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Pesquisa : D08.811.913.696.620.682.700.646 [Categoria DeCS]
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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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Fotocópia
[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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