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Science Signaling

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https://www.readbyqxmd.com/read/29162744/atp-promotes-the-fast-migration-of-dendritic-cells-through-the-activity-of-pannexin-1-channels-and-p2x7-receptors
#1
Pablo J Sáez, Pablo Vargas, Kenji F Shoji, Paloma A Harcha, Ana-María Lennon-Duménil, Juan C Sáez
Upon its release from injured cells, such as infected, transformed, inflamed, or necrotic cells, extracellular adenosine-5'-triphosphate (ATP) acts as a danger signal that recruits phagocytes, such as neutrophils, macrophages, and dendritic cells (DCs), to the site of injury. The sensing of extracellular ATP occurs through purinergic (P2) receptors. We investigated the cellular mechanisms linking purinergic signaling to DC motility. We found that ATP stimulated fast DC motility through an autocrine signaling loop, which was initiated by the activation of P2X7 receptors and further amplified by pannexin 1 (Panx1) channels...
November 21, 2017: Science Signaling
https://www.readbyqxmd.com/read/29162743/akap95-mediated-nuclear-anchoring-of-pka-mediates-cortisol-induced-ptgs2-expression-in-human-amnion-fibroblasts
#2
Jiangwen Lu, Wangsheng Wang, Yabing Mi, Chuyue Zhang, Hao Ying, Luyao Wang, Yawei Wang, Leslie Myatt, Kang Sun
Phosphorylation of the transcription factors cyclic adenosine monophosphate response element-binding protein (CREB) and signal transducer and activator of transcription 3 (STAT3) by protein kinase A (PKA) is required for the cortisol-induced production of cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2) in human amnion fibroblasts, which critically mediates human parturition (labor). We found that PKA was confined in the nucleus by A-kinase-anchoring protein 95 (AKAP95) in amnion fibroblasts and that this localization was key to the cortisol-induced expression of PTGS2, the gene encoding COX-2...
November 21, 2017: Science Signaling
https://www.readbyqxmd.com/read/29162742/microtubules-tune-mechanotransduction-through-nox2-and-trpv4-to-decrease-sclerostin-abundance-in-osteocytes
#3
James S Lyons, Humberto C Joca, Robert A Law, Katrina M Williams, Jaclyn P Kerr, Guoli Shi, Ramzi J Khairallah, Stuart S Martin, Konstantinos Konstantopoulos, Christopher W Ward, Joseph P Stains
The adaptation of the skeleton to its mechanical environment is orchestrated by mechanosensitive osteocytes, largely by regulating the abundance of sclerostin, a secreted inhibitor of bone formation. We defined a microtubule-dependent mechanotransduction pathway that linked fluid shear stress to reactive oxygen species (ROS) and calcium (Ca(2+)) signals that led to a reduction in sclerostin abundance in cultured osteocytes. We demonstrated that microtubules stabilized by detyrosination, a reversible posttranslational modification of polymerized α-tubulin, determined the stiffness of the cytoskeleton, which set the mechanoresponsive range of cultured osteocytes to fluid shear stress...
November 21, 2017: Science Signaling
https://www.readbyqxmd.com/read/29162741/nuclear-hyaluronidase-2-drives-alternative-splicing-of-cd44-pre-mrna-to-determine-profibrotic-or-antifibrotic-cell-phenotype
#4
Adam C Midgley, Sebastian Oltean, Vincent Hascall, Emma L Woods, Robert Steadman, Aled O Phillips, Soma Meran
The cell surface protein CD44 is involved in diverse physiological processes, and its aberrant function is linked to various pathologies such as cancer, immune dysregulation, and fibrosis. The diversity of CD44 biological activity is partly conferred by the generation of distinct CD44 isoforms through alternative splicing. We identified an unexpected function for the ubiquitous hyaluronan-degrading enzyme, hyaluronidase 2 (HYAL2), as a regulator of CD44 splicing. Standard CD44 is associated with fibrotic disease, and its production is promoted through serine-arginine-rich (SR) protein-mediated exon exclusion...
November 21, 2017: Science Signaling
https://www.readbyqxmd.com/read/29138297/mafb-enhances-oncogenic-notch-signaling-in-t-cell-acute-lymphoblastic-leukemia
#5
Kostandin V Pajcini, Lanwei Xu, Lijian Shao, Jelena Petrovic, Karol Palasiewicz, Yumi Ohtani, Will Bailis, Curtis Lee, Gerald B Wertheim, Rajeswaran Mani, Natarajan Musuthamy, Yunlei Li, Jules P P Meijerink, Stephen C Blacklow, Robert B Faryabi, Sara Cherry, Warren S Pear
Activating mutations in the gene encoding the cell-cell contact signaling protein Notch1 are common in human T cell acute lymphoblastic leukemias (T-ALLs). However, expressing Notch1 mutant alleles in mice fails to efficiently induce the development of leukemia. We performed a gain-of-function screen to identify proteins that enhanced signaling by leukemia-associated Notch1 mutants. The transcription factors MAFB and ETS2 emerged as candidates that individually enhanced Notch1 signaling, and when coexpressed, they synergistically increased signaling to an extent similar to that induced by core components of the Notch transcriptional complex...
November 14, 2017: Science Signaling
https://www.readbyqxmd.com/read/29138296/the-genetics-of-pkm%C3%AE-and-memory-maintenance
#6
REVIEW
Todd Charlton Sacktor, Johannes W Hell
Elucidating the molecular mechanisms that maintain long-term memory is a fundamental goal of neuroscience. Accumulating evidence suggests that persistent signaling by the atypical protein kinase C (PKC) isoform protein kinase Mζ (PKMζ) might maintain synaptic long-term potentiation (LTP) and long-term memory. However, the role of PKMζ has been challenged by genetic data from PKMζ-knockout mice showing intact LTP and long-term memory. Moreover, the PKMζ inhibitor peptide ζ inhibitory peptide (ZIP) reverses LTP and erases memory in both wild-type and knockout mice...
November 14, 2017: Science Signaling
https://www.readbyqxmd.com/read/29138295/generation-of-specific-inhibitors-of-sumo-1-and-sumo-2-3-mediated-protein-protein-interactions-using-affimer-adhiron-technology
#7
David J Hughes, Christian Tiede, Natalie Penswick, Anna Ah-San Tang, Chi H Trinh, Upasana Mandal, Katarzyna Z Zajac, Thembaninskosi Gaule, Gareth Howell, Thomas A Edwards, Jianxin Duan, Eric Feyfant, Michael J McPherson, Darren C Tomlinson, Adrian Whitehouse
Because protein-protein interactions underpin most biological processes, developing tools that target them to understand their function or to inform the development of therapeutics is an important task. SUMOylation is the posttranslational covalent attachment of proteins in the SUMO family (SUMO-1, SUMO-2, or SUMO-3), and it regulates numerous cellular pathways. SUMOylated proteins are recognized by proteins with SUMO-interaction motifs (SIMs) that facilitate noncovalent interactions with SUMO. We describe the use of the Affimer system of peptide display for the rapid isolation of synthetic binding proteins that inhibit SUMO-dependent protein-protein interactions mediated by SIMs both in vitro and in cells...
November 14, 2017: Science Signaling
https://www.readbyqxmd.com/read/29138294/isolation-of-isoform-specific-binding-proteins-affimers-by-phage-display-using-negative-selection
#8
Anna Ah-San Tang, Christian Tiede, David J Hughes, Michael J McPherson, Darren C Tomlinson
Some 30 years after its discovery, phage display remains one of the most widely used methods of in vitro selection. Initially developed to revolutionize the generation of therapeutic antibodies, phage display is now the first choice for screening artificial binding proteins. Artificial binding proteins can be used as reagents to study protein-protein interactions, target posttranslational modifications, and distinguish between homologous proteins. They can also be used as research and affinity reagents, for diagnostic purposes, and as therapeutics...
November 14, 2017: Science Signaling
https://www.readbyqxmd.com/read/29114039/neuronal-activity-drives-fmrp-and-hspg-dependent-matrix-metalloproteinase-function-required-for-rapid-synaptogenesis
#9
Mary L Dear, Jarrod Shilts, Kendal Broadie
Matrix metalloproteinase (MMP) functions modulate synapse formation and activity-dependent plasticity. Aberrant MMP activity is implicated in fragile X syndrome (FXS), a disease caused by the loss of the RNA-binding protein FMRP and characterized by neurological dysfunction and intellectual disability. Gene expression studies in Drosophila suggest that Mmps cooperate with the heparan sulfate proteoglycan (HSPG) glypican co-receptor Dally-like protein (Dlp) to restrict trans-synaptic Wnt signaling and that synaptogenic defects in the fly model of FXS are alleviated by either inhibition of Mmp or genetic reduction of Dlp...
November 7, 2017: Science Signaling
https://www.readbyqxmd.com/read/29114038/aberrant-rac1-cofilin-signaling-mediates-defects-in-dendritic-spines-synaptic-function-and-sensory-perception-in-fragile-x-syndrome
#10
Alexander Pyronneau, Qionger He, Jee-Yeon Hwang, Morgan Porch, Anis Contractor, R Suzanne Zukin
Fragile X syndrome (FXS) is the most common inherited cause of intellectual disabilities and a leading cause of autism. FXS is caused by a trinucleotide expansion in the gene FMR1 on the X chromosome. The neuroanatomical hallmark of FXS is an overabundance of immature dendritic spines, a factor thought to underlie synaptic dysfunction and impaired cognition. We showed that aberrantly increased activity of the Rho GTPase Rac1 inhibited the actin-depolymerizing factor cofilin, a major determinant of dendritic spine structure, and caused disease-associated spine abnormalities in the somatosensory cortex of FXS model mice...
November 7, 2017: Science Signaling
https://www.readbyqxmd.com/read/29114037/reducing-eif4e-eif4g-interactions-restores-the-balance-between-protein-synthesis-and-actin-dynamics-in-fragile-x-syndrome-model-mice
#11
Emanuela Santini, Thu N Huynh, Francesco Longo, So Yeon Koo, Edward Mojica, Laura D'Andrea, Claudia Bagni, Eric Klann
Fragile X syndrome (FXS) is the most common form of inherited intellectual disability and autism spectrum disorder. FXS is caused by silencing of the FMR1 gene, which encodes fragile X mental retardation protein (FMRP), an mRNA-binding protein that represses the translation of its target mRNAs. One mechanism by which FMRP represses translation is through its association with cytoplasmic FMRP-interacting protein 1 (CYFIP1), which subsequently sequesters and inhibits eukaryotic initiation factor 4E (eIF4E). CYFIP1 shuttles between the FMRP-eIF4E complex and the Rac1-Wave regulatory complex, thereby connecting translational regulation to actin dynamics and dendritic spine morphology, which are dysregulated in FXS model mice that lack FMRP...
November 7, 2017: Science Signaling
https://www.readbyqxmd.com/read/29089450/mark3-mediated-phosphorylation-of-arhgef2-couples-microtubules-to-the-actin-cytoskeleton-to-establish-cell-polarity
#12
María-José Sandí, Christopher B Marshall, Marc Balan, Étienne Coyaud, Ming Zhou, Daniel M Monson, Noboru Ishiyama, Arun A Chandrakumar, José La Rose, Amber L Couzens, Anne-Claude Gingras, Brian Raught, Wei Xu, Mitsuhiko Ikura, Deborah K Morrison, Robert Rottapel
The PAR-1-MARK pathway controls cell polarity through the phosphorylation of microtubule-associated proteins. Rho-Rac guanine nucleotide exchange factor 2 (ARHGEF2), which activates Ras homolog family member A (RHOA), is anchored to the microtubule network and sequestered in an inhibited state through binding to dynein light chain Tctex-1 type 1 (DYNLT1). We showed in mammalian cells that liver kinase B1 (LKB1) activated the microtubule affinity-regulating kinase 3 (MARK3), which in turn phosphorylated ARHGEF2 at Ser(151) This modification disrupted the interaction between ARHGEF2 and DYNLT1 by generating a 14-3-3 binding site in ARHGEF2, thus causing ARHGEF2 to dissociate from microtubules...
October 31, 2017: Science Signaling
https://www.readbyqxmd.com/read/29089449/quantitative-single-molecule-imaging-of-tlr4-reveals-ligand-specific-receptor-dimerization
#13
Carmen L Krüger, Marie-Theres Zeuner, Graeme S Cottrell, Darius Widera, Mike Heilemann
In humans, invading pathogens are recognized by Toll-like receptors (TLRs). Upon recognition of lipopolysaccharide (LPS) derived from the cell wall of Gram-negative bacteria, TLR4 dimerizes and can stimulate two different signaling pathways, the proinflammatory, MyD88-dependent pathway and the antiviral, MyD88-independent pathway. The balance between these two pathways is ligand-dependent, and ligand composition determines whether the invading pathogen activates or evades the host immune response. We investigated the dimerization behavior of TLR4 in intact cells in response to different LPS chemotypes through quantitative single-molecule localization microscopy...
October 31, 2017: Science Signaling
https://www.readbyqxmd.com/read/29089448/endogenous-retinoid-x-receptor-ligands-in-mouse-hematopoietic-cells
#14
Haixia Niu, Hideji Fujiwara, Orsola di Martino, Gayla Hadwiger, Thomas E Frederick, María P Menéndez-Gutiérrez, Mercedes Ricote, Gregory R Bowman, John S Welch
The retinoid X receptor α (RXRA) has been implicated in diverse hematological processes. To identify natural ligands of RXRA that are present in hematopoietic cells, we adapted an upstream activation sequence-green fluorescent protein (UAS-GFP) reporter mouse to detect natural RXRA ligands in vivo. We observed reporter activity in diverse types of hematopoietic cells in vivo. Reporter activity increased during granulocyte colony-stimulating factor (G-CSF)-induced granulopoiesis and after phenylhydrazine (PHZ)-induced anemia, suggesting the presence of dynamically regulated natural RXRA ligands in hematopoietic cells...
October 31, 2017: Science Signaling
https://www.readbyqxmd.com/read/29066540/tgf-%C3%AE-receptor-i-ii-trafficking-and-signaling-at-primary-cilia-are-inhibited-by-ceramide-to-attenuate-cell-migration-and-tumor-metastasis
#15
Salih Gencer, Natalia Oleinik, Jisun Kim, Shanmugam Panneer Selvam, Ryan De Palma, Mohammed Dany, Rose Nganga, Raquela J Thomas, Can E Senkal, Philip H Howe, Besim Ogretmen
Signaling by the transforming growth factor-β (TGF-β) receptors I and II (TβRI/II) and the primary cilia-localized sonic hedgehog (Shh) pathway promote cell migration and, consequently, tumor metastasis. In contrast, the sphingolipid ceramide inhibits cell proliferation and tumor metastasis. We investigated whether ceramide metabolism inhibited TβRI/II trafficking to primary cilia to attenuate cross-talk between TβRI/II and the Shh pathway. We found that ceramide synthase 4 (CerS4)-generated ceramide stabilized the association between TβRI and the inhibitory factor Smad7, which limited the trafficking of TβRI/II to primary cilia...
October 24, 2017: Science Signaling
https://www.readbyqxmd.com/read/29066539/tcr-stimulated-changes-in-cell-surface-cd46-expression-generate-type-1-regulatory-t-cells
#16
Siobhan Ni Choileain, Joanne Hay, Joelle Thomas, Anna Williams, Matthieu M Vermeren, Cecile Benezech, Mario Gomez-Salazar, Owen R Hugues, Sonja Vermeren, Sarah E M Howie, Ian Dransfield, Anne L Astier
A lack of regulatory T cell function is a critical factor in the pathogenesis of autoimmune diseases, such as multiple sclerosis (MS). Ligation of the complement regulatory protein CD46 facilitates the differentiation of T helper 1 (TH1) effector cells into interleukin-10 (IL-10)-secreting type 1 regulatory T cells (Tr1 cells), and this pathway is defective in MS patients. Cleavage of the ectodomain of CD46, which contains three N-glycosylation sites and multiple O-glycosylation sites, enables CD46 to activate T cells...
October 24, 2017: Science Signaling
https://www.readbyqxmd.com/read/29066538/the-scaffolding-protein-cnk-binds-to-the-receptor-tyrosine-kinase-alk-to-promote-visceral-founder-cell-specification-in-drosophila
#17
Georg Wolfstetter, Kathrin Pfeifer, Jesper R van Dijk, Fredrik Hugosson, Xiangyi Lu, Ruth H Palmer
In Drosophila melanogaster, the receptor tyrosine kinase (RTK) anaplastic lymphoma kinase (Alk) and its ligand jelly belly (Jeb) are required to specify muscle founder cells in the visceral mesoderm. We identified a critical role for the scaffolding protein Cnk (connector enhancer of kinase suppressor of Ras) in this signaling pathway. Embryos that ectopically expressed the minimal Alk interaction region in the carboxyl terminus of Cnk or lacked maternal and zygotic cnk did not generate visceral founder cells or a functional gut musculature, phenotypes that resemble those of jeb and Alk mutants...
October 24, 2017: Science Signaling
https://www.readbyqxmd.com/read/29042483/olfactory-experience-primes-the-heat-shock-transcription-factor-hsf-1-to-enhance-the-expression-of-molecular-chaperones-in-c-elegans
#18
Felicia K Ooi, Veena Prahlad
Learning, a process by which animals modify their behavior as a result of experience, enables organisms to synthesize information from their surroundings to acquire resources and avoid danger. We showed that a previous encounter with only the odor of pathogenic bacteria prepared Caenorhabditis elegans to survive exposure to the pathogen by increasing the heat shock factor 1 (HSF-1)-dependent expression of genes encoding molecular chaperones. Experience-mediated enhancement of chaperone gene expression required serotonin, which primed HSF-1 to enhance the expression of molecular chaperone genes by promoting its localization to RNA polymerase II-enriched nuclear loci, even before transcription occurred...
October 17, 2017: Science Signaling
https://www.readbyqxmd.com/read/29042482/resveratrol-stimulates-the-metabolic-reprogramming-of-human-cd4-t-cells-to-enhance-effector-function
#19
Marco Craveiro, Gaspard Cretenet, Cédric Mongellaz, Maria I Matias, Olivier Caron, Maria C Pedroso de Lima, Valérie S Zimmermann, Eric Solary, Valérie Dardalhon, Vjekoslav Dulić, Naomi Taylor
The polyphenol resveratrol activates the deacetylase Sirt1, resulting in various antioxidant, chemoprotectant, neuroprotective, cardioprotective, and anti-inflammatory properties. We found that at high concentrations of resveratrol, human CD4(+) T cells showed defective antigen receptor signaling and arrest at the G1 stage of the cell cycle, whereas at low concentrations, cells were readily activated and exhibited enhanced Sirt1 deacetylase activity. Nevertheless, low-dose resveratrol rapidly stimulated genotoxic stress in the T cells, which resulted in engagement of a DNA damage response pathway that depended on the kinase ATR [ataxia telangiectasia-mutated (ATM) and Rad3-related], but not ATM, and subsequently in premitotic cell cycle arrest...
October 17, 2017: Science Signaling
https://www.readbyqxmd.com/read/29042481/the-matricellular-protein-tsp1-promotes-human-and-mouse-endothelial-cell-senescence-through-cd47-and-nox1
#20
Daniel N Meijles, Sanghamitra Sahoo, Imad Al Ghouleh, Jefferson H Amaral, Raquel Bienes-Martinez, Heather E Knupp, Shireen Attaran, John C Sembrat, Seyed M Nouraie, Mauricio M Rojas, Enrico M Novelli, Mark T Gladwin, Jeffrey S Isenberg, Eugenia Cifuentes-Pagano, Patrick J Pagano
Senescent cells withdraw from the cell cycle and do not proliferate. The prevalence of senescent compared to normally functioning parenchymal cells increases with age, impairing tissue and organ homeostasis. A contentious principle governing this process has been the redox theory of aging. We linked matricellular protein thrombospondin 1 (TSP1) and its receptor CD47 to the activation of NADPH oxidase 1 (Nox1), but not of the other closely related Nox isoforms, and associated oxidative stress, and to senescence in human cells and aged tissue...
October 17, 2017: Science Signaling
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