Base de dados : MEDLINE Pesquisa : D08.811.913.696.620.682.700.646 [Categoria DeCS] Referências encontradas : 50 [refinar] Mostrando: 1 .. 10   no formato [Detalhado]

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[PMID]: 22742992 [Au] Autor: Martin L; Latypova X; Wilson CM; Magnaudeix A; Perrin ML; Yardin C; Terro F [Ad] Endereço: Groupe de Neurobiologie Cellulaire - Homéostasie cellulaire et pathologies, Faculté de Médecine, Limoges, France. lmartin.phd@gmail.com [Ti] Título: Tau protein kinases: involvement in Alzheimer's disease. [So] Source: Ageing Res Rev;12(1):289-309, 2013 Jan. [Is] ISSN: 1872-9649 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Tau phosphorylation is regulated by a balance between tau kinase and phosphatase activities. Disruption of this equilibrium was suggested to be at the origin of abnormal tau phosphorylation and thereby might contribute to tau aggregation. Thus, understanding the regulation modes of tau phosphorylation is of high interest in determining the possible causes at the origin of the formation of tau aggregates in order to elaborate protection strategies to cope with these lesions in Alzheimer's disease. Among the possible and specific interventions that reverse tau phosphorylation is the inhibition of certain tau kinases. Here, we extensively reviewed tau protein kinases, their physiological roles and regulation, their involvement in tau phosphorylation and their relevance to AD. We also reviewed the most common inhibitory compounds acting on each tau kinase. [Mh] Termos MeSH primário: Doença de Alzheimer/enzimologia Quinase 3 da Glicogênio Sintase/fisiologia Proteínas tau/fisiologia [Mh] Termos MeSH secundário: Doença de Alzheimer/genética Doença de Alzheimer/metabolismo Animais Quinase 3 da Glicogênio Sintase/genética Seres Humanos Fosforilação Proteínas Quinases Direcionadas a Prolina/genética Proteínas Quinases Direcionadas a Prolina/fisiologia Proteínas Tirosina Quinases/genética Proteínas Tirosina Quinases/fisiologia Proteínas tau/genética Proteínas tau/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; REVIEW [Nm] Nome de substância: 0 (tau Proteins); EC 2.7.10.1 (Protein-Tyrosine Kinases); EC 2.7.11.- (Proline-Directed Protein Kinases); EC 2.7.11.26 (Glycogen Synthase Kinase 3); EC 2.7.11.26 (tau-protein kinase) [Em] Mês de entrada: 1306 [Cu] Atualização por classe: 130121 [Lr] Data última revisão: 130121 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 120630 [St] Status: MEDLINE

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[PMID]: 22561452 [Au] Autor: Hu JH; Yang L; Kammermeier PJ; Moore CG; Brakeman PR; Tu J; Yu S; Petralia RS; Li Z; Zhang PW; Park JM; Dong X; Xiao B; Worley PF [Ad] Endereço: Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA. [Ti] Título: Preso1 dynamically regulates group I metabotropic glutamate receptors. [So] Source: Nat Neurosci;15(6):836-44, 2012 Jun. [Is] ISSN: 1546-1726 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Group I metabotropic glutamate receptors (mGluRs), including mGluR1 and mGluR5, are G protein­coupled receptors (GPCRs) that are expressed at excitatory synapses in brain and spinal cord. GPCRs are often negatively regulated by specific G protein­coupled receptor kinases and subsequent binding of arrestin-like molecules. Here we demonstrate an alternative mechanism in which group I mGluRs are negatively regulated by proline-directed kinases that phosphorylate the binding site for the adaptor protein Homer, and thereby enhance mGluR­Homer binding to reduce signaling. This mechanism is dependent on a multidomain scaffolding protein, Preso1, that binds mGluR, Homer and proline-directed kinases and that is required for their phosphorylation of mGluR at the Homer binding site. Genetic ablation of Preso1 prevents dynamic phosphorylation of mGluR5, and Preso1(−/−) mice exhibit sustained, mGluR5-dependent inflammatory pain that is linked to enhanced mGluR signaling. Preso1 creates a microdomain for proline-directed kinases with broad substrate specificity to phosphorylate mGluR and to mediate negative regulation. [Mh] Termos MeSH primário: Proteínas de Transporte/metabolismo Neurônios/metabolismo Receptores de Glutamato Metabotrópico/metabolismo Transdução de Sinais/fisiologia [Mh] Termos MeSH secundário: Sequência de Aminoácidos Animais Western Blotting Encéfalo/metabolismo Proteínas de Transporte/química Células HEK293 Proteínas de Arcabouço Homer Seres Humanos Imuno-Histoquímica Imunoprecipitação Masculino Camundongos Camundongos Knockout Dados de Sequência Molecular Fosforilação Densidade Pós-Sináptica Proteínas Quinases Direcionadas a Prolina/metabolismo Ligação Proteica Estrutura Terciária de Proteína Ratos Ratos Wistar Receptores de Glutamato Metabotrópico/química Transfecção [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, N.I.H., INTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Carrier Proteins); 0 (Homer Scaffolding Proteins); 0 (Receptors, Metabotropic Glutamate); EC 2.7.11.- (Proline-Directed Protein Kinases) [Em] Mês de entrada: 1209 [Cu] Atualização por classe: 170220 [Lr] Data última revisão: 170220 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 120508 [St] Status: MEDLINE [do] DOI: 10.1038/nn.3103

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[PMID]: 20861372 [Au] Autor: Ko HW; Kim EY; Chiu J; Vanselow JT; Kramer A; Edery I [Ad] Endereço: Neurodegeneration Control Research Center, School of Medicine, Kyung Hee University, Seoul, 130-701, South Korea. [Ti] Título: A hierarchical phosphorylation cascade that regulates the timing of PERIOD nuclear entry reveals novel roles for proline-directed kinases and GSK-3beta/SGG in circadian clocks. [So] Source: J Neurosci;30(38):12664-75, 2010 Sep 22. [Is] ISSN: 1529-2401 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: The daily timing of when PERIOD (PER) proteins translocate from the cytoplasm to the nucleus is a critical step in clock mechanisms underpinning circadian rhythms in animals. Numerous lines of evidence indicate that phosphorylation plays a prominent role in regulating various aspects of PER function and metabolism, including changes in its daily stability and subcellular distribution. In this report, we show that phosphorylation of serine 661 (Ser661) by a proline-directed kinase(s) is a key phospho-signal on the Drosophila PER protein (dPER) that regulates the timing of its nuclear accumulation. Mutations that block phosphorylation at Ser661 do not affect dPER stability but delay its nuclear entry in key pacemaker neurons, yielding longer behavioral rhythms. Intriguingly, abolishing phosphorylation at Ser661 also attenuates the extent of dPER hyperphosphorylation in vivo, suggesting the phosphorylated state of Ser661 regulates phosphorylation at other sites on dPER. Indeed, we identify Ser657 as a site that is phosphorylated by the glycogen synthase kinase GSK-3ß (SHAGGY; SGG) in a manner dependent on priming at Ser661. Although not as dramatic as mutating Ser661, mutations that abolish phosphorylation at Ser657 also lead to longer behavioral periods, suggesting that a multi-kinase hierarchical phosphorylation module regulates the timing of dPER nuclear entry. Together with evidence in mammalian systems, our findings implicate proline-directed kinases in clock mechanisms and suggest that PER proteins are key downstream targets of lithium therapy, a potent inhibitor of GSK-3ß used to treat manic depression, a disorder associated with clock malfunction in humans. [Mh] Termos MeSH primário: Núcleo Celular/metabolismo Ritmo Circadiano/fisiologia Proteínas de Drosophila/metabolismo Proteínas Circadianas Period/metabolismo Fosforilação/fisiologia Proteínas Quinases Direcionadas a Prolina/metabolismo Transdução de Sinais/fisiologia [Mh] Termos MeSH secundário: Animais Animais Geneticamente Modificados Western Blotting Núcleo Celular/genética Drosophila Proteínas de Drosophila/genética Atividade Motora/fisiologia Proteínas Circadianas Period/genética Proteínas Quinases Direcionadas a Prolina/genética Transporte Proteico/fisiologia Reação em Cadeia da Polimerase Via Transcriptase Reversa [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Drosophila Proteins); 0 (PER protein, Drosophila); 0 (Period Circadian Proteins); EC 2.7.11.- (Proline-Directed Protein Kinases) [Em] Mês de entrada: 1010 [Cu] Atualização por classe: 170220 [Lr] Data última revisão: 170220 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 100924 [St] Status: MEDLINE [do] DOI: 10.1523/JNEUROSCI.1586-10.2010

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[PMID]: 20484411 [Au] Autor: Sierra OL; Towler DA [Ad] Endereço: Washington University School of Medicine, Internal Medicine-Endocrinology/Metabolism, Campus Box 8301, 660 South Euclid Avenue, St. Louis, Missouri 63110, USA. towler@im.wustl.edu [Ti] Título: Runx2 trans-activation mediated by the MSX2-interacting nuclear target requires homeodomain interacting protein kinase-3. [So] Source: Mol Endocrinol;24(7):1478-97, 2010 Jul. [Is] ISSN: 1944-9917 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Runt-related transcription factor 2 (Runx2) and muscle segment homeobox homolog 2-interacting nuclear target (MINT) (Spen homolog) are transcriptional regulators critical for mammalian development. MINT enhances Runx2 activation of osteocalcin (OC) fibroblast growth factor (FGF) response element in an FGF2-dependent fashion in C3H10T1/2 cells. Although the MINT N-terminal RNA recognition motif domain contributes, the muscle segment homeobox homolog 2-interacting domain is sufficient for Runx2 activation. Intriguingly, Runx1 cannot replace Runx2 in this assay. To better understand this Runx2 signaling cascade, we performed structure-function analysis of the Runx2-MINT trans-activation relationship. Systematic truncation and domain swapping in Runx1:Runx2 chimeras identified that the unique Runx2 activation domain 3 (AD3), encompassed by residues 316-421, conveys MINT+FGF2 trans-activation in transfection assays. Ala mutagenesis of Runx2 Ser/Thr residues identified that S301 and T326 in AD3 are necessary for full MINT+FGF2 trans-activation. Conversely, phosphomimetic Asp substitution of these AD3 Ser/Thr residues enhanced activation by MINT. Adjacent Pro residues implicated regulation by a proline-directed protein kinase (PDPK). Systematic screening with PDPK inhibitors identified that the casein kinase-2/homeodomain-interacting protein kinase (HIPK)/dual specificity tyrosine phosphorylation regulated kinase inhibitor 2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole (DMAT), but not ERK, c-Jun N-terminal kinase, p38MAPK, or other casein kinase-2 inhibitors, abrogated Runx2-, MINT-, and FGF2-activation. Systematic small interfering RNA-mediated silencing of DMAT-inhibited PDPKs revealed that HIPK3 depletion reduced MINT+FGF2-dependent activation of Runx2. HIPK3 and Runx2 coprecipitate after in vitro transcription-translation, and recombinant HIPK3 recognizes Runx2 AD3 as kinase substrate. Furthermore, DMAT treatment and HIPK3 RNAi inhibited MINT+FGF2 activation of Runx2 AD3, and nuclear HIPK3 colocalized with MINT. HIPK3 antisense oligodeoxynucleotide selectively reduced Runx2 protein accumulation and OC gene expression in C3H10T1/2 cells. Thus, HIPK3 participates in MINT+FGF2 regulation of Runx2 AD3 activity and controls Runx2-dependent OC expression. [Mh] Termos MeSH primário: Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo Proteínas Nucleares/metabolismo Proteínas Serina-Treonina Quinases/metabolismo [Mh] Termos MeSH secundário: Animais Benzimidazóis/farmacologia Linhagem Celular Subunidade alfa 1 de Fator de Ligação ao Core/genética Inativação Gênica Imunoprecipitação Camundongos Microscopia Confocal Proteínas Nucleares/genética Fosforilação Proteínas Quinases Direcionadas a Prolina/antagonistas & inibidores Proteínas Quinases Direcionadas a Prolina/genética Proteínas Quinases Direcionadas a Prolina/metabolismo Ligação Proteica Estrutura Terciária de Proteína/genética Estrutura Terciária de Proteína/fisiologia Proteínas Serina-Treonina Quinases/genética RNA Antissenso RNA Interferente Pequeno Ativação Transcricional [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole); 0 (Benzimidazoles); 0 (Core Binding Factor Alpha 1 Subunit); 0 (Nuclear Proteins); 0 (RNA, Antisense); 0 (RNA, Small Interfering); 0 (Spen protein, mouse); EC 2.7.11.- (Proline-Directed Protein Kinases); EC 2.7.11.1 (Protein-Serine-Threonine Kinases) [Em] Mês de entrada: 1009 [Cu] Atualização por classe: 161019 [Lr] Data última revisão: 161019 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 100521 [St] Status: MEDLINE [do] DOI: 10.1210/me.2010-0029

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[PMID]: 19566594 [Au] Autor: Bai L; Zhang G; Zhou Y; Zhang Z; Wang W; Du Y; Wu Z; Song CP [Ad] Endereço: Henan Key Laboratory of Plant Stress Biology, Department of Biology, Henan University, Kaifeng, China. [Ti] Título: Plasma membrane-associated proline-rich extensin-like receptor kinase 4, a novel regulator of Ca signalling, is required for abscisic acid responses in Arabidopsis thaliana. [So] Source: Plant J;60(2):314-27, 2009 Oct. [Is] ISSN: 1365-313X [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Plant roots respond to environmental stresses or the exogenous plant hormone abscisic acid (ABA) by undergoing marked physiological and morphological changes. We show here that PERK4, a gene that encodes a member of the Arabidopsis thaliana proline-rich extensin-like receptor kinase family, plays an important role in ABA responses. Mutation of PERK4 by T-DNA insertion decreased sensitivity to ABA with respect to seed germination, seedling growth and primary root tip growth. The effect on root growth was due to enhanced cell elongation rather than cell division. The cytosolic free calcium concentration and Ca(2+) channel currents were lower in perk4 root cells than in wild-type cells in the presence of ABA. Root growth was similar in wild-type and perk4 plants after the application of a Ca(2+) channel blocker. PERK4 localised to the plasma membrane, and was shown to be an ABA- and Ca(2+)-activated protein kinase. Our data suggest that the receptor-like kinase encoded by PERK4 functions at an early stage of ABA signalling to inhibit root cell elongation by perturbing Ca(2+) homeostasis. [Mh] Termos MeSH primário: Ácido Abscísico/metabolismo Proteínas de Arabidopsis/metabolismo Arabidopsis/genética Sinalização do Cálcio Proteínas de Membrana/metabolismo Proteínas Quinases Direcionadas a Prolina/metabolismo [Mh] Termos MeSH secundário: Arabidopsis/enzimologia Arabidopsis/fisiologia Proteínas de Arabidopsis/genética Canais de Cálcio/metabolismo Crescimento Celular DNA Bacteriano/genética DNA de Plantas/genética Regulação da Expressão Gênica de Plantas Proteínas de Membrana/genética Mutagênese Insercional Mutação Técnicas de Patch-Clamp Raízes de Plantas/citologia Raízes de Plantas/crescimento & desenvolvimento Proteínas Quinases Direcionadas a Prolina/genética Transdução de Sinais [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Arabidopsis Proteins); 0 (Calcium Channels); 0 (DNA, Bacterial); 0 (DNA, Plant); 0 (Membrane Proteins); 0 (T-DNA); 72S9A8J5GW (Abscisic Acid); EC 2.7.11.- (Proline-Directed Protein Kinases) [Em] Mês de entrada: 0912 [Cu] Atualização por classe: 131121 [Lr] Data última revisão: 131121 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 090702 [St] Status: MEDLINE [do] DOI: 10.1111/j.1365-313X.2009.03956.x

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[PMID]: 18715269 [Au] Autor: Veeranna; Lee JH; Pareek TK; Jaffee H; Boland B; Vinod KY; Amin N; Kulkarni AB; Pant HC; Nixon RA [Ad] Endereço: Center for Dementia Research, Nathan Kline Institute for Psychiatric Research, Orangeburg, New York, USA. [Ti] Título: Neurofilament tail phosphorylation: identity of the RT-97 phosphoepitope and regulation in neurons by cross-talk among proline-directed kinases. [So] Source: J Neurochem;107(1):35-49, 2008 Oct. [Is] ISSN: 1471-4159 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: As axons myelinate, establish a stable neurofilament network, and expand in caliber, neurofilament proteins are extensively phosphorylated along their C-terminal tails, which is recognized by the monoclonal antibody, RT-97. Here, we demonstrate in vivo that RT-97 immunoreactivity (IR) is generated by phosphorylation at KSPXK or KSPXXXK motifs and requires flanking lysines at specific positions. extracellular signal regulated kinase 1,2 (ERK1,2) and pERK1,2 levels increase in parallel with phosphorylation at the RT-97 epitope during early postnatal brain development. Purified ERK1,2 generated RT-97 on both KSP motifs on recombinant NF-H tail domain proteins, while cdk5 phosphorylated only KSPXK motifs. RT-97 epitope generation in primary hippocampal neurons was regulated by extensive cross-talk among ERK1,2, c-Jun N-terminal kinase 1,2 (JNK1,2) and cdk5. Inhibition of both ERK1,2 and JNK1,2 completely blocked RT-97 generation. Cdk5 influenced RT-97 generation indirectly by modulating JNK activation. In mice, cdk5 gene deletion did not significantly alter RT-97 IR or ERK1,2 and JNK activation. In mice lacking the cdk5 activator P35, the partial suppression of cdk5 activity increased RT-97 IR by activating ERK1,2. Thus, cdk5 influences RT-97 epitope generation partly by modulating ERKs and JNKs, which are the two principal kinases regulating neurofilament phosphorylation. The regulation of a single target by multiple protein kinases underscores the importance of monitoring other relevant kinases when the activity of a particular one is blocked. [Mh] Termos MeSH primário: Encéfalo/embriologia Encéfalo/metabolismo Epitopos/metabolismo Proteínas de Neurofilamentos/metabolismo Neurônios/metabolismo Proteínas Quinases Direcionadas a Prolina/metabolismo [Mh] Termos MeSH secundário: Motivos de Aminoácidos/imunologia Sequência de Aminoácidos/fisiologia Animais Anticorpos Monoclonais/imunologia Especificidade de Anticorpos/imunologia Encéfalo/ultraestrutura Células Cultivadas Quinase 5 Dependente de Ciclina/metabolismo Ativação Enzimática/fisiologia Epitopos/química Epitopos/imunologia MAP Quinases Reguladas por Sinal Extracelular/metabolismo Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo Lisina/metabolismo Camundongos Camundongos Endogâmicos C57BL Proteínas do Tecido Nervoso/metabolismo Proteínas de Neurofilamentos/química Proteínas de Neurofilamentos/imunologia Neurônios/ultraestrutura Fosforilação Proteínas Quinases Direcionadas a Prolina/imunologia Estrutura Terciária de Proteína/fisiologia Ratos Ratos Sprague-Dawley [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, N.I.H., INTRAMURAL [Nm] Nome de substância: 0 (Antibodies, Monoclonal); 0 (Epitopes); 0 (Nerve Tissue Proteins); 0 (Neurofilament Proteins); 0 (neuronal Cdk5 activator (p25-p35)); EC 2.7.11.- (Proline-Directed Protein Kinases); EC 2.7.11.1 (Cyclin-Dependent Kinase 5); EC 2.7.11.22 (Cdk5 protein, mouse); EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases); EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases); K3Z4F929H6 (Lysine) [Em] Mês de entrada: 0811 [Cu] Atualização por classe: 170220 [Lr] Data última revisão: 170220 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 080822 [St] Status: MEDLINE [do] DOI: 10.1111/j.1471-4159.2008.05547.x

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[PMID]: 18366453 [Au] Autor: Avila J [Ad] Endereço: Centro de Biología Molecular Severo Ochoa (CSIC-UAM), C/ Nicolás Cabrera, 1 Universidad Autónoma de Madrid, Cantoblanco, Madrid, Spain. javila@cbm.uam.es [Ti] Título: Tau kinases and phosphatases. [So] Source: J Cell Mol Med;12(1):258-9, 2008 Jan-Feb. [Is] ISSN: 1582-1838 [Cp] País de publicação: England [La] Idioma: eng [Mh] Termos MeSH primário: Doença de Alzheimer/enzimologia Emaranhados Neurofibrilares/enzimologia Proteínas Quinases Direcionadas a Prolina/metabolismo Proteína Fosfatase 2/metabolismo [Mh] Termos MeSH secundário: Precursor de Proteína beta-Amiloide/metabolismo Seres Humanos Emaranhados Neurofibrilares/patologia Fosforilação [Pt] Tipo de publicação: COMMENT; JOURNAL ARTICLE [Nm] Nome de substância: 0 (Amyloid beta-Protein Precursor); EC 2.7.11.- (Proline-Directed Protein Kinases); EC 3.1.3.16 (Protein Phosphatase 2) [Em] Mês de entrada: 0807 [Cu] Atualização por classe: 170220 [Lr] Data última revisão: 170220 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 080328 [St] Status: MEDLINE [do] DOI: 10.1111/j.1582-4934.2007.00214.x

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[PMID]: 17335084 [Au] Autor: Steinhilb ML; Dias-Santagata D; Mulkearns EE; Shulman JM; Biernat J; Mandelkow EM; Feany MB [Ad] Endereço: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. [Ti] Título: S/P and T/P phosphorylation is critical for tau neurotoxicity in Drosophila. [So] Source: J Neurosci Res;85(6):1271-8, 2007 May 01. [Is] ISSN: 0360-4012 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: The microtubule-associated protein tau is hyperphosphorylated abnormally in AD and related neurodegenerative disorders. Many phospho epitopes created by proline directed kinases (SP/TP sites) show relative specificity for disease states. To test whether phosphorylation at the disease-associated SP/TP sites affects tau toxicity in vivo, we expressed a form of tau in Drosophila in which all SP/TP sites are mutated to alanine. We find that blocking phosphorylation at SP/TP motifs markedly reduces tau toxicity in vivo. Using phosphorylation-specific antibodies, we identify a positive correlation between increased phosphorylation at disease-associated sites and neurotoxicity. We use the phosphorylation-incompetent version of tau to show that kinase and phosphatase modifiers of tau neurotoxicity, including cdk5/p35, the JNK kinase hemipterous and PP2A act via SP/TP phosphorylation sites. We provide direct evidence in an animal model system to support the role of phosphorylation at SP/TP sites in playing a critical role in tau neurotoxicity. [Mh] Termos MeSH primário: Síndromes Neurotóxicas/enzimologia Proteínas Quinases Direcionadas a Prolina/metabolismo Proteínas tau/fisiologia [Mh] Termos MeSH secundário: Alanina/genética Animais Animais Geneticamente Modificados Modelos Animais de Doenças Drosophila Proteínas de Drosophila/genética Proteínas de Drosophila/metabolismo Ativação Enzimática/fisiologia Olho/patologia Olho/ultraestrutura Microscopia Eletrônica de Varredura/métodos Mutação/fisiologia Síndromes Neurotóxicas/genética Síndromes Neurotóxicas/patologia Monoéster Fosfórico Hidrolases/metabolismo Fosforilação Proteínas Quinases/genética Proteínas Quinases/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Drosophila Proteins); 0 (tau Proteins); EC 2.7.- (Protein Kinases); EC 2.7.11.- (Proline-Directed Protein Kinases); EC 3.1.3.2 (Phosphoric Monoester Hydrolases); OF5P57N2ZX (Alanine) [Em] Mês de entrada: 0707 [Cu] Atualização por classe: 161124 [Lr] Data última revisão: 161124 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 070306 [St] Status: MEDLINE

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[PMID]: 16362082 [Au] Autor: Yang SD [Ad] Endereço: Institute of Molecular and Cellular Biology, Department of Life Science, National Tsing Hua University, Taiwan, Republic of China. lsysd@life.nthu.edu.tw [Ti] Título: Proline-directed protein kinase FA as a new signal transducing target for lethal cancer treatment. [So] Source: Drug News Perspect;18(7):432-6, 2005 Sep. [Is] ISSN: 0214-0934 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Proline-directed protein kinase F(A) (PDPK F(A)) has been established as a multisubstrate/multifunctional PDPK essential for the development of highly malignant phenotypes and rapid progression of lethal cancers. The recent immunohistochemical, immunocytochemical and clinicopathologic studies combined demonstrate that overexpressed PDPK F(A) is dynamically and closely associated with the most aggressive malignant cells disseminating from primary tumors to peripheral blood, ascites, pleural effusions and second metastatic tumors of various types of cancer patients with poor prognosis. The antisense gene therapeutic studies further demonstrate that overexpressed PDPK F(A) is essential for the development of all aspects of neoplasia including highly metastatic spread, peritoneal dissemination, splenomegaly and chemoradioresistances. The inhibition of cancer progression together with the simultaneous enhancement of chemoradiosensitivities through the suppression of overexpressed PDPK F(A) by specific drug design may work synergistically with surgery and chemoradiotherapy to improve the poor survival rate and life quality of the patients with lethal malignancies. PDPK F(A), therefore, may represent the heel of Achilles and a new promising target for the strategic development of more efficacious treatment for lethal cancers [Mh] Termos MeSH primário: Biologia Molecular Neoplasias Proteínas Quinases Direcionadas a Prolina Transdução de Sinais/efeitos dos fármacos [Mh] Termos MeSH secundário: Seres Humanos Neoplasias/tratamento farmacológico Neoplasias/etiologia Neoplasias/metabolismo Proteínas Quinases Direcionadas a Prolina/efeitos adversos Proteínas Quinases Direcionadas a Prolina/antagonistas & inibidores Proteínas Quinases Direcionadas a Prolina/fisiologia [Pt] Tipo de publicação: JOURNAL ARTICLE; REVIEW [Nm] Nome de substância: EC 2.7.11.- (Proline-Directed Protein Kinases) [Em] Mês de entrada: 0603 [Cu] Atualização por classe: 091119 [Lr] Data última revisão: 091119 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 051220 [St] Status: MEDLINE

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[PMID]: 15822905 [Au] Autor: DeGiorgis JA; Jaffe H; Moreira JE; Carlotti CG; Leite JP; Pant HC; Dosemeci A [Ad] Endereço: Laboratory of Neurobiology, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA. [Ti] Título: Phosphoproteomic analysis of synaptosomes from human cerebral cortex. [So] Source: J Proteome Res;4(2):306-15, 2005 Mar-Apr. [Is] ISSN: 1535-3893 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Protein phosphorylation is a crucial post-translational modification mechanism in the regulation of synaptic organization and function. Here, we analyzed synaptosome fractions from human cerebral cortex obtained during therapeutic surgery. To minimize changes in the phosphorylation state of proteins, the tissue was homogenized within two minutes of excision. Synaptosomal proteins were digested with trypsin and phosphopeptides were isolated by immobilized metal affinity chromatography and analyzed by liquid chromatography and tandem mass spectrometry. The method allowed the detection of residues on synaptic proteins that were presumably phosphorylated in the intact cell, including synapsin 1, syntaxin 1, and SNIP, PSD-93, NCAM, GABA-B receptor, chaperone molecules, and protein kinases. Some of the residues identified are the same or homologous to sites that had been previously described to be phosphorylated in mammals whereas others appear to be novel sites which, to our knowledge, have not been reported previously. The study shows that new phosphoproteomic strategies can be used to analyze subcellular fractions from small amounts of tissue for the identification of phosphorylated residues for research and potentially for diagnostic purposes. [Mh] Termos MeSH primário: Córtex Cerebral/química Fosfoproteínas/química Proteômica [Mh] Termos MeSH secundário: Sequência de Aminoácidos Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina Proteínas Quinases Dependentes de Cálcio-Calmodulina/química Proteínas Quinases Dependentes de Cálcio-Calmodulina/metabolismo Seres Humanos Dados de Sequência Molecular Fosfoproteínas/metabolismo Proteínas Quinases Direcionadas a Prolina/química Proteínas Quinases Direcionadas a Prolina/metabolismo Especificidade por Substrato [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Phosphoproteins); EC 2.7.11.- (Proline-Directed Protein Kinases); EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Type 2); EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinases) [Em] Mês de entrada: 0507 [Cu] Atualização por classe: 091119 [Lr] Data última revisão: 091119 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 050413 [St] Status: MEDLINE

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