administração & dosagem
Benzoatos/administração & dosagem
Bovinos
Células Cultivadas
Relação Dose-Resposta a Droga
Células Endoteliais/metabolismo
Hiperglicemia/metabolismo
Inflamação/metabolismo
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Fosforilação/efeitos dos fármacos
Relação Estrutura-Atividade
Vasculite/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Benzimidazoles); 0 (Benzoates); 17885-08-4 (Phosphoserine); EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta); U5SYW473RQ (telmisartan)
[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:170730
[St] Status:MEDLINE


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[PMID]:28715213
[Au] Autor:Sayama M; Inoue A; Nakamura S; Jung S; Ikubo M; Otani Y; Uwamizu A; Kishi T; Makide K; Aoki J; Hirokawa T; Ohwada T
[Ad] Endereço:Laboratory of Organic and Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo , 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
[Ti] Título:Probing the Hydrophobic Binding Pocket of G-Protein-Coupled Lysophosphatidylserine Receptor GPR34/LPS by Docking-Aided Structure-Activity Analysis.
[So] Source:J Med Chem;60(14):6384-6399, 2017 Jul 27.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The ligands of certain G-protein-coupled receptors (GPCRs) have been identified as endogenous lipids, such as lysophosphatidylserine (LysoPS). Here, we analyzed the molecular basis of the structure-activity relationship of ligands of GPR34, one of the LysoPS receptor subtypes, focusing on recognition of the long-chain fatty acid moiety by the hydrophobic pocket. By introducing benzene ring(s) into the fatty acid moiety of 2-deoxy-LysoPS, we explored the binding site's preference for the hydrophobic shape. A tribenzene-containing fatty acid surrogate with modifications of the terminal aromatic moiety showed potent agonistic activity toward GPR34. Computational docking of these derivatives with a homology modeling/molecular dynamics-based virtual binding site of GPR34 indicated that a kink in the benzene-based lipid surrogates matches the L-shaped hydrophobic pocket of GPR34. A tetrabenzene-based lipid analogue bearing a bulky tert-butyl group at the 4-position of the terminal benzene ring exhibited potent GPR34 agonistic activity, validating the present hydrophobic binding pocket model.
[Mh] Termos MeSH primário: Derivados de Benzeno/química
Ácidos Graxos/química
Fosfosserina/análogos & derivados
Receptores de Lisofosfolipídeos/química
[Mh] Termos MeSH secundário: Animais
Derivados de Benzeno/síntese química
Derivados de Benzeno/farmacologia
Sítios de Ligação
Ácidos Graxos/síntese química
Ácidos Graxos/farmacologia
Células HEK293
Seres Humanos
Interações Hidrofóbicas e Hidrofílicas
Camundongos
Simulação de Acoplamento Molecular
Simulação de Dinâmica Molecular
Fosfosserina/síntese química
Fosfosserina/química
Fosfosserina/farmacologia
Receptores de Lisofosfolipídeos/agonistas
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Benzene Derivatives); 0 (Fatty Acids); 0 (G-protein-coupled receptor 34); 0 (Receptors, Lysophospholipid); 17885-08-4 (Phosphoserine)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170906
[Lr] Data última revisão:
170906
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170718
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jmedchem.7b00693


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[PMID]:28705041
[Au] Autor:Graves PR; Din SU; Ashamalla M; Ashamalla H; Gilbert TSK; Graves LM
[Ad] Endereço:a Department of Radiation Oncology , New York-Presbyterian Brooklyn Methodist Hospital , Brooklyn , NY , USA.
[Ti] Título:Ionizing radiation induces EphA2 S897 phosphorylation in a MEK/ERK/RSK-dependent manner.
[So] Source:Int J Radiat Biol;93(9):929-936, 2017 Sep.
[Is] ISSN:1362-3095
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:PURPOSE: The EphA2 tyrosine kinase is frequently overexpressed in human tumors that are also treated with radiation. However, few studies have examined the effect of radiation on the EphA2 receptor itself. The purpose of this project was to investigate the impact of radiation on EphA2 to better understand mechanisms of radioresistance. MATERIALS AND METHODS: Cell lines were exposed to X-rays and assayed for changes in EphA2 protein levels and phosphorylation over time by Western blotting. HEK293 cells stably expressing wild-type EphA2 or the S897A mutant were analyzed for cell survival from X-rays. RESULTS: Treatment of different cancer cell lines with 2 Gy of X-rays induced the phosphorylation of EphA2 on S897 but no changes were found in EphA2 total levels or its tyrosine phosphorylation. Radiation-induced S897 phosphorylation was unaffected by an AKT inhibitor but blocked by a MEK or RSK inhibitor. HEK293 cells expressing the EphA2 S897A mutant had a nearly 2-fold lower level of cell survival from X-rays than cells expressing wild-type EphA2. CONCLUSIONS: These findings show that radiation induces S897 EphA2 phosphorylation, an event associated with increased cell survival. Therefore, targeting pathways that mediate EphA2 S897 phosphorylation may be a beneficial strategy to reduce radioresistance.
[Mh] Termos MeSH primário: Sobrevivência Celular/fisiologia
Sobrevivência Celular/efeitos da radiação
Sistema de Sinalização das MAP Quinases/fisiologia
Sistema de Sinalização das MAP Quinases/efeitos da radiação
Fosfosserina/metabolismo
Radiação Ionizante
Receptor EphA2/metabolismo
[Mh] Termos MeSH secundário: Relação Dose-Resposta à Radiação
Células HEK293
Seres Humanos
Fosforilação/efeitos da radiação
Dose de Radiação
Proteínas Quinases S6 Ribossômicas 90-kDa/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
17885-08-4 (Phosphoserine); EC 2.7.10.1 (Receptor, EphA2); EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 90-kDa)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM; S
[Da] Data de entrada para processamento:170715
[St] Status:MEDLINE
[do] DOI:10.1080/09553002.2017.1355580


  9 / 2960 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


  10 / 2960 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



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