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Pesquisa : D08.811.277.352.650.775.400.300 [Categoria DeCS]
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[PMID]:27778249
[Au] Autor:Campochiaro PA; Peters KG
[Ad] Endereço:Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. pcampo@jhmi.edu.
[Ti] Título:Targeting Tie2 for Treatment of Diabetic Retinopathy and Diabetic Macular Edema.
[So] Source:Curr Diab Rep;16(12):126, 2016 12.
[Is] ISSN:1539-0829
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Tie2 is a tyrosine kinase receptor located predominantly on vascular endothelial cells that plays a central role in vascular stability. Angiopoietin-1 (Angpt1), produced by perivascular cells, binds, clusters, and activates Tie2, leading to Tie2 autophosphorylation and downstream signaling. Activated Tie2 increases endothelial cell survival, adhesion, and cell junction integrity, thereby stabilizing the vasculature. Angiopoietin-2 (Angpt2) and vascular endothelial-protein tyrosine phosphatase (VE-PTP) are negative regulators increased by hypoxia; they inactivate Tie2, destabilizing the vasculature and increasing responsiveness to vascular endothelial growth factor (VEGF) and other inflammatory cytokines that stimulate vascular leakage and neovascularization. AKB-9778 is a small-molecule antagonist of VE-PTP which increases phosphorylation of Tie2 even in the presence of high Angpt2 levels. In preclinical studies, AKB-9778 reduced VEGF-induced leakage and ocular neovascularization (NV) and showed additive benefit when combined with VEGF suppression. In two clinical trials in diabetic macular edema (DME) patients, subcutaneous injections of AKB-9778 were safe and provided added benefit to VEGF suppression. Preliminary data suggest that AKB-9778 monotherapy improves diabetic retinopathy. These data suggest that Tie2 activation may be a valuable strategy to treat or prevent diabetic retinopathy.
[Mh] Termos MeSH primário: Compostos de Anilina/uso terapêutico
Retinopatia Diabética/tratamento farmacológico
Edema Macular/tratamento farmacológico
Receptor TIE-2/antagonistas & inibidores
Ácidos Sulfônicos/uso terapêutico
[Mh] Termos MeSH secundário: Angiopoietina-1/fisiologia
Angiopoietina-2/fisiologia
Seres Humanos
Receptor TIE-2/fisiologia
Proteínas Tirosina Fosfatases Classe 3 Semelhantes a Receptores/fisiologia
Transdução de Sinais
Fator A de Crescimento do Endotélio Vascular/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (AKB-9778); 0 (Angiopoietin-1); 0 (Angiopoietin-2); 0 (Aniline Compounds); 0 (Sulfonic Acids); 0 (Vascular Endothelial Growth Factor A); EC 2.7.10.1 (Receptor, TIE-2); EC 3.1.3.48 (Receptor-Like Protein Tyrosine Phosphatases, Class 3)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171210
[Lr] Data última revisão:
171210
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161026
[St] Status:MEDLINE


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[PMID]:28926625
[Au] Autor:Dorofejeva O; Barr AJ
[Ad] Endereço:Department of Biomedical Science, Faculty of Science & Technology, University of Westminster, London, United Kingdom.
[Ti] Título:Defining the molecular basis of interaction between R3 receptor-type protein tyrosine phosphatases and VE-cadherin.
[So] Source:PLoS One;12(9):e0184574, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Receptor-type protein tyrosine phosphatases (RPTPs) of the R3 subgroup play key roles in the immune, vascular and nervous systems. They are characterised by a large ectodomain comprising multiple FNIII-like repeats, a transmembrane domain, and a single intracellular phosphatase domain. The functional role of the extracellular region has not been clearly defined and potential roles in ligand interaction, dimerization, and regulation of cell-cell contacts have been reported. Here bimolecular fluorescence complementation (BiFC) in live cells was used to examine the molecular basis for the interaction of VE-PTP with VE-cadherin, two proteins involved in endothelial cell contact and maintenance of vascular integrity. The potential of other R3-PTPs to interact with VE-cadherin was also explored using this method. Quantitative BiFC analysis, using a VE-PTP construct expressing only the ectodomain and transmembrane domain, revealed a specific interaction with VE-cadherin, when compared with controls. Controls were sialophorin, an unrelated membrane protein with a large ectodomain, and a membrane anchored C-terminal Venus-YFP fragment, lacking both ectodomain and transmembrane domains. Truncation of the first 16 FNIII-like repeats from the ectodomain of VE-PTP indicated that removal of this region is not sufficient to disrupt the interaction with VE-cadherin, although it occurs predominantly in an intracellular location. A construct with a deletion of only the 17th domain of VE-PTP was, in contrast to previous studies, still able to interact with VE-cadherin, although this also was predominantly intracellular. Other members of the R3-PTP family (DEP-1, GLEPP1 and SAP-1) also exhibited the potential to interact with VE-cadherin. The direct interaction of DEP-1 with VE-cadherin is likely to be of physiological relevance since both proteins are expressed in endothelial cells. Together the data presented in the study suggest a role for both the ectodomain and transmembrane domain of R3-PTPs in interaction with VE-cadherin.
[Mh] Termos MeSH primário: Antígenos CD/metabolismo
Caderinas/metabolismo
Proteínas Tirosina Fosfatases Classe 3 Semelhantes a Receptores/metabolismo
[Mh] Termos MeSH secundário: Antígenos CD/química
Antígenos CD/genética
Caderinas/química
Caderinas/genética
Vetores Genéticos/metabolismo
Células HEK293
Seres Humanos
Microscopia Confocal
Mutagênese
Proteínas Tirosina Fosfatases Classe 3 Semelhantes a Receptores/química
Proteínas Tirosina Fosfatases Classe 3 Semelhantes a Receptores/genética
Proteínas Recombinantes de Fusão/biossíntese
Proteínas Recombinantes de Fusão/química
Transfecção
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antigens, CD); 0 (Cadherins); 0 (Recombinant Fusion Proteins); 0 (cadherin 5); EC 3.1.3.48 (Receptor-Like Protein Tyrosine Phosphatases, Class 3)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171020
[Lr] Data última revisão:
171020
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170920
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0184574


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[PMID]:28871037
[Au] Autor:Jiang W; Wei M; Liu M; Pan Y; Cao D; Yang X; Zhang C
[Ad] Endereço:Key Laboratory of Cognitive Science, Hubei Key Laboratory of Medical Information Analysis and Tumor Diagnosis and Treatment, Laboratory of Membrane Ion Channels and Medicine, College of Biomedical Engineering, South-Central University for Nationalities, Wuhan 430074, China.
[Ti] Título:Identification of Protein Tyrosine Phosphatase Receptor Type O (PTPRO) as a Synaptic Adhesion Molecule that Promotes Synapse Formation.
[So] Source:J Neurosci;37(41):9828-9843, 2017 Oct 11.
[Is] ISSN:1529-2401
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The proper formation of synapses-specialized unitary structures formed between two neurons-is critical to mediating information flow in the brain. Synaptic cell adhesion molecules (CAMs) are thought to participate in the initiation of the synapse formation process. However, functional analysis demonstrates that most well known synaptic CAMs regulate synaptic maturation and plasticity rather than synapse formation, suggesting that either CAMs work synergistically in the process of forming synapses or more CAMs remain to be found. By screening for unknown CAMs using a co-culture system, we revealed that protein tyrosine phosphatase receptor type O (PTPRO) is a potent CAM that induces the formation of artificial synapse clusters in co-cultures of human embryonic kidney 293 cells and hippocampal neurons cultured from newborn mice regardless of gender. PTPRO was enriched in the mouse brain and localized to postsynaptic sites at excitatory synapses. The overexpression of PTPRO in cultured hippocampal neurons increased the number of synapses and the frequency of miniature EPSCs (mEPSCs). The knock-down (KD) of PTPRO expression in cultured neurons by short hairpin RNA (shRNA) reduced the number of synapses and the frequencies of the mEPSCs. The effects of shRNA KD were rescued by expressing either full-length PTPRO or a truncated PTPRO lacking the cytoplasmic domain. Consistent with these results, the N-terminal extracellular domain of PTPRO was required for its synaptogenic activity in the co-culture assay. Our data show that PTPRO is a synaptic CAM that serves as a potent initiator of the formation of excitatory synapses. The formation of synapses is critical for the brain to execute its function and synaptic cell adhesion molecules (CAMs) play essential roles in initiating the formation of synapses. By screening for unknown CAMs using a co-culture system, we revealed that protein tyrosine phosphatase receptor type O (PTPRO) is a potent CAM that induces the formation of artificial synapse clusters. Using loss-of-function and gain-of-function approaches, we show that PTPRO promotes the formation of excitatory synapses. The N-terminal extracellular domain of PTPRO was required for its synaptogenic activity in cultured hippocampal neurons and the co-culture assay. Together, our data show that PTPRO is a synaptic CAM that serves as a potent initiator of synapse formation.
[Mh] Termos MeSH primário: Moléculas de Adesão de Célula Nervosa/fisiologia
Proteínas Tirosina Fosfatases Classe 3 Semelhantes a Receptores/fisiologia
Sinapses/fisiologia
[Mh] Termos MeSH secundário: Animais
Animais Recém-Nascidos
Técnicas de Cocultura
Potenciais Pós-Sinápticos Excitadores/fisiologia
Técnicas de Silenciamento de Genes
Células HEK293
Hipocampo/citologia
Hipocampo/crescimento & desenvolvimento
Seres Humanos
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Moléculas de Adesão de Célula Nervosa/genética
Técnicas de Patch-Clamp
Proteínas Tirosina Fosfatases Classe 3 Semelhantes a Receptores/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Neural Cell Adhesion Molecules); EC 3.1.3.48 (Ptpro protein, mouse); EC 3.1.3.48 (Receptor-Like Protein Tyrosine Phosphatases, Class 3)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171023
[Lr] Data última revisão:
171023
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170906
[St] Status:MEDLINE
[do] DOI:10.1523/JNEUROSCI.0729-17.2017


  4 / 316 MEDLINE  
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[PMID]:28870991
[Au] Autor:Soady KJ; Tornillo G; Kendrick H; Meniel V; Olijnyk-Dallis D; Morris JS; Stein T; Gusterson BA; Isacke CM; Smalley MJ
[Ad] Endereço:Division of Breast Cancer Research, Breast Cancer Now Research Centre, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
[Ti] Título:The receptor protein tyrosine phosphatase PTPRB negatively regulates FGF2-dependent branching morphogenesis.
[So] Source:Development;144(20):3777-3788, 2017 10 15.
[Is] ISSN:1477-9129
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:PTPRB is a transmembrane protein tyrosine phosphatase known to regulate blood vessel remodelling and angiogenesis. Here, we demonstrate that PTPRB negatively regulates branching morphogenesis in the mouse mammary epithelium. We show that is highly expressed in adult mammary stem cells and also, although at lower levels, in oestrogen receptor-positive luminal cells. During mammary development, expression is downregulated during puberty, a period of extensive ductal outgrowth and branching. shRNA knockdown of in the cleared mammary fat pad transplant assay resulted in smaller epithelial outgrowths with an increased branching density and also increased branching in an organoid assay. Organoid branching was dependent on stimulation by FGF2, and knockdown in mammary epithelial cells resulted in a higher level of fibroblast growth factor receptor (FGFR) activation and ERK1/2 phosphorylation, both at baseline and following FGF2 stimulation. Therefore, PTPRB regulates branching morphogenesis in the mammary epithelium by modulating the response of the FGFR signalling pathway to FGF stimulation. Considering the importance of branching morphogenesis in multiple taxa, our findings have general importance outside mammary developmental biology.
[Mh] Termos MeSH primário: Fator 2 de Crescimento de Fibroblastos/farmacologia
Glândulas Mamárias Animais/crescimento & desenvolvimento
Morfogênese
Proteínas Tirosina Fosfatases Classe 3 Semelhantes a Receptores/metabolismo
[Mh] Termos MeSH secundário: Animais
Padronização Corporal
Células Epiteliais/citologia
MAP Quinases Reguladas por Sinal Extracelular/metabolismo
Feminino
Perfilação da Expressão Gênica
Regulação da Expressão Gênica no Desenvolvimento
Proteínas de Fluorescência Verde/metabolismo
Camundongos
Neovascularização Fisiológica
Análise de Sequência com Séries de Oligonucleotídeos
Organoides/crescimento & desenvolvimento
Fosforilação
RNA Interferente Pequeno/metabolismo
Proteínas Tirosina Fosfatases Classe 3 Semelhantes a Receptores/genética
Receptores Estrogênicos/metabolismo
Receptores de Fatores de Crescimento de Fibroblastos/metabolismo
Transdução de Sinais
Células-Tronco/citologia
Transgenes
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (RNA, Small Interfering); 0 (Receptors, Estrogen); 0 (Receptors, Fibroblast Growth Factor); 103107-01-3 (Fibroblast Growth Factor 2); 147336-22-9 (Green Fluorescent Proteins); EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases); EC 3.1.3.48 (Ptprb protein, mouse); EC 3.1.3.48 (Receptor-Like Protein Tyrosine Phosphatases, Class 3)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171126
[Lr] Data última revisão:
171126
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170906
[St] Status:MEDLINE
[do] DOI:10.1242/dev.149120


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[PMID]:28684416
[Au] Autor:Dagnell M; Pace PE; Cheng Q; Frijhoff J; Östman A; Arnér ESJ; Hampton MB; Winterbourn CC
[Ad] Endereço:From the Centre for Free Radical Research, Department of Pathology, University of Otago, Christchurch 8041, New Zealand.
[Ti] Título:Thioredoxin reductase 1 and NADPH directly protect protein tyrosine phosphatase 1B from inactivation during H O exposure.
[So] Source:J Biol Chem;292(35):14371-14380, 2017 Sep 01.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Regulation of growth factor signaling involves reversible inactivation of protein tyrosine phosphatases (PTPs) through the oxidation and reduction of their active site cysteine. However, there is limited mechanistic understanding of these redox events and their co-ordination in the presence of cellular antioxidant networks. Here we investigated interactions between PTP1B and the peroxiredoxin 2 (Prx2)/thioredoxin 1 (Trx1)/thioredoxin reductase 1 (TrxR1) network. We found that Prx2 becomes oxidized in PDGF-treated fibroblasts, but only when TrxR1 has first been inhibited. Using purified proteins, we also found that PTP1B is relatively insensitive to inactivation by H O but found no evidence for a relay mechanism in which Prx2 or Trx1 facilitates PTP1B oxidation. Instead, these proteins prevented PTP1B inactivation by H O Intriguingly, we discovered that TrxR1/NADPH directly protects PTP1B from inactivation when present during the H O exposure. This protection was dependent on the concentration of TrxR1 and independent of Trx1 and Prx2. The protection was blocked by auranofin and required an intact selenocysteine residue in TrxR1. This activity likely involves reduction of the sulfenic acid intermediate form of PTP1B by TrxR1 and is therefore distinct from the previously described reactivation of end-point oxidized PTP1B, which requires both Trx1 and TrxR1. The ability of TrxR1 to directly reduce an oxidized phosphatase is a novel activity that can help explain previously observed increases in PTP1B oxidation and PDGF receptor phosphorylation in TrxR1 knockout cells. The activity of TrxR1 is therefore of potential relevance for understanding the mechanisms of redox regulation of growth factor signaling pathways.
[Mh] Termos MeSH primário: NADP/metabolismo
Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo
Proteínas Tirosina Fosfatases Classe 3 Semelhantes a Receptores/metabolismo
Tiorredoxina Redutase 1/metabolismo
[Mh] Termos MeSH secundário: Animais
Auranofina/farmacologia
Domínio Catalítico
Células Cultivadas
Dimerização
Embrião de Mamíferos/citologia
Proteínas de Homeodomínio/química
Proteínas de Homeodomínio/genética
Proteínas de Homeodomínio/metabolismo
Seres Humanos
Peróxido de Hidrogênio/farmacologia
Camundongos
Oxidantes/farmacologia
Oxirredução
Fragmentos de Peptídeos/química
Fragmentos de Peptídeos/genética
Fragmentos de Peptídeos/metabolismo
Domínios e Motivos de Interação entre Proteínas
Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores
Proteína Tirosina Fosfatase não Receptora Tipo 1/genética
Ratos
Proteínas Tirosina Fosfatases Classe 3 Semelhantes a Receptores/química
Proteínas Tirosina Fosfatases Classe 3 Semelhantes a Receptores/genética
Proteínas Recombinantes de Fusão/química
Proteínas Recombinantes de Fusão/metabolismo
Selenocisteína/química
Selenocisteína/metabolismo
Tiorredoxina Redutase 1/antagonistas & inibidores
Tiorredoxina Redutase 1/química
Tiorredoxina Redutase 1/genética
Tiorredoxinas/química
Tiorredoxinas/genética
Tiorredoxinas/metabolismo
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Homeodomain Proteins); 0 (Oxidants); 0 (PRRX2 protein, human); 0 (Peptide Fragments); 0 (Recombinant Fusion Proteins); 0 (TXN protein, human); 0CH9049VIS (Selenocysteine); 3H04W2810V (Auranofin); 52500-60-4 (Thioredoxins); 53-59-8 (NADP); BBX060AN9V (Hydrogen Peroxide); EC 1.8.1.9 (Thioredoxin Reductase 1); EC 1.8.1.9 (Txnrd1 protein, rat); EC 3.1.3.48 (PTPN1 protein, human); EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 1); EC 3.1.3.48 (Receptor-Like Protein Tyrosine Phosphatases, Class 3)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170708
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M117.793745


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[PMID]:28578349
[Au] Autor:Liang C; Wang X; Hu J; Lian X; Zhu T; Zhang H; Gu N
[Ad] Endereço:Nanjing University of Chinese Medicine, Nanjing, China.
[Ti] Título:PTPRO Promotes Oxidized Low-Density Lipoprotein Induced Oxidative Stress and Cell Apoptosis through Toll-Like Receptor 4/Nuclear Factor κB Pathway.
[So] Source:Cell Physiol Biochem;42(2):495-505, 2017.
[Is] ISSN:1421-9778
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:BACKGROUND/AIMS: Critical roles of phosphatase receptor type O (PTPRO) and toll-like receptor 4 (TLR4) have been implicated in inflammation. However, little is known about their functional effects on atherosclerosis (AS). We aim to study their potential function in AS. METHODS: An oxidized low-density lipoprotein (ox-LDL) induced AS model constructed with PTPRO over-expressing RAW264.7 cells and PTPRO knockout macrophages. Cell apoptosis was assayed by flow cytometry and fatty accumulation was evaluated by oil red staining. The production of ROS (reactive oxygen species), SOD (superoxide dismutase), MDA (malondialdehyde), TC (Triglyceride), and TG (total cholesterol) was evaluated. Western blot was performed to detect the expression of CD36, TLR4 and nuclear factor kB (NF-κB). RESULTS: PTPRO expression was promoted in a dose-dependent and time-dependent manner following ox-LDL challenging. In PTPRO-over-expressing cells, CD36 expression and the level of oil-red staining, TC and TG were increased; ROS production, MDA and level of cell apoptosis were improved, but SOD was reduced. However, in PTPRO knockout cells opposite results were found. TLR4 and NF-κB/p65 phosphorylation was significantly enhanced in PTPRO over-expressing cells, while significantly down-regulated in PTPRO knockout cells. CONCLUSION: PTPRO plays ital roles in AS via promoting ox-LDL induced oxidative stress and cell apoptosis through TLR4/NF-κB pathway.
[Mh] Termos MeSH primário: Aterosclerose/genética
Colesterol/genética
Inflamação/genética
Proteínas Tirosina Fosfatases Classe 3 Semelhantes a Receptores/biossíntese
Receptor 4 Toll-Like/biossíntese
[Mh] Termos MeSH secundário: Animais
Apoptose/genética
Aterosclerose/metabolismo
Aterosclerose/patologia
Colesterol/metabolismo
Regulação da Expressão Gênica
Técnicas de Inativação de Genes
Seres Humanos
Inflamação/metabolismo
Inflamação/patologia
Lipoproteínas LDL/genética
Lipoproteínas LDL/metabolismo
Macrófagos/metabolismo
Camundongos
Estresse Oxidativo/genética
Células RAW 264.7
Proteínas Tirosina Fosfatases Classe 3 Semelhantes a Receptores/genética
Receptor 4 Toll-Like/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Lipoproteins, LDL); 0 (Tlr4 protein, mouse); 0 (Toll-Like Receptor 4); 0 (oxidized low density lipoprotein); 97C5T2UQ7J (Cholesterol); EC 3.1.3.48 (Ptpro protein, mouse); EC 3.1.3.48 (Receptor-Like Protein Tyrosine Phosphatases, Class 3)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170927
[Lr] Data última revisão:
170927
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170605
[St] Status:MEDLINE
[do] DOI:10.1159/000477596


  7 / 316 MEDLINE  
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[PMID]:28385807
[Au] Autor:Soni D; Regmi SC; Wang DM; DebRoy A; Zhao YY; Vogel SM; Malik AB; Tiruppathi C
[Ad] Endereço:Department of Pharmacology and Center for Lung and Vascular Biology, College of Medicine, University of Illinois, Chicago, Illinois.
[Ti] Título:Pyk2 phosphorylation of VE-PTP downstream of STIM1-induced Ca entry regulates disassembly of adherens junctions.
[So] Source:Am J Physiol Lung Cell Mol Physiol;312(6):L1003-L1017, 2017 Jun 01.
[Is] ISSN:1522-1504
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Vascular endothelial protein tyrosine phosphatase (VE-PTP) stabilizes endothelial adherens junctions (AJs) through constitutive dephosphorylation of VE-cadherin. Here we investigated the role of stromal interaction molecule 1 (STIM1) activation of store-operated Ca entry (SOCE) in regulating AJ assembly. We observed that SOCE induced by STIM1 activated Pyk2 in human lung microvascular endothelial cells (ECs) and induced tyrosine phosphorylation of VE-PTP at Y1981. Pyk2-induced tyrosine phosphorylation of VE-PTP promoted binding to VE-PTP, activation, and subsequent VE-cadherin phosphorylation and thereby increased the endothelial permeability response. The increase in permeability was secondary to disassembly of AJs. Pyk2-mediated responses were blocked in EC-restricted knockout mice, indicating the requirement for STIM1 in initiating the signaling cascade. A peptide derived from the Pyk2 phosphorylation site on VE-PTP abolished the STIM1/SOCE-activated permeability response. Thus Pyk2 activation secondary to STIM1-induced SOCE causes tyrosine phosphorylation of VE-PTP, and VE-PTP, in turn, binds to and activates , thereby phosphorylating VE-cadherin to increase endothelial permeability through disassembly of AJs. Our results thus identify a novel signaling mechanism by which STIM1-induced Ca signaling activates Pyk2 to inhibit the interaction of VE-PTP and VE-cadherin and hence increase endothelial permeability. Therefore, targeting the Pyk2 activation pathway may be a potentially important anti-inflammatory strategy.
[Mh] Termos MeSH primário: Junções Aderentes/metabolismo
Cálcio/metabolismo
Quinase 2 de Adesão Focal/metabolismo
Proteínas Tirosina Fosfatases Classe 3 Semelhantes a Receptores/metabolismo
Molécula 1 de Interação Estromal/metabolismo
[Mh] Termos MeSH secundário: Animais
Antígenos CD/metabolismo
Caderinas/metabolismo
Permeabilidade Capilar
Permeabilidade da Membrana Celular
Células Endoteliais/metabolismo
Ativação Enzimática
Técnicas de Silenciamento de Genes
Inativação Gênica
Seres Humanos
Camundongos Endogâmicos C57BL
Microvasos/citologia
Modelos Biológicos
Proteínas de Neoplasias/metabolismo
Peptídeos/metabolismo
Fosforilação
Fosfotirosina/metabolismo
Receptor PAR-1/metabolismo
Quinases da Família src/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antigens, CD); 0 (Cadherins); 0 (Neoplasm Proteins); 0 (Peptides); 0 (Receptor, PAR-1); 0 (STIM1 protein, human); 0 (Stim1 protein, mouse); 0 (Stromal Interaction Molecule 1); 0 (cadherin 5); 21820-51-9 (Phosphotyrosine); EC 2.7.10.2 (Focal Adhesion Kinase 2); EC 2.7.10.2 (src-Family Kinases); EC 3.1.3.48 (Receptor-Like Protein Tyrosine Phosphatases, Class 3); SY7Q814VUP (Calcium)
[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:170408
[St] Status:MEDLINE
[do] DOI:10.1152/ajplung.00008.2017


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[PMID]:28257417
[Au] Autor:Chicote JU; DeSalle R; García-España A
[Ad] Endereço:Hospital Universitari de Tarragona Joan XXIII, Institut d'Investigació Sanitària Pere Virgili, Universitat Rovira i Virgili, Tarragona, Spain.
[Ti] Título:Phosphotyrosine phosphatase R3 receptors: Origin, evolution and structural diversification.
[So] Source:PLoS One;12(3):e0172887, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Subtype R3 phosphotyrosine phosphatase receptors (R3 RPTPs) are single-spanning membrane proteins characterized by a unique modular composition of extracellular fibronectin repeats and a single cytoplasmatic protein tyrosine phosphatase (PTP) domain. Vertebrate R3 RPTPs consist of five members: PTPRB, PTPRJ, PTPRH and PTPRO, which dephosphorylate tyrosine residues, and PTPRQ, which dephosphorylates phophoinositides. R3 RPTPs are considered novel therapeutic targets in several pathologies such as ear diseases, nephrotic syndromes and cancer. R3 RPTP vertebrate receptors, as well as their known invertebrate counterparts from animal models: PTP52F, PTP10D and PTP4e from the fruitfly Drosophila melanogaster and F44G4.8/DEP-1 from the nematode Caenorhabditis elegans, participate in the regulation of cellular activities including cell growth and differentiation. Despite sharing structural and functional properties, the evolutionary relationships between vertebrate and invertebrate R3 RPTPs are not fully understood. Here we gathered R3 RPTPs from organisms covering a broad evolutionary distance, annotated their structure and analyzed their phylogenetic relationships. We show that R3 RPTPs (i) have probably originated in the common ancestor of animals (metazoans), (ii) are variants of a single ancestral gene in protostomes (arthropods, annelids and nematodes); (iii) a likely duplication of this ancestral gene in invertebrate deuterostomes (echinodermes, hemichordates and tunicates) generated the precursors of PTPRQ and PTPRB genes, and (iv) R3 RPTP groups are monophyletic in vertebrates and have specific conserved structural characteristics. These findings could have implications for the interpretation of past studies and provide a framework for future studies and functional analysis of this important family of proteins.
[Mh] Termos MeSH primário: Evolução Molecular
Filogenia
Proteínas Tirosina Fosfatases Classe 3 Semelhantes a Receptores/genética
[Mh] Termos MeSH secundário: Animais
Caenorhabditis elegans/genética
Diferenciação Celular/genética
Sequência Conservada/genética
Proteínas de Drosophila/genética
Drosophila melanogaster/genética
Seres Humanos
Proteínas Tirosina Fosfatases/genética
Proteínas Tirosina Fosfatases Classe 4 Semelhantes a Receptores/genética
Transdução de Sinais/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Drosophila Proteins); EC 3.1.3.48 (Protein Tyrosine Phosphatases); EC 3.1.3.48 (Ptp10D protein, Drosophila); EC 3.1.3.48 (Ptp4E protein, Drosophila); EC 3.1.3.48 (Ptp52F protein, Drosophila); EC 3.1.3.48 (Receptor-Like Protein Tyrosine Phosphatases, Class 3); EC 3.1.3.48 (Receptor-Like Protein Tyrosine Phosphatases, Class 4)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170822
[Lr] Data última revisão:
170822
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170304
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0172887


  9 / 316 MEDLINE  
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[PMID]:28199135
[Au] Autor:Radder JE; Zhang Y; Gregory AD; Yu S; Kelly NJ; Leader JK; Kaminski N; Sciurba FC; Shapiro SD
[Ad] Endereço:1 Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, and.
[Ti] Título:Extreme Trait Whole-Genome Sequencing Identifies PTPRO as a Novel Candidate Gene in Emphysema with Severe Airflow Obstruction.
[So] Source:Am J Respir Crit Care Med;196(2):159-171, 2017 Jul 15.
[Is] ISSN:1535-4970
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:RATIONALE: Genetic association studies in chronic obstructive pulmonary disease have primarily tested for association with common variants, the results of which explain only a portion of disease heritability. Because rare variation is also likely to contribute to susceptibility, we used whole-genome sequencing of subjects with clinically extreme phenotypes to identify genomic regions enriched for rare variation contributing to chronic obstructive pulmonary disease susceptibility. OBJECTIVES: To identify regions of rare genetic variation contributing to emphysema with severe airflow obstruction. METHODS: We identified heavy smokers that were resistant (n = 65) or susceptible (n = 64) to emphysema with severe airflow obstruction in the Pittsburgh Specialized Center of Clinically Oriented Research cohort. We filtered whole-genome sequencing results to include only rare variants and conducted single variant tests, region-based tests across the genome, gene-based tests, and exome-wide tests. MEASUREMENTS AND MAIN RESULTS: We identified several suggestive associations with emphysema with severe airflow obstruction, including a suggestive association of all rare variation in a region within the gene ZNF816 (19q13.41; P = 4.5 × 10 ), and a suggestive association of nonsynonymous coding rare variation in the gene PTPRO (P = 4.0 × 10 ). Association of rs61754411, a rare nonsynonymous variant in PTPRO, with emphysema and obstruction was demonstrated in all non-Hispanic white individuals in the Pittsburgh Specialized Center of Clinically Oriented Research cohort. We found that cells containing this variant have decreased signaling in cellular pathways necessary for survival and proliferation. CONCLUSIONS: PTPRO is a novel candidate gene in emphysema with severe airflow obstruction, and rs61754411 is a previously unreported rare variant contributing to emphysema susceptibility. Other suggestive candidate genes, such as ZNF816, are of interest for future studies.
[Mh] Termos MeSH primário: Predisposição Genética para Doença/genética
Estudo de Associação Genômica Ampla/métodos
Enfisema Pulmonar/genética
Proteínas Tirosina Fosfatases Classe 3 Semelhantes a Receptores/genética
[Mh] Termos MeSH secundário: Idoso
Feminino
Seres Humanos
Masculino
Meia-Idade
Doença Pulmonar Obstrutiva Crônica/genética
Índice de Gravidade de Doença
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 3.1.3.48 (PTPRO protein, human); EC 3.1.3.48 (Receptor-Like Protein Tyrosine Phosphatases, Class 3)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170810
[Lr] Data última revisão:
170810
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170216
[St] Status:MEDLINE
[do] DOI:10.1164/rccm.201606-1147OC


  10 / 316 MEDLINE  
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[PMID]:28166196
[Au] Autor:Wakim J; Arman E; Becker-Herman S; Kramer MP; Bakos E; Shachar I; Elson A
[Ad] Endereço:Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot, Israel.
[Ti] Título:The PTPROt tyrosine phosphatase functions as an obligate haploinsufficient tumor suppressor in vivo in B-cell chronic lymphocytic leukemia.
[So] Source:Oncogene;36(26):3686-3694, 2017 Jun 29.
[Is] ISSN:1476-5594
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The tyrosine phosphatase PTPROt is a suggested tumor suppressor (TS) in B-cell chronic lymphocytic leukemia (CLL), and its expression is reduced in this disease. In order to examine how reduced PTPROt expression affects CLL in vivo we induced CLL in PTPROt-targeted mice. Unexpectedly, loss of both Ptprot alleles delayed disease detection and progression and lengthened survival relative to mice carrying two intact alleles, indicating that PTPROt fulfills a novel tumor-promoting role in CLL. Tumor cells from mice lacking PTPROt exhibited reduced B-cell receptor (BCR)-induced signaling, as well as increased apoptosis and autophagy. Inhibition of BCR/Src signaling in CLL cells induced their apoptosis, indicating that these findings are linked causally. These results suggest a cell-autonomous mechanism for the weakened CLL phenotype of PTPROt-deficient mice and uncover non-redundant roles for PTPROt in support of BCR signaling and survival of CLL cells. In contrast, loss of only one Ptprot allele induced earlier detection and progression of CLL and reduced survival, consistent with a tumor-suppressing role for PTPROt. Tumor cells from mice lacking one or both Ptprot allele exhibited increased interleukin-10 (IL-10) expression and signaling, factors known to support CLL; cells lacking one Ptprot alleles exhibited normal BCR signaling and cell death rates. We conclude that loss of one Ptprot allele promotes CLL, most likely by activating IL-10 signaling. Loss of both Ptprot alleles also reduces BCR signaling and increases cell death rates, offsetting the IL-10 effects and reducing the severity of the disease. PTPROt thus functions as an obligate haploinsufficient TS in CLL, where its expression levels determine its role as a promoter or inhibitor of the tumorigenic process in mice. Partial loss of PTPROt generates the strongest disease phenotype, suggesting that its intermediate expression levels in CLL are selected for.
[Mh] Termos MeSH primário: Leucemia Linfocítica Crônica de Células B/enzimologia
Leucemia Linfocítica Crônica de Células B/genética
Proteínas Tirosina Fosfatases Classe 3 Semelhantes a Receptores/biossíntese
Proteínas Tirosina Fosfatases Classe 3 Semelhantes a Receptores/genética
[Mh] Termos MeSH secundário: Animais
Linhagem Celular Tumoral
Feminino
Haploinsuficiência
Leucemia Linfocítica Crônica de Células B/patologia
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Knockout
Fosforilação
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 3.1.3.48 (Ptpro protein, mouse); EC 3.1.3.48 (Receptor-Like Protein Tyrosine Phosphatases, Class 3)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171027
[Lr] Data última revisão:
171027
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170207
[St] Status:MEDLINE
[do] DOI:10.1038/onc.2016.523



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