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Science Signaling

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https://www.readbyqxmd.com/read/27923915/late-phase-synthesis-of-i%C3%AE%C2%BAb%C3%AE-insulates-the-tlr4-activated-canonical-nf-%C3%AE%C2%BAb-pathway-from-noncanonical-nf-%C3%AE%C2%BAb-signaling-in-macrophages
#1
Budhaditya Chatterjee, Balaji Banoth, Tapas Mukherjee, Nandaraj Taye, Bharath Vijayaragavan, Samit Chattopadhyay, James Gomes, Soumen Basak
The nuclear factor κB (NF-κB) transcription factors coordinate the inflammatory immune response during microbial infection. Pathogenic substances engage canonical NF-κB signaling through the heterodimer RelA:p50, which is subjected to rapid negative feedback by inhibitor of κBα (IκBα). The noncanonical NF-κB pathway is required for the differentiation of immune cells; however, cross-talk between both pathways can occur. Concomitantly activated noncanonical signaling generates p52 from the p100 precursor...
December 6, 2016: Science Signaling
https://www.readbyqxmd.com/read/27923914/widespread-control-of-calcium-signaling-by-a-family-of-serca-inhibiting-micropeptides
#2
Douglas M Anderson, Catherine A Makarewich, Kelly M Anderson, John M Shelton, Svetlana Bezprozvannaya, Rhonda Bassel-Duby, Eric N Olson
Micropeptides function as master regulators of calcium-dependent signaling in muscle. Sarco/endoplasmic reticulum Ca(2+) ATPase (SERCA), the membrane pump that promotes muscle relaxation by taking up Ca(2+) into the sarcoplasmic reticulum, is directly inhibited by three muscle-specific micropeptides: myoregulin (MLN), phospholamban (PLN), and sarcolipin (SLN). The widespread and essential function of SERCA across diverse cell types has raised questions as to how SERCA is regulated in cells that lack MLN, PLN, and SLN...
December 6, 2016: Science Signaling
https://www.readbyqxmd.com/read/27923913/a-tgf%C3%AE-mir-182-brca1-axis-controls-the-mammary-differentiation-hierarchy
#3
Haydeliz Martinez-Ruiz, Irineu Illa-Bochaca, Coral Omene, Douglas Hanniford, Qi Liu, Eva Hernando, Mary Helen Barcellos-Hoff
Maintenance of mammary functional capacity during cycles of proliferation and regression depends on appropriate cell fate decisions of mammary progenitor cells to populate an epithelium consisting of secretory luminal cells and contractile myoepithelial cells. It is well established that transforming growth factor-β (TGFβ) restricts mammary epithelial cell proliferation and that sensitivity to TGFβ is decreased in breast cancer. We show that TGFβ also exerts control of mammary progenitor self-renewal and lineage commitment decisions by stringent regulation of breast cancer associated 1 (BRCA1), which controls stem cell self-renewal and lineage commitment...
December 6, 2016: Science Signaling
https://www.readbyqxmd.com/read/27923912/erratum-for-the-research-article-a-computationally-identified-compound-antagonizes-excess-fgf-23-signaling-in-renal-tubules-and-a-mouse-model-of-hypophosphatemia-by-z-xiao-d-riccardi-h-a-velazquez-a-l-chin-c-r-yates-j-d-carrick-j-c-smith-j-baudry-l-d-quarles
#4
https://www.readbyqxmd.com/read/27923911/emerging-roles-for-organelles-in-cellular-regulation
#5
EDITORIAL
Nancy R Gough
This Editorial Guide describes the emerging confluence of cellular regulation and organelle biology. The signals and molecular machineries that regulate organelle function, dynamics, and replication and the signals produced by organelles are beginning to be discovered.
December 6, 2016: Science Signaling
https://www.readbyqxmd.com/read/27899527/biased-agonists-of-the-kappa-opioid-receptor-suppress-pain-and-itch-without-causing-sedation-or-dysphoria
#6
Tarsis F Brust, Jenny Morgenweck, Susy A Kim, Jamie H Rose, Jason L Locke, Cullen L Schmid, Lei Zhou, Edward L Stahl, Michael D Cameron, Sarah M Scarry, Jeffrey Aubé, Sara R Jones, Thomas J Martin, Laura M Bohn
Agonists targeting the kappa opioid receptor (KOR) have been promising therapeutic candidates because of their efficacy for treating intractable itch and relieving pain. Unlike typical opioid narcotics, KOR agonists do not produce euphoria or lead to respiratory suppression or overdose. However, they do produce dysphoria and sedation, side effects that have precluded their clinical development as therapeutics. KOR signaling can be fine-tuned to preferentially activate certain pathways over others, such that agonists can bias signaling so that the receptor signals through G proteins rather than other effectors such as βarrestin2...
November 29, 2016: Science Signaling
https://www.readbyqxmd.com/read/27899526/dynamic-pre-bcr-homodimers-fine-tune-autonomous-survival-signals-in-b-cell-precursor-acute-lymphoblastic-leukemia
#7
M Frank Erasmus, Ksenia Matlawska-Wasowska, Ichiko Kinjyo, Avanika Mahajan, Stuart S Winter, Li Xu, Michael Horowitz, Diane S Lidke, Bridget S Wilson
The pre-B cell receptor (pre-BCR) is an immature form of the BCR critical for early B lymphocyte development. It is composed of the membrane-bound immunoglobulin (Ig) heavy chain, surrogate light chain components, and the signaling subunits Igα and Igβ. We developed monovalent quantum dot (QD)-labeled probes specific for Igβ to study the behavior of pre-BCRs engaged in autonomous, ligand-independent signaling in live B cells. Single-particle tracking revealed that QD-labeled pre-BCRs engaged in transient, but frequent, homotypic interactions...
November 29, 2016: Science Signaling
https://www.readbyqxmd.com/read/27899525/reactive-oxygen-species-induce-virus-independent-mavs-oligomerization-in-systemic-lupus-erythematosus
#8
Iwona A Buskiewicz, Theresa Montgomery, Elizabeth C Yasewicz, Sally A Huber, Michael P Murphy, Richard C Hartley, Ryan Kelly, Mary K Crow, Andras Perl, Ralph C Budd, Andreas Koenig
The increased expression of genes induced by type I interferon (IFN) is characteristic of viral infections and systemic lupus erythematosus (SLE). We showed that mitochondrial antiviral signaling (MAVS) protein, which normally forms a complex with retinoic acid gene I (RIG-I)-like helicases during viral infection, was activated by oxidative stress independently of RIG-I helicases. We found that chemically generated oxidative stress stimulated the formation of MAVS oligomers, which led to mitochondrial hyperpolarization and decreased adenosine triphosphate production and spare respiratory capacity, responses that were not observed in similarly treated cells lacking MAVS...
November 29, 2016: Science Signaling
https://www.readbyqxmd.com/read/27899524/science-signaling-podcast-for-29-november-2016-pre-b-cell-receptor-signaling-in-leukemia
#9
Bridget S Wilson, Annalisa M VanHook
This Podcast features an interview with Bridget Wilson, author of a Research Article that appears in the 29 November 2016 issue of Science Signaling, about pre-B cell receptor (pre-BCR) signaling in B cell precursor acute lymphoblastic leukemia (BCP-ALL). Signaling through the pre-BCR, an immature form of the BCR, promotes the survival of B cell progenitors and has been implicated in the pathology of BCP-ALL. Erasmus et al found that pre-BCRs formed transient homomeric complexes that correlated with pro-survival signaling...
November 29, 2016: Science Signaling
https://www.readbyqxmd.com/read/27879396/integrating-network-reconstruction-with-mechanistic-modeling-to-predict-cancer-therapies
#10
Melinda Halasz, Boris N Kholodenko, Walter Kolch, Tapesh Santra
Signal transduction networks are often rewired in cancer cells. Identifying these alterations will enable more effective cancer treatment. We developed a computational framework that can identify, reconstruct, and mechanistically model these rewired networks from noisy and incomplete perturbation response data and then predict potential targets for intervention. As a proof of principle, we analyzed a perturbation data set targeting epidermal growth factor receptor (EGFR) and insulin-like growth factor 1 receptor (IGF1R) pathways in a panel of colorectal cancer cells...
November 22, 2016: Science Signaling
https://www.readbyqxmd.com/read/27879395/a-computationally-identified-compound-antagonizes-excess-fgf-23-signaling-in-renal-tubules-and-a-mouse-model-of-hypophosphatemia
#11
Zhousheng Xiao, Demian Riccardi, Hector A Velazquez, Ai L Chin, Charles R Yates, Jesse D Carrick, Jeremy C Smith, Jerome Baudry, L Darryl Quarles
Fibroblast growth factor-23 (FGF-23) interacts with a binary receptor complex composed of α-Klotho (α-KL) and FGF receptors (FGFRs) to regulate phosphate and vitamin D metabolism in the kidney. Excess FGF-23 production, which causes hypophosphatemia, is genetically inherited or occurs with chronic kidney disease. Among other symptoms, hypophosphatemia causes vitamin D deficiency and the bone-softening disorder rickets. Current therapeutics that target the receptor complex have limited utility clinically. Using a computationally driven, structure-based, ensemble docking and virtual high-throughput screening approach, we identified four novel compounds predicted to selectively inhibit FGF-23-induced activation of the FGFR/α-KL complex...
November 22, 2016: Science Signaling
https://www.readbyqxmd.com/read/27879394/selective-control-of-up-regulated-and-down-regulated-genes-by-temporal-patterns-and-doses-of-insulin
#12
Takanori Sano, Kentaro Kawata, Satoshi Ohno, Katsuyuki Yugi, Hiroaki Kakuda, Hiroyuki Kubota, Shinsuke Uda, Masashi Fujii, Katsuyuki Kunida, Daisuke Hoshino, Atsushi Hatano, Yuki Ito, Miharu Sato, Yutaka Suzuki, Shinya Kuroda
Secretion of insulin transiently increases after eating, resulting in a high circulating concentration. Fasting limits insulin secretion, resulting in a low concentration of insulin in the circulation. We analyzed transcriptional responses to different temporal patterns and doses of insulin in the hepatoma FAO cells and identified 13 up-regulated and 16 down-regulated insulin-responsive genes (IRGs). The up-regulated IRGs responded more rapidly than did the down-regulated IRGs to transient stepwise or pulsatile increases in insulin concentration, whereas the down-regulated IRGs were repressed at lower concentrations of insulin than those required to stimulate the up-regulated IRGs...
November 22, 2016: Science Signaling
https://www.readbyqxmd.com/read/27902448/rasgrp1-promotes-amphetamine-induced-motor-behavior-through-a-rhes-interaction-network-rhesactome-in-the-striatum
#13
Neelam Shahani, Supriya Swarnkar, Vincenzo Giovinazzo, Jenny Morgenweck, Laura M Bohn, Catherina Scharager-Tapia, Bruce Pascal, Pablo Martinez-Acedo, Kshitij Khare, Srinivasa Subramaniam
The striatum of the brain coordinates motor function. Dopamine-related drugs may be therapeutic to patients with striatal neurodegeneration, such as Huntington's disease (HD) and Parkinson's disease (PD), but these drugs have unwanted side effects. In addition to stimulating the release of norepinephrine, amphetamines, which are used for narcolepsy and attention-deficit/hyperactivity disorder (ADHD), trigger dopamine release in the striatum. The guanosine triphosphatase Ras homolog enriched in the striatum (Rhes) inhibits dopaminergic signaling in the striatum, is implicated in HD and L-dopa-induced dyskinesia, and has a role in striatal motor control...
November 15, 2016: Science Signaling
https://www.readbyqxmd.com/read/27902447/a-unique-type-of-gsk-3-inhibitor-brings-new-opportunities-to-the-clinic
#14
Avital Licht-Murava, Rom Paz, Lilach Vaks, Limor Avrahami, Batya Plotkin, Miriam Eisenstein, Hagit Eldar-Finkelman
Development of protein kinase inhibitors is a focus of many drug discovery programs. A major problem, however, is the limited specificity of the commonly used adenosine triphosphate-competitive inhibitors and the weak inhibition of the more selective substrate-competitive inhibitors. Glycogen synthase kinase-3 (GSK-3) is a promising drug target for treating neurodegenerative disorders, including Alzheimer's disease (AD), but most GSK-3 inhibitors have not reached the clinic. We describe a new type of GSK-3 inhibitor, L807mts, that acts through a substrate-to-inhibitor conversion mechanism that occurs within the catalytic site of the enzyme...
November 15, 2016: Science Signaling
https://www.readbyqxmd.com/read/27902446/science-signaling-podcast-for-15-november-2016-a-new-type-of-kinase-inhibitor
#15
Hagit Eldar-Finkelman, Annalisa M VanHook
This Podcast features an interview with Hagit Eldar-Finkelman, author of a Research Article that appears in the 15 November 2016 issue of Science Signaling, about a newly developed inhibitor of glycogen synthase kinase 3 (GSK-3). GSK-3 participates in several signaling networks and has been implicated in various pathologies, including neurodegenerative diseases, cognitive impairments, and cancer. Licht-Murava et al developed L807mts, a substrate-competitive peptide inhibitor that blocks GSK-3 activity through an unusual mechanism...
November 15, 2016: Science Signaling
https://www.readbyqxmd.com/read/27902445/focus-issue-new-horizons-for-treating-neurological-disease
#16
EDITORIAL
Leslie K Ferrarelli
This issue of Science Signaling highlights research that uncovers protein interaction networks and potential drug targets, as well as research that identifies molecular mechanisms of action of novel or existing drugs, for neurological and psychological disease. This Editorial Guide features a handful of papers from 2016 that join the ranks of Science Signaling's vast archive of articles related to neuroscience.
November 15, 2016: Science Signaling
https://www.readbyqxmd.com/read/27919027/phosphorylation-of-janus-kinase-1-jak1-by-amp-activated-protein-kinase-ampk-links-energy-sensing-to-anti-inflammatory-signaling
#17
Claire Rutherford, Claire Speirs, Jamie J L Williams, Marie-Ann Ewart, Sarah J Mancini, Simon A Hawley, Christian Delles, Benoit Viollet, Ana P Costa-Pereira, George S Baillie, Ian P Salt, Timothy M Palmer
Adenosine 5'-monophosphate-activated protein kinase (AMPK) is a pivotal regulator of metabolism at cellular and organismal levels. AMPK also suppresses inflammation. We found that pharmacological activation of AMPK rapidly inhibited the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway in various cells. In vitro kinase assays revealed that AMPK directly phosphorylated two residues (Ser(515) and Ser(518)) within the Src homology 2 domain of JAK1. Activation of AMPK enhanced the interaction between JAK1 and 14-3-3 proteins in cultured vascular endothelial cells and fibroblasts, an effect that required the presence of Ser(515) and Ser(518) and was abolished in cells lacking AMPK catalytic subunits...
November 8, 2016: Science Signaling
https://www.readbyqxmd.com/read/27919026/hindered-cytoplasmic-diffusion-of-inositol-trisphosphate-restricts-its-cellular-range-of-action
#18
George D Dickinson, Kyle L Ellefsen, Silvina Ponce Dawson, John E Pearson, Ian Parker
The range of action of intracellular messengers is determined by their rates of diffusion and degradation. Previous measurements in oocyte cytoplasmic extracts indicated that the Ca(2+)-liberating second messenger inositol trisphosphate (IP3) diffuses with a coefficient (~280 μm(2) s(-1)) similar to that in water, corresponding to a range of action of ~25 μm. Consequently, IP3 is generally considered a "global" cellular messenger. We reexamined this issue by measuring local IP3-evoked Ca(2+) puffs to monitor IP3 diffusing from spot photorelease in neuroblastoma cells...
November 8, 2016: Science Signaling
https://www.readbyqxmd.com/read/27919025/ip3-still-on-the-move-but-now-in-the-slow-lane
#19
REVIEW
Luc Leybaert
In this issue of Science Signaling, Dickinson et al show that the intracellular messenger inositol 1,4,5-trisphosphate (IP3), which triggers the release of calcium (Ca(2+)) from the endoplasmic reticulum, is a slowly diffusing local signal, rather than a rapidly diffusing global one. These findings have implications for the understanding of the mechanisms of Ca(2+) wave propagation, especially long-range, cell-to-cell propagating Ca(2+) waves.
November 8, 2016: Science Signaling
https://www.readbyqxmd.com/read/27803285/heparan-sulfate-differentially-controls-cxcl12%C3%AE-and-cxcl12%C3%AE-mediated-cell-migration-through-differential-presentation-to-their-receptor-cxcr4
#20
Bridgette J Connell, Rabia Sadir, Françoise Baleux, Cédric Laguri, Jean-Philippe Kleman, Lingjie Luo, Fernando Arenzana-Seisdedos, Hugues Lortat-Jacob
Chemokines stimulate signals in cells by binding to G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptors. These chemoattractant cytokines also interact with heparan sulfate (HS), which provides positional information within tissues in the form of haptotactic gradients along which cells can migrate directionally. To investigate the mechanism by which HS modulates chemokine functions, we used the CXC chemokine CXCL12, which exists in different isoforms that all signal through CXCR4 but have distinct HS-binding domains...
November 1, 2016: Science Signaling
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