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Pesquisa : G02.111.570.820.709.275.500.898 [Categoria DeCS]
Referências encontradas : 11 [refinar]
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  1 / 11 MEDLINE  
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[PMID]:27776928
[Au] Autor:Singh DR; Ahmed F; Paul MD; Gedam M; Pasquale EB; Hristova K
[Ad] Endereço:Department of Materials Science and Engineering, Johns Hopkins University, 3400 Charles Street, Baltimore, MD 21218, United States.
[Ti] Título:The SAM domain inhibits EphA2 interactions in the plasma membrane.
[So] Source:Biochim Biophys Acta;1864(1):31-38, 2017 01.
[Is] ISSN:0006-3002
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:All members of the Eph receptor family of tyrosine kinases contain a SAM domain near the C terminus, which has been proposed to play a role in receptor homotypic interactions and/or interactions with binding partners. The SAM domain of EphA2 is known to be important for receptor function, but its contribution to EphA2 lateral interactions in the plasma membrane has not been determined. Here we use a FRET-based approach to directly measure the effect of the SAM domain on the stability of EphA2 dimers on the cell surface in the absence of ligand binding. We also investigate the functional consequences of EphA2 SAM domain deletion. Surprisingly, we find that the EphA2 SAM domain inhibits receptor dimerization and decreases EphA2 tyrosine phosphorylation. This role is dramatically different from the role of the SAM domain of the related EphA3 receptor, which we previously found to stabilize EphA3 dimers and increase EphA3 tyrosine phosphorylation in cells in the absence of ligand. Thus, the EphA2 SAM domain likely contributes to a unique mode of EphA2 interaction that leads to distinct signaling outputs.
[Mh] Termos MeSH primário: Sequência de Aminoácidos
Membrana Celular/metabolismo
Efrina-A1/metabolismo
Receptor EphA2/metabolismo
Deleção de Sequência
Motivo Estéril alfa
[Mh] Termos MeSH secundário: Membrana Celular/química
Movimento Celular
Efrina-A1/genética
Transferência Ressonante de Energia de Fluorescência
Expressão Gênica
Células HEK293
Seres Humanos
Cinética
Fosforilação
Ligação Proteica
Isoformas de Proteínas/genética
Isoformas de Proteínas/metabolismo
Multimerização Proteica
Receptor EphA2/genética
Proteínas Recombinantes/genética
Proteínas Recombinantes/metabolismo
Tirosina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.
[Nm] Nome de substância:
0 (Ephrin-A1); 0 (Protein Isoforms); 0 (Recombinant Proteins); 42HK56048U (Tyrosine); EC 2.7.10.1 (Receptor, EphA2)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:180101
[Lr] Data última revisão:
180101
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161027
[St] Status:MEDLINE


  2 / 11 MEDLINE  
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[PMID]:28388653
[Au] Autor:Yagai T; Matsui S; Harada K; Inagaki FF; Saijou E; Miura Y; Nakanuma Y; Miyajima A; Tanaka M
[Ad] Endereço:Laboratory of Cell Growth and Differentiation, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo, Japan.
[Ti] Título:Expression and localization of sterile alpha motif domain containing 5 is associated with cell type and malignancy of biliary tree.
[So] Source:PLoS One;12(4):e0175355, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cholangiocarcinoma (CC) is a type of relatively rare neoplasm in adenocarcinoma. The characteristics of CCs as well as biliary epithelial cells are heterogeneous at the different portion of the biliary tree. There are two candidate stem/progenitor cells of the biliary tree, i.e., biliary tree stem/progenitor cell (BTSC) at the peribiliary gland (PBG) of large bile ducts and liver stem/progenitor cell (LPC) at the canals of Hering of peripheral small bile duct. Although previous reports suggest that intrahepatic CC (ICC) can arise from such stem/progenitor cells, the characteristic difference between BTSC and LPC in pathological process needs further investigation, and the etiology of CC remains poorly understood. Here we show that Sterile alpha motif domain containing 5 (SAMD5) is exclusively expressed in PBGs of large bile ducts in normal mice. Using a mouse model of cholestatic liver disease, we demonstrated that SAMD5 expression was upregulated in the large bile duct at the hepatic hilum, the extrahepatic bile duct and PBGs, but not in proliferating intrahepatic ductules, suggesting that SAMD5 is expressed in BTSC but not LPC. Intriguingly, human ICCs and extrahepatic CCs exhibited striking nuclear localization of SAMD5 while the normal hilar large bile duct displayed slight-to-moderate expression in cytoplasm. In vitro experiments using siRNA for SAMD5 revealed that SAMD5 expression was associated with the cell cycle regulation of CC cell lines. CONCLUSION: SAMD5 is a novel marker for PBG but not LPC in mice. In humans, the expression and location of SAMD5 could become a promising diagnostic marker for the cell type as well as malignancy of bile ducts and CCs.
[Mh] Termos MeSH primário: Neoplasias do Sistema Biliar/metabolismo
Colangiocarcinoma/metabolismo
Motivo Estéril alfa
[Mh] Termos MeSH secundário: Animais
Neoplasias do Sistema Biliar/patologia
Núcleo Celular/metabolismo
Proliferação Celular
Colangiocarcinoma/patologia
Camundongos
Camundongos Endogâmicos C57BL
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170907
[Lr] Data última revisão:
170907
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170408
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0175355


  3 / 11 MEDLINE  
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[PMID]:28235466
[Au] Autor:Neira JL; Cámara-Artigas A
[Ad] Endereço:Instituto de Biología Molecular y Celular, Universidad Miguel Hernández, Elche, Alicante, Spain; Instituto de Biocomputación y Física de Sistemas Complejos, Zaragoza, Spain. Electronic address: jlneira@umh.es.
[Ti] Título:Trifluoroethanol-induced conformational transition of the C-terminal sterile alpha motif (SAM) of human p73.
[So] Source:Arch Biochem Biophys;619:1-9, 2017 Apr 01.
[Is] ISSN:1096-0384
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The alpha splice variant of p73 (p73α), a homologue of the tumour suppressor p53, has at its C terminus a sterile alpha motif (SAM); this domain, SAMp73, is involved in lipid binding and it is thought to mediate in protein-protein interactions. As SAMp73 is a 68-residue-long helical bundle, it could be a good model to study the (2,2,2-trifluoroethanol) TFE-induced conformational transitions of α-helical proteins. Furthermore, as SAMp73 binds to lipids through a well-known polypeptide patch, we can test whether TFE is a good mimic of lipids and membranes. To address those questions, we used several biophysical probes, namely, fluorescence, circular dichroism, 1D, 2D and 3D-NMR spectroscopies, and dynamic light scattering. The TFE-induced conformational transition of SAMp73 was complex, involving several species as detected by the biophysical probes. The last TFE-induced transition occurred at a concentration of TFE of ∼20% (v/v), where the protein lost its compactness. None of those TFE-induced species accumulated during the two-state folding of SAMp73 in aqueous solution. The final state at 40% TFE was highly helical, but its structure was not rigid. For SAMp73, TFE did not properly mimic a membrane-like environment, since at very low TFE concentrations, other residues, together with those known to interact with lipids, were also affected by the co-solvent. Comparison with studies on isolated peptides, comprising the helical regions of SAMp73, suggests that peptides were good models of the intact protein in TFE.
[Mh] Termos MeSH primário: Motivo Estéril alfa/genética
Trifluoretanol/química
Proteína Tumoral p73/química
[Mh] Termos MeSH secundário: Membrana Celular/metabolismo
Dicroísmo Circular
Seres Humanos
Luz
Espectroscopia de Ressonância Magnética
Peptídeos/química
Ligação Proteica
Domínios Proteicos
Dobramento de Proteína
Mapeamento de Interação de Proteínas
Estrutura Secundária de Proteína
Espalhamento de Radiação
Solventes/química
Espectrometria de Fluorescência
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Peptides); 0 (Solvents); 0 (Tumor Protein p73); 0 (p73 protein, human); 75-89-8 (Trifluoroethanol)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170515
[Lr] Data última revisão:
170515
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170226
[St] Status:MEDLINE


  4 / 11 MEDLINE  
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[PMID]:27769899
[Au] Autor:Fischer A; Weber W; Warscheid B; Radziwill G
[Ad] Endereço:Department of Biochemistry and Synthetic Biology, Faculty of Biology, University of Freiburg, Schänzlestr. 18, 79104 Freiburg, Germany; Department of Biochemistry and Functional Proteomics, Faculty of Biology, University of Freiburg, Schänzlestr. 1, 79104 Freiburg, Germany; BIOSS - Centre for Biolog
[Ti] Título:AKT-dependent phosphorylation of the SAM domain induces oligomerization and activation of the scaffold protein CNK1.
[So] Source:Biochim Biophys Acta;1864(1):89-100, 2017 01.
[Is] ISSN:0006-3002
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Scaffold proteins are hubs for the coordination of intracellular signaling networks. The scaffold protein CNK1 promotes several signal transduction pathway. Here we demonstrate that sterile motif alpha (SAM) domain-dependent oligomerization of CNK1 stimulates CNK1-mediated signaling in growth factor-stimulated cells. We identified Ser22 located within the SAM domain as AKT-dependent phosphorylation site triggering CNK1 oligomerization. Oligomeric CNK1 increased the affinity for active AKT indicating a positive AKT feedback mechanism. A CNK1 mutant lacking the SAM domain and the phosphorylation-defective mutant CNK1 antagonizes oligomerization and prevents CNK1-driven cell proliferation and matrix metalloproteinase 14 promoter activation. The phosphomimetic mutant CNK1 constitutively oligomerizes and stimulates CNK1 downstream signaling. Searching the COSMIC database revealed Ser22 as putative target for oncogenic activation of CNK1. Like the phosphomimetic mutant CNK1 , the oncogenic mutant CNK1 forms clusters in serum-starved cells comparable to clusters of CNK1 in growth factor-stimulated cells. CNK1 clusters induced by activating Ser22 mutants correlate with enhanced cell invasion and binding to and activation of ADP ribosylation factor 1 associated with tumor formation. Mutational analysis indicate that EGF-triggered phosphorylation of Thr8 within the SAM domain prevents AKT binding and antagonizes CNK1-mediated AKT signaling. Our findings reveal SAM domain-dependent oligomerization by AKT as switch for CNK1 activation.
[Mh] Termos MeSH primário: Retroalimentação Fisiológica
Regulação Neoplásica da Expressão Gênica
Peptídeos e Proteínas de Sinalização Intracelular/genética
Proteínas Proto-Oncogênicas c-akt/genética
Motivo Estéril alfa
[Mh] Termos MeSH secundário: Adesão Celular
Movimento Celular
Proliferação Celular
Bases de Dados Genéticas
Células HEK293
Células HeLa
Seres Humanos
Peptídeos e Proteínas de Sinalização Intracelular/metabolismo
Metaloproteinase 14 da Matriz/genética
Metaloproteinase 14 da Matriz/metabolismo
Mimetismo Molecular
Mutação
Fosforilação
Regiões Promotoras Genéticas
Multimerização Proteica
Proteínas Proto-Oncogênicas c-akt/metabolismo
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (CNKSR1 protein, human); 0 (Intracellular Signaling Peptides and Proteins); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt); EC 3.4.24.80 (MMP14 protein, human); EC 3.4.24.80 (Matrix Metalloproteinase 14)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171004
[Lr] Data última revisão:
171004
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161023
[St] Status:MEDLINE


  5 / 11 MEDLINE  
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[PMID]:27804871
[Au] Autor:Mercurio FA; Leone M
[Ti] Título:The Sam Domain of EphA2 Receptor and its Relevance to Cancer: A Novel Challenge for Drug Discovery?
[So] Source:Curr Med Chem;23(42):4718-4734, 2016.
[Is] ISSN:1875-533X
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Eph receptors play important functions in developmental processes and diseases and among them EphA2 is well known for its controversial role in cancer. Drug discovery strategies are mainly centered on EphA2 extracellular ligand-binding domain however, the receptor also contains a largely unexplored cytosolic Sam (Sterile alpha motif) domain at the C-terminus. EphA2-Sam binds the Sam domain from the lipid phosphatase Ship2 and the first Sam domain of Odin. Sam-Sam interactions may be important to regulate ligand-induced receptor endocytosis and degradation i.e., processes that could be engaged against tumor malignancy. METHODS: We critically analyzed literature related to a) Eph receptors with particular emphasis on EphA2 and its role in cancer, b) Sam domains, c) heterotypic Sam-Sam interactions involving EphA2-Sam. RESULTS: While literature data indicate that binding of EphA2-Sam to Ship2-Sam should largely generate pro-oncogenic effects in cancer cells, the correlation between EphA2- Sam/Odin-Sam1 complex and the disease is unclear. Recently a few linear peptides encompassing binding interfaces from either Ship2-Sam and Odin-Sam1 have been characterized but failed to efficiently block heterotypic Sam-Sam interactions involving EphA2-Sam due to the lack of a native like fold. CONCLUSION: Molecule antagonists of heterotypic EphA2-Sam associations could work as potential anticancer agents or be implemented as tools to further clarify receptor functions and eventually validate its role as a novel target in the field of anti-cancer drug discovery. Due to the failure of linear peptides there is a crucial need for novel approaches, based on cyclic or helical molecules, to target Sam-Sam interfaces.
[Mh] Termos MeSH primário: Descoberta de Drogas/métodos
Receptor EphA2/química
Receptor EphA2/metabolismo
Motivo Estéril alfa
[Mh] Termos MeSH secundário: Animais
Seres Humanos
Peptídeos/metabolismo
Peptídeos/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Peptides); EC 2.7.10.1 (Receptor, EphA2)
[Em] Mês de entrada:1701
[Cu] Atualização por classe:170131
[Lr] Data última revisão:
170131
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161103
[St] Status:MEDLINE


  6 / 11 MEDLINE  
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[PMID]:27763725
[Au] Autor:Mercurio FA; Marasco D; Di Natale C; Pirone L; Costantini S; Pedone EM; Leone M
[Ad] Endereço:Institute of Biostructures and Bioimaging, National Research Council, Via Mezzocannone 16, 80134, Naples, Italy.
[Ti] Título:Targeting EphA2-Sam and Its Interactome: Design and Evaluation of Helical Peptides Enriched in Charged Residues.
[So] Source:Chembiochem;17(22):2179-2188, 2016 Nov 17.
[Is] ISSN:1439-7633
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:The EphA2 receptor controls diverse physiological and pathological conditions and its levels are often upregulated in cancer. Targeting receptor overexpression, through modulation of endocytosis and consequent degradation, appears to be an appealing strategy for attacking tumor malignancy. In this scenario, the Sam domain of EphA2 plays a pivotal role because it is the site where protein regulators of endocytosis and stability are recruited by means of heterotypic Sam-Sam interactions. Because EphA2-Sam heterotypic complexes are largely based on electrostatic contacts, we have investigated the possibility of attacking these interactions with helical peptides enriched in charged residues. Several peptide sequences with high predicted helical propensities were designed, and detailed conformational analyses were conducted by diverse techniques including NMR, CD, and molecular dynamics (MD) simulations. Interaction studies were also performed by NMR, surface plasmon resonance (SPR), and microscale thermophoresis (MST) and led to the identification of two peptides capable of binding to the first Sam domain of Odin. These molecules represent early candidates for the generation of efficient Sam domain binders and antagonists of Sam-Sam interactions involving EphA2.
[Mh] Termos MeSH primário: Peptídeos/química
Receptor EphA2/química
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Dicroísmo Circular
Desenho de Drogas
Cinética
Espectroscopia de Ressonância Magnética
Simulação de Dinâmica Molecular
Peptídeos/síntese química
Peptídeos/metabolismo
Ligação Proteica
Estrutura Secundária de Proteína
Receptor EphA2/genética
Receptor EphA2/metabolismo
Proteínas Recombinantes/biossíntese
Proteínas Recombinantes/química
Proteínas Recombinantes/isolamento & purificação
Técnicas de Síntese em Fase Sólida
Motivo Estéril alfa
Ressonância de Plasmônio de Superfície
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Peptides); 0 (Recombinant Proteins); EC 2.7.10.1 (Receptor, EphA2)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170516
[Lr] Data última revisão:
170516
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161021
[St] Status:MEDLINE
[do] DOI:10.1002/cbic.201600413


  7 / 11 MEDLINE  
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[PMID]:27655071
[Au] Autor:Chang Y; Zhang Q; Li Z; Ding K; Lu X
[Ti] Título:Leucine-zipper and Sterile-α Motif Kinase (ZAK): A Potential Target for Drug Discovery.
[So] Source:Curr Med Chem;23(33):3801-3812, 2016.
[Is] ISSN:1875-533X
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Leucine-zipper and sterile-α motif kinase (ZAK) is a member of mixed-lineage kinase family (MLKs), which is considered as a new potential target for different physiological disorders, including myocardial hypertrophy and cardiac fibrosis, inflammation and cancer. However, the progress on its biological functions and small molecule inhibitors is limited. Only several multi-kinases inhibitors are reported to non-selectively bind with ZAK with various potencies. Herein, we provide an updated overview on the biological functions and small molecular inhibitors of ZAKs.
[Mh] Termos MeSH primário: Descoberta de Drogas
Proteínas Quinases Ativadas por Mitógeno/química
[Mh] Termos MeSH secundário: Cardiomegalia/metabolismo
Cardiomegalia/patologia
Cardiomegalia/terapia
Seres Humanos
Zíper de Leucina
MAP Quinase Quinase Quinases/química
MAP Quinase Quinase Quinases/genética
MAP Quinase Quinase Quinases/metabolismo
Proteínas Quinases Ativadas por Mitógeno/genética
Proteínas Quinases Ativadas por Mitógeno/metabolismo
Simulação de Acoplamento Molecular
Neoplasias/metabolismo
Neoplasias/patologia
Neoplasias/terapia
Interferência de RNA
Motivo Estéril alfa
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
EC 2.7.11.24 (Mitogen-Activated Protein Kinases); EC 2.7.11.25 (MAP Kinase Kinase Kinases)
[Em] Mês de entrada:1702
[Cu] Atualização por classe:170208
[Lr] Data última revisão:
170208
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160923
[St] Status:MEDLINE


  8 / 11 MEDLINE  
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[PMID]:27499439
[Au] Autor:Riccio AA; McCauley M; Langelier MF; Pascal JM
[Ad] Endereço:Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, Québec H3T 1J4, Canada.
[Ti] Título:Tankyrase Sterile α Motif Domain Polymerization Is Required for Its Role in Wnt Signaling.
[So] Source:Structure;24(9):1573-81, 2016 Sep 06.
[Is] ISSN:1878-4186
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Tankyrase-1 (TNKS1/PARP-5a) is a poly(ADP-ribose) polymerase (PARP) enzyme that regulates multiple cellular processes creating a poly(ADP-ribose) posttranslational modification that can lead to target protein turnover. TNKS1 thereby controls protein levels of key components of signaling pathways, including Axin1, the limiting component of the destruction complex in canonical Wnt signaling that degrades ß-catenin to prevent its coactivator function in gene expression. There are limited molecular level insights into TNKS1 regulation in cell signaling pathways. TNKS1 has a sterile α motif (SAM) domain that is known to mediate polymerization, but the functional requirement for SAM polymerization has not been assessed. We have determined the crystal structure of wild-type human TNKS1 SAM domain and used structure-based mutagenesis to disrupt polymer formation and assess the consequences on TNKS1 regulation of ß-catenin-dependent transcription. Our data indicate the SAM polymer is critical for TNKS1 catalytic activity and allows TNKS1 to efficiently access cytoplasmic signaling complexes.
[Mh] Termos MeSH primário: Proteína Axina/química
Proteínas Recombinantes de Fusão/química
Motivo Estéril alfa
Tanquirases/química
beta Catenina/química
[Mh] Termos MeSH secundário: Proteína Axina/genética
Proteína Axina/metabolismo
Sítios de Ligação
Proliferação Celular
Clonagem Molecular
Cristalografia por Raios X
Escherichia coli/genética
Escherichia coli/metabolismo
Expressão Gênica
Regulação da Expressão Gênica
Proteínas de Fluorescência Verde/genética
Proteínas de Fluorescência Verde/metabolismo
Células HEK293
Células HeLa
Seres Humanos
Modelos Moleculares
Polimerização
Ligação Proteica
Conformação Proteica em alfa-Hélice
Domínios e Motivos de Interação entre Proteínas
Proteínas Recombinantes de Fusão/genética
Proteínas Recombinantes de Fusão/metabolismo
Proteínas Recombinantes/química
Proteínas Recombinantes/genética
Proteínas Recombinantes/metabolismo
Tanquirases/genética
Tanquirases/metabolismo
Via de Sinalização Wnt
beta Catenina/genética
beta Catenina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (AXIN1 protein, human); 0 (Axin Protein); 0 (CTNNB1 protein, human); 0 (Recombinant Fusion Proteins); 0 (Recombinant Proteins); 0 (beta Catenin); 147336-22-9 (Green Fluorescent Proteins); EC 2.4.2.30 (Tankyrases); EC 2.4.4.30 (TNKS protein, human)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171005
[Lr] Data última revisão:
171005
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160809
[St] Status:MEDLINE


  9 / 11 MEDLINE  
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[PMID]:27494558
[Au] Autor:Mariotti L; Templeton CM; Ranes M; Paracuellos P; Cronin N; Beuron F; Morris E; Guettler S
[Ad] Endereço:Division of Structural Biology, The Institute of Cancer Research (ICR), London SW7 3RP, UK; Division of Cancer Biology, The Institute of Cancer Research (ICR), London SW7 3RP, UK.
[Ti] Título:Tankyrase Requires SAM Domain-Dependent Polymerization to Support Wnt-ß-Catenin Signaling.
[So] Source:Mol Cell;63(3):498-513, 2016 Aug 04.
[Is] ISSN:1097-4164
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The poly(ADP-ribose) polymerase (PARP) Tankyrase (TNKS and TNKS2) is paramount to Wnt-ß-catenin signaling and a promising therapeutic target in Wnt-dependent cancers. The pool of active ß-catenin is normally limited by destruction complexes, whose assembly depends on the polymeric master scaffolding protein AXIN. Tankyrase, which poly(ADP-ribosyl)ates and thereby destabilizes AXIN, also can polymerize, but the relevance of these polymers has remained unclear. We report crystal structures of the polymerizing TNKS and TNKS2 sterile alpha motif (SAM) domains, revealing versatile head-to-tail interactions. Biochemical studies informed by these structures demonstrate that polymerization is required for Tankyrase to drive ß-catenin-dependent transcription. We show that the polymeric state supports PARP activity and allows Tankyrase to effectively access destruction complexes through enabling avidity-dependent AXIN binding. This study provides an example for regulated signal transduction in non-membrane-enclosed compartments (signalosomes), and it points to novel potential strategies to inhibit Tankyrase function in oncogenic Wnt signaling.
[Mh] Termos MeSH primário: Motivo Estéril alfa
Tanquirases/metabolismo
Via de Sinalização Wnt
[Mh] Termos MeSH secundário: Proteína Axina/metabolismo
Sítios de Ligação
Domínio de Ativação e Recrutamento de Caspases
Catálise
Cristalografia
Proteínas de Drosophila/genética
Proteínas de Drosophila/metabolismo
Células HEK293
Células HeLa
Seres Humanos
Modelos Moleculares
Mutação
Poli(ADP-Ribose) Polimerases/metabolismo
Ligação Proteica
Conformação Proteica
Multimerização Proteica
Relação Estrutura-Atividade
Tanquirases/química
Tanquirases/genética
Transfecção
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (AXIN1 protein, human); 0 (Axin Protein); 0 (Drosophila Proteins); EC 2.4.2.30 (Poly(ADP-ribose) Polymerases); EC 2.4.2.30 (TNKS2 protein, human); EC 2.4.2.30 (Tankyrases); EC 2.4.4.30 (TNKS protein, human)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170830
[Lr] Data última revisão:
170830
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160806
[St] Status:MEDLINE


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[PMID]:27373307
[Au] Autor:Mohd-Zin SW; Abdullah NL; Abdullah A; Greene ND; Cheah PS; Ling KH; Yusof H; Marwan AI; Williams SM; York KT; Ahmad-Annuar A; Abdul-Aziz NM
[Ad] Endereço:a Department of Parasitology, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia.
[Ti] Título:Identification of the genomic mutation in Epha4(rb-2J/rb-2J) mice.
[So] Source:Genome;59(7):439-48, 2016 Jul.
[Is] ISSN:1480-3321
[Cp] País de publicação:Canada
[La] Idioma:eng
[Ab] Resumo:The EphA4 receptor tyrosine kinase is involved in numerous cell-signalling activities during embryonic development. EphA4 has the ability to bind to both types of ephrin ligands, the ephrinAs and ephrinBs. The C57BL/6J-Epha4rb-2J/GrsrJ strain, denoted Epha4(rb-2J/rb-2J), is a spontaneous mouse mutant that arose at The Jackson Laboratory. These mutants exhibited a synchronous hind limb locomotion defect or "hopping gait" phenotype, which is also characteristic of EphA4 null mice. Genetic complementation experiments suggested that Epha4(rb-2J) corresponds to an allele of EphA4, but details of the genomic defect in this mouse mutant are currently unavailable. We found a single base-pair deletion in exon 9 resulting in a frame shift mutation that subsequently resulted in a premature stop codon. Analysis of the predicted structure of the truncated protein suggests that both the kinase and sterile α motif (SAM) domains are absent. Definitive determination of genotype is needed for experimental studies of mice carrying the Epha4(rb-2J) allele, and we have also developed a method to ease detection of the mutation through RFLP. Eph-ephrin family members are reportedly expressed as numerous isoforms. Hence, delineation of the specific mutation in EphA4 in this strain is important for further functional studies, such as protein-protein interactions, immunostaining and gene compensatory studies, investigating the mechanism underlying the effects of altered function of Eph family of receptor tyrosine kinases on phenotype.
[Mh] Termos MeSH primário: Receptor EphA4/genética
Deleção de Sequência
[Mh] Termos MeSH secundário: Alelos
Animais
Códon de Terminação
Éxons
Feminino
Expressão Gênica
Genômica
Hipocampo/metabolismo
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Knockout
Reação em Cadeia da Polimerase/métodos
Polimorfismo de Fragmento de Restrição
RNA/genética
RNA/isolamento & purificação
Transdução de Sinais
Motivo Estéril alfa
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Codon, Terminator); 63231-63-0 (RNA); EC 2.7.10.1 (Receptor, EphA4)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170404
[Lr] Data última revisão:
170404
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160705
[St] Status:MEDLINE
[do] DOI:10.1139/gen-2015-0142



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