2,133 results match your criteria Science Signaling [Journal]


Mutations in the NPxxY motif stabilize pharmacologically distinct conformational states of the α- and β-adrenoceptors.

Sci Signal 2019 Mar 12;12(572). Epub 2019 Mar 12.

Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.

G protein-coupled receptors (GPCRs) convert extracellular stimuli to intracellular responses that regulate numerous physiological processes. Crystallographic and biophysical advances in GPCR structural analysis have aided investigations of structure-function relationships that clarify our understanding of these dynamic receptors, but the molecular mechanisms associated with activation and signaling for individual GPCRs may be more complex than was previously appreciated. Here, we investigated the proposed water-mediated, hydrogen-bonded activation switch between the conserved NPxxY motif on transmembrane helix 7 (TMH7) and a conserved tyrosine in TMH5, which contributes to α-adrenoceptor (α-AR) and β-AR activation. Read More

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http://dx.doi.org/10.1126/scisignal.aas9485DOI Listing

Eye on ion channels in immune cells.

Sci Signal 2019 Mar 12;12(572). Epub 2019 Mar 12.

Department of Pediatrics, New York University School of Medicine, New York, NY 10016, USA.

Ion channels facilitate the movement of ions across the plasma and organellar membranes. A recent symposium brought together scientists who study ion channels and transporters in immune cells, which highlighted advances in this emerging field and served to chart new avenues for investigating the roles of ion channels in immunity. Read More

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http://dx.doi.org/10.1126/scisignal.aaw8014DOI Listing

Manganese promotes the aggregation and prion-like cell-to-cell exosomal transmission of α-synuclein.

Sci Signal 2019 Mar 12;12(572). Epub 2019 Mar 12.

Parkinson's Disorder Research Program, Iowa Center for Advanced Neurotoxicology, Department of Biomedical Sciences, Iowa State University, Ames, IA 50011, USA.

The aggregation of α-synuclein (αSyn) is considered a key pathophysiological feature of certain neurodegenerative disorders, collectively termed synucleinopathies. Given that a prion-like, cell-to-cell transfer of misfolded αSyn has been recognized in the spreading of αSyn pathology in synucleinopathies, we investigated the biological mechanisms underlying the propagation of the disease with respect to environmental neurotoxic stress. Considering the potential role of the divalent metal manganese (Mn) in protein aggregation, we characterized its effect on αSyn misfolding and transmission in experimental models of Parkinson's disease. Read More

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http://dx.doi.org/10.1126/scisignal.aau4543DOI Listing

Carbohydrate-dependent B cell activation by fucose-binding bacterial lectins.

Sci Signal 2019 Mar 5;12(571). Epub 2019 Mar 5.

Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany.

Bacterial lectins are typically multivalent and bind noncovalently to specific carbohydrates on host tissues to facilitate bacterial adhesion. Here, we analyzed the effects of two fucose-binding lectins, BambL from and LecB from , on specific signaling pathways in B cells. We found that these bacterial lectins induced B cell activation, which, in vitro, was dependent on the cell surface expression of the B cell antigen receptor (BCR) and its co-receptor CD19, as well as on spleen tyrosine kinase (Syk) activity. Read More

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http://stke.sciencemag.org/lookup/doi/10.1126/scisignal.aao7
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http://dx.doi.org/10.1126/scisignal.aao7194DOI Listing
March 2019
6 Reads

Excitatory neuron-specific SHP2-ERK signaling network regulates synaptic plasticity and memory.

Sci Signal 2019 Mar 5;12(571). Epub 2019 Mar 5.

Department of Physiology, Seoul National University College of Medicine, Seoul 03080, Korea.

Mutations in RAS signaling pathway components cause diverse neurodevelopmental disorders, collectively called RASopathies. Previous studies have suggested that dysregulation in RAS-extracellular signal-regulated kinase (ERK) activation is restricted to distinct cell types in different RASopathies. Some cases of Noonan syndrome (NS) are associated with gain-of-function mutations in the phosphatase SHP2 (encoded by ); however, SHP2 is abundant in multiple cell types, so it is unclear which cell type(s) contribute to NS phenotypes. Read More

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http://dx.doi.org/10.1126/scisignal.aau5755DOI Listing
March 2019
1 Read
6.279 Impact Factor

Desynchronization of the molecular clock contributes to the heterogeneity of the inflammatory response.

Sci Signal 2019 Mar 5;12(571). Epub 2019 Mar 5.

Howard Hughes Medical Institute, Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06510, USA.

Heterogeneity in the behavior of genetically and developmentally equivalent cells is becoming increasingly appreciated. There are several sources of cellular heterogeneity, including both intrinsic and extrinsic noise. We found that some aspects of heterogeneity in the response of macrophages to bacterial lipopolysaccharide (LPS) were due to intercellular desynchronization of the molecular clock, a cell-intrinsic oscillator. Read More

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http://dx.doi.org/10.1126/scisignal.aau1851DOI Listing

Chronic TGF-β exposure drives stabilized EMT, tumor stemness, and cancer drug resistance with vulnerability to bitopic mTOR inhibition.

Sci Signal 2019 Feb 26;12(570). Epub 2019 Feb 26.

Department of Cell and Tissue Biology, University of California at San Francisco, San Francisco, CA 94143, USA.

Tumors comprise cancer stem cells (CSCs) and their heterogeneous progeny within a stromal microenvironment. In response to transforming growth factor-β (TGF-β), epithelial and carcinoma cells undergo a partial or complete epithelial-mesenchymal transition (EMT), which contributes to cancer progression. This process is seen as reversible because cells revert to an epithelial phenotype upon TGF-β removal. Read More

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http://dx.doi.org/10.1126/scisignal.aau8544DOI Listing
February 2019
1 Read

Specificity, versatility, and control of TGF-β family signaling.

Sci Signal 2019 Feb 26;12(570). Epub 2019 Feb 26.

Department of Cell and Tissue Biology and Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California at San Francisco, San Francisco, CA 94143, USA.

Encoded in mammalian cells by 33 genes, the transforming growth factor-β (TGF-β) family of secreted, homodimeric and heterodimeric proteins controls the differentiation of most, if not all, cell lineages and many aspects of cell and tissue physiology in multicellular eukaryotes. Deregulation of TGF-β family signaling leads to developmental anomalies and disease, whereas enhanced TGF-β signaling contributes to cancer and fibrosis. Here, we review the fundamentals of the signaling mechanisms that are initiated upon TGF-β ligand binding to its cell surface receptors and the dependence of the signaling responses on input from and cooperation with other signaling pathways. Read More

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http://dx.doi.org/10.1126/scisignal.aav5183DOI Listing
February 2019
4 Reads

Immunometabolism regulates TCR recycling and iNKT cell functions.

Sci Signal 2019 Feb 26;12(570). Epub 2019 Feb 26.

Division of Molecular Medicine, Hefei National Laboratory for Physical Sciences at Microscale, The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei 230027, China.

Invariant natural killer T (iNKT) cells are innate-like T lymphocytes that express an invariant T cell receptor (TCR), which recognizes glycolipid antigens presented on CD1d molecules. These cells are phenotypically and functionally distinct from conventional T cells. When we characterized the metabolic activity of iNKT cells, consistent with their activated phenotype, we found that they had much less mitochondrial respiratory capacity but increased glycolytic activity in comparison to naïve conventional CD4 T cells. Read More

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http://dx.doi.org/10.1126/scisignal.aau1788DOI Listing
February 2019
6.279 Impact Factor

Disabling the Gβγ-SNARE interaction disrupts GPCR-mediated presynaptic inhibition, leading to physiological and behavioral phenotypes.

Sci Signal 2019 Feb 19;12(569). Epub 2019 Feb 19.

Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA.

G protein-coupled receptors (GPCRs) that couple to G proteins modulate neurotransmission presynaptically by inhibiting exocytosis. Release of Gβγ subunits from activated G proteins decreases the activity of voltage-gated Ca channels (VGCCs), decreasing excitability. A less understood Gβγ-mediated mechanism downstream of Ca entry is the binding of Gβγ to SNARE complexes, which facilitate the fusion of vesicles with the cell plasma membrane in exocytosis. Read More

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http://dx.doi.org/10.1126/scisignal.aat8595DOI Listing
February 2019

Structure of the C-terminal guanine nucleotide exchange factor module of Trio in an autoinhibited conformation reveals its oncogenic potential.

Sci Signal 2019 Feb 19;12(569). Epub 2019 Feb 19.

Departments of Biological Sciences and of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA.

The C-terminal guanine nucleotide exchange factor (GEF) module of Trio (TrioC) transfers signals from the Gα subfamily of heterotrimeric G proteins to the small guanosine triphosphatase (GTPase) RhoA, enabling Gα-coupled G protein-coupled receptors (GPCRs) to control downstream events, such as cell motility and gene transcription. This conserved signal transduction axis is crucial for tumor growth in uveal melanoma. Previous studies indicate that the GEF activity of the TrioC module is autoinhibited, with release of autoinhibition upon Gα binding. Read More

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http://dx.doi.org/10.1126/scisignal.aav2449DOI Listing
February 2019

Glutathione -transferases promote proinflammatory astrocyte-microglia communication during brain inflammation.

Sci Signal 2019 Feb 19;12(569). Epub 2019 Feb 19.

Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.

Astrocytes and microglia play critical roles in brain inflammation. Here, we report that glutathione -transferases (GSTs), particularly GSTM1, promote proinflammatory signaling in astrocytes and contribute to astrocyte-mediated microglia activation during brain inflammation. In vivo, astrocyte-specific knockdown of GSTM1 in the prefrontal cortex attenuated microglia activation in brain inflammation induced by systemic injection of lipopolysaccharides (LPS). Read More

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http://dx.doi.org/10.1126/scisignal.aar2124DOI Listing
February 2019

An immunoproteomic approach to characterize the CAR interactome and signalosome.

Sci Signal 2019 Feb 12;12(568). Epub 2019 Feb 12.

Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.

Adoptive transfer of T cells that express a chimeric antigen receptor (CAR) is an approved immunotherapy that may be curative for some hematological cancers. To better understand the therapeutic mechanism of action, we systematically analyzed CAR signaling in human primary T cells by mass spectrometry. When we compared the interactomes and the signaling pathways activated by distinct CAR-T cells that shared the same antigen-binding domain but differed in their intracellular domains and their in vivo antitumor efficacy, we found that only second-generation CARs induced the expression of a constitutively phosphorylated form of CD3ζ that resembled the endogenous species. Read More

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http://stke.sciencemag.org/lookup/doi/10.1126/scisignal.aap9
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http://dx.doi.org/10.1126/scisignal.aap9777DOI Listing
February 2019
1 Read

Inflammation, necrosis, and the kinase RIP3 are key mediators of AAG-dependent alkylation-induced retinal degeneration.

Sci Signal 2019 Feb 12;12(568). Epub 2019 Feb 12.

Department of Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.

DNA-alkylating agents are commonly used to kill cancer cells, but the base excision repair (BER) pathway they trigger can also produce toxic intermediates that cause tissue damage, such as retinal degeneration (RD). Apoptosis, a process of programmed cell death, is assumed to be the main mechanism of this alkylation-induced photoreceptor (PR) cell death in RD. Here, we studied the involvement of necroptosis (another programmed cell death process) and inflammation in alkylation-induced RD. Read More

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http://dx.doi.org/10.1126/scisignal.aau9216DOI Listing
February 2019

Mitochondrial reactive oxygen species enable proinflammatory signaling through disulfide linkage of NEMO.

Sci Signal 2019 Feb 12;12(568). Epub 2019 Feb 12.

Institute for Medical Microbiology, Immunology and Hygiene, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50935 Cologne, Germany.

A major function of macrophages during infection is initiation of the proinflammatory response, leading to the secretion of cytokines that help to orchestrate the immune response. Here, we identify reactive oxygen species (ROS) as crucial mediators of proinflammatory signaling leading to cytokine secretion in infected macrophages. ROS produced by NADPH oxidases (Noxes), such as Nox2, are key components of the macrophage response to invading pathogens; however, our data show that the ROS that mediated proinflammatory signaling were produced by mitochondria (mtROS). Read More

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http://dx.doi.org/10.1126/scisignal.aar5926DOI Listing
February 2019
2 Reads

Hypoxic cancer-associated fibroblasts increase NCBP2-AS2/HIAR to promote endothelial sprouting through enhanced VEGF signaling.

Sci Signal 2019 Feb 5;12(567). Epub 2019 Feb 5.

Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK.

Intratumoral hypoxia causes the formation of dysfunctional blood vessels, which contribute to tumor metastasis and reduce the efficacy of therapeutic treatments. Blood vessels are embedded in the tumor stroma of which cancer-associated fibroblasts (CAFs) constitute a prominent cellular component. We found that hypoxic human mammary CAFs promoted angiogenesis in CAF-endothelial cell cocultures in vitro. Read More

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http://dx.doi.org/10.1126/scisignal.aan8247DOI Listing
February 2019

Inhibition of T cell activation and function by the adaptor protein CIN85.

Sci Signal 2019 Feb 5;12(567). Epub 2019 Feb 5.

Laboratory for Cell Signaling, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa 230-0045, Japan.

T cell activation is initiated by signaling molecules downstream of the T cell receptor (TCR) that are organized by adaptor proteins. CIN85 (Cbl-interacting protein of 85 kDa) is one such adaptor protein. Here, we showed that CIN85 limited T cell responses to TCR stimulation. Read More

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http://dx.doi.org/10.1126/scisignal.aav4373DOI Listing
February 2019

Interrogating B cell signaling pathways: A quest for novel therapies for mantle cell lymphoma.

Sci Signal 2019 Feb 5;12(567). Epub 2019 Feb 5.

Department of Lymphoma and Myeloma, the University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard Unit 0429, Houston, TX 77030-4009, USA.

Mantle cell lymphoma (MCL) is an aggressive B cell lymphoma that is largely chemoresistant. Ibrutinib, a drug that inhibits Bruton's tyrosine kinase (BTK), has improved the overall survival of patients with MCL; however, resistance to ibrutinib has emerged as a decisive, negative factor in the prognosis of MCL. Adopting a more patient-centric therapeutic approach that incorporates applied genomics and interrogation of B cell signaling pathways may offer an alternative route to reach durable remission in patients with MCL. Read More

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http://dx.doi.org/10.1126/scisignal.aat4105DOI Listing
February 2019
2 Reads
6.279 Impact Factor

Targeting NOTCH activation in small cell lung cancer through LSD1 inhibition.

Sci Signal 2019 Feb 5;12(567). Epub 2019 Feb 5.

Divisions of Human Biology and Public Health Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N, Seattle, WA 98109, USA.

Small cell lung cancer (SCLC) is a recalcitrant, aggressive neuroendocrine-type cancer for which little change to first-line standard-of-care treatment has occurred within the last few decades. Unlike nonsmall cell lung cancer (NSCLC), SCLC harbors few actionable mutations for therapeutic intervention. Lysine-specific histone demethylase 1A (LSD1 also known as KDM1A) inhibitors were previously shown to have selective activity in SCLC models, but the underlying mechanism was elusive. Read More

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http://stke.sciencemag.org/lookup/doi/10.1126/scisignal.aau2
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http://dx.doi.org/10.1126/scisignal.aau2922DOI Listing
February 2019
18 Reads

The transcription factor SP3 drives TNF-α expression in response to Smac mimetics.

Sci Signal 2019 Jan 29;12(566). Epub 2019 Jan 29.

Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, 401 Smyth Road, Ottawa, Ontario K1H 8L1, Canada.

The controlled production and downstream signaling of the inflammatory cytokine tumor necrosis factor-α (TNF-α) are important for immunity and its anticancer effects. Although chronic stimulation with TNF-α is detrimental to the health of the host in several autoimmune and inflammatory disorders, TNF-α-contrary to what its name implies-leads to cancer formation by promoting cell proliferation and survival. Smac mimetic compounds (SMCs), small-molecule antagonists of inhibitor of apoptosis proteins (IAPs), switch the TNF-α signal from promoting survival to promoting death in cancer cells. Read More

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http://dx.doi.org/10.1126/scisignal.aat9563DOI Listing
January 2019
1 Read

The pseudokinase domains of guanylyl cyclase-A and -B allosterically increase the affinity of their catalytic domains for substrate.

Sci Signal 2019 Jan 29;12(566). Epub 2019 Jan 29.

Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, 6-155 Jackson Hall, 321 Church St. SE, Minneapolis, MN 55455, USA.

Natriuretic peptides regulate multiple physiologic systems by activating transmembrane receptors containing intracellular guanylyl cyclase domains, such as GC-A and GC-B, also known as Npr1 and Npr2, respectively. Both enzymes contain an intracellular, phosphorylated pseudokinase domain (PKD) critical for activation of the C-terminal cGMP-synthesizing guanylyl cyclase domain. Because ATP allosterically activates GC-A and GC-B, we investigated how ATP binding to the PKD influenced guanylyl cyclase activity. Read More

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http://dx.doi.org/10.1126/scisignal.aau5378DOI Listing
January 2019
1 Read

Transcriptional repressor REST drives lineage stage-specific chromatin compaction at and increases AKT activation in a mouse model of medulloblastoma.

Sci Signal 2019 Jan 22;12(565). Epub 2019 Jan 22.

Department of Pediatrics, University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA.

In medulloblastomas (MBs), the expression and activity of RE1-silencing transcription factor (REST) is increased in tumors driven by the sonic hedgehog (SHH) pathway, specifically the SHH-α (children 3 to 16 years) and SHH-β (infants) subgroups. Neuronal maturation is greater in SHH-β than SHH-α tumors, but both correlate with poor overall patient survival. We studied the contribution of REST to MB using a transgenic mouse model ( ) wherein conditional -controlled transgene expression in lineage-committed cerebellar granule neuron progenitors (CGNPs) accelerated tumorigenesis and increased penetrance and infiltrative disease. Read More

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http://stke.sciencemag.org/lookup/doi/10.1126/scisignal.aan8
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http://dx.doi.org/10.1126/scisignal.aan8680DOI Listing
January 2019
7 Reads
6.279 Impact Factor

Illuminating the dark phosphoproteome.

Sci Signal 2019 Jan 22;12(565). Epub 2019 Jan 22.

School of Life and Environmental Sciences, University of Sydney, Sydney, NSW 2006, Australia.

Protein phosphorylation is a major regulator of protein function and biological outcomes. This was first recognized through functional biochemical experiments, and in the past decade, major technological advances in mass spectrometry have enabled the study of protein phosphorylation on a global scale. This rapidly growing field of phosphoproteomics has revealed that more than 100,000 distinct phosphorylation events occur in human cells, which likely affect the function of every protein. Read More

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http://stke.sciencemag.org/lookup/doi/10.1126/scisignal.aau8
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http://dx.doi.org/10.1126/scisignal.aau8645DOI Listing
January 2019
4 Reads

Why geneticists stole cancer research even though cancer is primarily a signaling disease.

Authors:
Michael B Yaffe

Sci Signal 2019 Jan 22;12(565). Epub 2019 Jan 22.

Chief Scientific Advisor and Academic Editor, Science Signaling, American Association for the Advancement of Science, Washington, DC 20005, USA.

Genetic approaches to cancer research have dramatically advanced our understanding of the pathophysiology of this disease, leading to similar genetics-based approaches for precision therapy, which have been less successful. Reconfiguring and adapting the types of technologies that underlie genetic research to dissect tumor cell signaling in clinical samples may offer an alternative road forward. Read More

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http://dx.doi.org/10.1126/scisignal.aaw3483DOI Listing
January 2019
1 Read

Systemic analysis of tyrosine kinase signaling reveals a common adaptive response program in a HER2-positive breast cancer.

Sci Signal 2019 Jan 22;12(565). Epub 2019 Jan 22.

Department of Biochemistry, University of Zurich, Winterthurerstr. 190, 8057 Zurich, Switzerland.

Drug-induced compensatory signaling and subsequent rewiring of the signaling pathways that support cell proliferation and survival promote the development of acquired drug resistance in tumors. Here, we sought to analyze the adaptive kinase response in cancer cells after distinct treatment with agents targeting human epidermal growth factor receptor 2 (HER2), specifically those that induce either only temporary cell cycle arrest or, alternatively, apoptosis in HER2-overexpressing cancers. We compared trastuzumab, ARRY380, the combination thereof, and a biparatopic, HER2-targeted designed ankyrin repeat protein (DARPin; specifically, 6L1G) and quantified the phosphoproteome by isobaric tagging using tandem mass tag liquid chromatography/tandem mass spectrometry (TMT LC-MS/MS). Read More

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http://dx.doi.org/10.1126/scisignal.aau2875DOI Listing
January 2019
1 Read

Mapping the stochastic sequence of individual ligand-receptor binding events to cellular activation: T cells act on the rare events.

Sci Signal 2019 Jan 15;12(564). Epub 2019 Jan 15.

Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA.

T cell receptor (TCR) binding to agonist peptide major histocompatibility complex (pMHC) triggers signaling events that initiate T cell responses. This system is remarkably sensitive, requiring only a few binding events to successfully activate a cellular response. On average, activating pMHC ligands exhibit mean dwell times of at least a few seconds when bound to the TCR. Read More

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http://dx.doi.org/10.1126/scisignal.aat8715DOI Listing
January 2019
2 Reads

The phytosphingosine-CD300b interaction promotes zymosan-induced, nitric oxide-dependent neutrophil recruitment.

Sci Signal 2019 Jan 15;12(564). Epub 2019 Jan 15.

Division of Cellular Therapy/Division of Stem Cell Signaling, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.

Zymosan is a glucan that is a component of the yeast cell wall. Here, we determined the mechanisms underlying the zymosan-induced accumulation of neutrophils in mice. Loss of the receptor CD300b reduced the number of neutrophils recruited to dorsal air pouches in response to zymosan, but not in response to lipopolysaccharide (LPS), a bacterial membrane component recognized by Toll-like receptor 4 (TLR4). Read More

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http://stke.sciencemag.org/lookup/doi/10.1126/scisignal.aar5
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http://dx.doi.org/10.1126/scisignal.aar5514DOI Listing
January 2019
6 Reads

Cadherin-11-mediated adhesion of macrophages to myofibroblasts establishes a profibrotic niche of active TGF-β.

Sci Signal 2019 Jan 15;12(564). Epub 2019 Jan 15.

Laboratory of Tissue Repair and Regeneration, Faculty of Dentistry, University of Toronto, Toronto, Ontario M5G 1G6, Canada.

Macrophages contribute to the activation of fibroblastic cells into myofibroblasts, which secrete collagen and contract the collagen matrix to acutely repair injured tissue. Persistent myofibroblast activation leads to the accumulation of fibrotic scar tissue that impairs organ function. We investigated the key processes that turn acute beneficial repair into destructive progressive fibrosis. Read More

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http://stke.sciencemag.org/lookup/doi/10.1126/scisignal.aao3
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http://dx.doi.org/10.1126/scisignal.aao3469DOI Listing
January 2019
6 Reads

Manganese activates NLRP3 inflammasome signaling and propagates exosomal release of ASC in microglial cells.

Sci Signal 2019 Jan 8;12(563). Epub 2019 Jan 8.

Department of Biomedical Sciences, Parkinson Disorders Research Laboratory, Iowa Center for Advanced Neurotoxicology, Iowa State University, 2062 Veterinary Medicine Building, Ames, IA 50011, USA.

Chronic, sustained inflammation underlies many pathological conditions, including neurodegenerative diseases. Divalent manganese (Mn) exposure can stimulate neurotoxicity by increasing inflammation. In this study, we examined whether Mn activates the multiprotein NLRP3 inflammasome complex to promote neuroinflammation. Read More

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http://stke.sciencemag.org/lookup/doi/10.1126/scisignal.aat9
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http://dx.doi.org/10.1126/scisignal.aat9900DOI Listing
January 2019
12 Reads

LIPID MAPS: Serving the next generation of lipid researchers with tools, resources, data, and training.

Sci Signal 2019 Jan 8;12(563). Epub 2019 Jan 8.

Department of Bioengineering, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.

Lipids are increasingly recognized as dynamic, critical metabolites affecting human physiology and pathophysiology. LIPID MAPS is a free resource dedicated to serving the lipid research community. Read More

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http://dx.doi.org/10.1126/scisignal.aaw2964DOI Listing
January 2019
1 Read

Phosphorylation of the phosphatase PTPROt at Tyr is a molecular switch that controls osteoclast activity and bone mass in vivo.

Sci Signal 2019 Jan 8;12(563). Epub 2019 Jan 8.

Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel.

Bone resorption by osteoclasts is essential for bone homeostasis. The kinase Src promotes osteoclast activity and is activated in osteoclasts by the receptor-type tyrosine phosphatase PTPROt. In other contexts, however, PTPROt can inhibit Src activity. Read More

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http://dx.doi.org/10.1126/scisignal.aau0240DOI Listing
January 2019
1 Read

GPR35 promotes glycolysis, proliferation, and oncogenic signaling by engaging with the sodium potassium pump.

Sci Signal 2019 Jan 1;12(562). Epub 2019 Jan 1.

Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK.

The sodium potassium pump (Na/K-ATPase) ensures the electrochemical gradient of a cell through an energy-dependent process that consumes about one-third of regenerated ATP. We report that the G protein-coupled receptor GPR35 interacted with the α chain of Na/K-ATPase and promotes its ion transport and Src signaling activity in a ligand-independent manner. Deletion of Gpr35 increased baseline Ca to maximal levels and reduced Src activation and overall metabolic activity in macrophages and intestinal epithelial cells (IECs). Read More

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http://dx.doi.org/10.1126/scisignal.aau9048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6364804PMC
January 2019
8 Reads

A posttranslational modification code for CFTR maturation is altered in cystic fibrosis.

Sci Signal 2019 Jan 1;12(562). Epub 2019 Jan 1.

Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.

The multistep process regulating the maturation of membrane proteins in the endoplasmic reticulum (ER) and the secretory pathway is disrupted in many protein misfolding disorders. Mutations in the ion channel CFTR that impair its folding and subsequent localization to the plasma membrane cause cystic fibrosis (CF), an inherited and eventually lethal disease that impairs the function of multiple organs, mostly the lungs. Here, we found that proper maturation of CFTR is dependent on cross-talk between phosphorylation and methylation events in the regulatory insertion (RI) element of the protein. Read More

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http://dx.doi.org/10.1126/scisignal.aan7984DOI Listing
January 2019
27 Reads

Mechanisms of postsynaptic localization of AMPA-type glutamate receptors and their regulation during long-term potentiation.

Sci Signal 2019 Jan 1;12(562). Epub 2019 Jan 1.

Department of Pharmacology, University of California at Davis, Davis, CA 95616-8636, USA.

l-Glutamate is the main excitatory neurotransmitter in the brain, with postsynaptic responses to its release predominantly mediated by AMPA-type glutamate receptors (AMPARs). A critical component of synaptic plasticity involves changes in the number of responding postsynaptic receptors, which are dynamically recruited to and anchored at postsynaptic sites. Emerging findings continue to shed new light on molecular mechanisms that mediate AMPAR postsynaptic trafficking and localization. Read More

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http://dx.doi.org/10.1126/scisignal.aar6889DOI Listing
January 2019
1 Read

Activation of atypical protein kinase C by sphingosine 1-phosphate revealed by an aPKC-specific activity reporter.

Sci Signal 2019 Jan 1;12(562). Epub 2019 Jan 1.

Department of Pharmacology, University of California at San Diego, La Jolla, CA 92037, USA.

Atypical protein kinase C (aPKC) isozymes are unique in the PKC superfamily in that they are not regulated by the lipid second messenger diacylglycerol, which has led to speculation about whether a different second messenger acutely controls their function. Here, using a genetically encoded reporter that we designed, aPKC-specific C kinase activity reporter (aCKAR), we found that the lipid mediator sphingosine 1-phosphate (S1P) promoted the cellular activity of aPKC. Intracellular S1P directly bound to the purified kinase domain of aPKC and relieved autoinhibitory constraints, thereby activating the kinase. Read More

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http://dx.doi.org/10.1126/scisignal.aat6662DOI Listing
January 2019
1 Read

Spatially structured cell populations process multiple sensory signals in parallel in intact vascular endothelium.

Sci Signal 2018 Dec 18;11(561). Epub 2018 Dec 18.

Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, UK.

Blood flow, blood clotting, angiogenesis, vascular permeability, and vascular remodeling are each controlled by a large number of variable, noisy, and interacting chemical inputs to the vascular endothelium. The endothelium processes the entirety of the chemical composition to which the cardiovascular system is exposed, carrying out sophisticated computations that determine physiological output. Processing this enormous quantity of information is a major challenge facing the endothelium. Read More

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http://dx.doi.org/10.1126/scisignal.aar4411DOI Listing
December 2018
1 Read

5-oxoETE triggers nociception in constipation-predominant irritable bowel syndrome through MAS-related G protein-coupled receptor D.

Sci Signal 2018 Dec 18;11(561). Epub 2018 Dec 18.

INSERM, UMR1220, IRSD, Université de Toulouse, INRA, ENVT, UPS, Toulouse, France.

Irritable bowel syndrome (IBS) is a common gastrointestinal disorder that is characterized by chronic abdominal pain concurrent with altered bowel habit. Polyunsaturated fatty acid (PUFA) metabolites are increased in abundance in IBS and are implicated in the alteration of sensation to mechanical stimuli, which is defined as visceral hypersensitivity. We sought to quantify PUFA metabolites in patients with IBS and evaluate their role in pain. Read More

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http://dx.doi.org/10.1126/scisignal.aal2171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6411128PMC
December 2018
2 Reads

CD45 exclusion- and cross-linking-based receptor signaling together broaden FcεRI reactivity.

Sci Signal 2018 Dec 18;11(561). Epub 2018 Dec 18.

MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.

For many years, the high-affinity receptor for immunoglobulin E (IgE) FcεRI, which is expressed by mast cells and basophils, has been widely held to be the exemplar of cross-linking (that is, aggregation dependent) signaling receptors. We found, however, that FcεRI signaling could occur in the presence or absence of receptor cross-linking. Using both cell and cell-free systems, we showed that FcεRI signaling was stimulated by surface-associated monovalent ligands through the passive, size-dependent exclusion of the receptor-type tyrosine phosphatase CD45 from plasma membrane regions of FcεRI-ligand engagement. Read More

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http://dx.doi.org/10.1126/scisignal.aat0756DOI Listing
December 2018
2 Reads

ORAI1, STIM1/2, and RYR1 shape subsecond Ca microdomains upon T cell activation.

Sci Signal 2018 Dec 18;11(561). Epub 2018 Dec 18.

The Calcium Signaling Group, Department of Biochemistry and Molecular Cell Biology, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany.

The earliest intracellular signals that occur after T cell activation are local, subsecond Ca microdomains. Here, we identified a Ca entry component involved in Ca microdomain formation in both unstimulated and stimulated T cells. In unstimulated T cells, spontaneously generated small Ca microdomains required ORAI1, STIM1, and STIM2. Read More

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http://dx.doi.org/10.1126/scisignal.aat0358DOI Listing
December 2018
2 Reads

All three IP receptor isoforms generate Ca puffs that display similar characteristics.

Sci Signal 2018 Dec 18;11(561). Epub 2018 Dec 18.

Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA 92697, USA.

Inositol 1,4,5-trisphosphate (IP) evokes Ca release through IP receptors (IPRs) to generate both local Ca puffs arising from concerted openings of clustered IPRs and cell-wide Ca waves. Imaging Ca puffs with single-channel resolution yields information on the localization and properties of native IPRs in intact cells, but interpretation has been complicated because cells express varying proportions of three structurally and functionally distinct isoforms of IPRs. Here, we used TIRF and light-sheet microscopy to image Ca puffs in HEK-293 cell lines generated by CRISPR-Cas9 technology to express exclusively IPR type 1, 2, or 3. Read More

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http://stke.sciencemag.org/lookup/doi/10.1126/scisignal.aau0
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http://dx.doi.org/10.1126/scisignal.aau0344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6402561PMC
December 2018
7 Reads

The microRNA miR-7a-5p ameliorates ischemic brain damage by repressing α-synuclein.

Sci Signal 2018 Dec 11;11(560). Epub 2018 Dec 11.

Department of Neurological Surgery, University of Wisconsin-Madison, Madison, WI 53792, USA.

Ischemic stroke, which is caused by a clot that blocks blood flow to the brain, can be severely disabling and sometimes fatal. We previously showed that transient focal ischemia in a rat model induces extensive temporal changes in the expression of cerebral microRNAs, with a sustained decrease in the abundance of miR-7a-5p (miR-7). Here, we evaluated the therapeutic efficacy of a miR-7 mimic oligonucleotide after cerebral ischemia in rodents according to the Stroke Treatment Academic Industry Roundtable (STAIR) criteria. Read More

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http://dx.doi.org/10.1126/scisignal.aat4285DOI Listing
December 2018
7 Reads
6.279 Impact Factor

Crk adaptor proteins mediate actin-dependent T cell migration and mechanosensing induced by the integrin LFA-1.

Sci Signal 2018 Dec 11;11(560). Epub 2018 Dec 11.

Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia Research Institute, Philadelphia, PA, USA.

T cell entry into inflamed tissue involves firm adhesion, spreading, and migration of the T cells across endothelial barriers. These events depend on "outside-in" signals through which engaged integrins direct cytoskeletal reorganization. We investigated the molecular events that mediate this process and found that T cells from mice lacking expression of the adaptor protein Crk exhibited defects in phenotypes induced by the integrin lymphocyte function-associated antigen 1 (LFA-1), namely, actin polymerization, leading edge formation, and two-dimensional cell migration. Read More

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http://dx.doi.org/10.1126/scisignal.aat3178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6333317PMC
December 2018
1 Read

The β subunit of Ca1.2 channels is required for an optimal interferon response in cardiac muscle cells.

Sci Signal 2018 Dec 11;11(560). Epub 2018 Dec 11.

Departamento de Farmacología, Centro de Investigación y de Estudios Avanzados del IPN, Ciudad de México, México.

The auxiliary β subunit of the cardiac Ca1.2 channel plays a poorly understood role in gene transcription. Here, we characterized the regulatory effects of the β subunit in H9c2 rat cardiac cells on the abundances of mRNA [which encodes interferon-β (IFN-β)] and of the IFN-β-related genes , , , , , and , as well as on the abundances of the antiviral proteins DDX58, IRF7, STAT2, and IFITM3. Read More

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http://dx.doi.org/10.1126/scisignal.aaj1676DOI Listing
December 2018
11 Reads

Restricting mitochondrial GRK2 post-ischemia confers cardioprotection by reducing myocyte death and maintaining glucose oxidation.

Sci Signal 2018 Dec 11;11(560). Epub 2018 Dec 11.

Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.

Increased abundance of GRK2 [G protein-coupled receptor (GPCR) kinase 2] is associated with poor cardiac function in heart failure patients. In animal models, GRK2 contributes to the pathogenesis of heart failure after ischemia-reperfusion (IR) injury. In addition to its role in down-regulating activated GPCRs, GRK2 also localizes to mitochondria both basally and post-IR injury, where it regulates cellular metabolism. Read More

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http://dx.doi.org/10.1126/scisignal.aau0144DOI Listing
December 2018
3 Reads
6.279 Impact Factor

Regulated proteolysis of p62/SQSTM1 enables differential control of autophagy and nutrient sensing.

Sci Signal 2018 Dec 4;11(559). Epub 2018 Dec 4.

Section of Microbiology, Medical Research Council Centre for Molecular Bacteriology and Infection, Imperial College London, London SW7 2AZ, UK.

The multidomain scaffold protein p62 (also called sequestosome-1) is involved in autophagy, antimicrobial immunity, and oncogenesis. Mutations in , which encodes p62, are linked to hereditary inflammatory conditions such as Paget's disease of the bone, frontotemporal dementia (FTD), amyotrophic lateral sclerosis, and distal myopathy with rimmed vacuoles. Here, we report that p62 was proteolytically trimmed by the protease caspase-8 into a stable protein, which we called p62 We found that p62, but not full-length p62, was involved in nutrient sensing and homeostasis through the mechanistic target of rapamycin complex 1 (mTORC1). Read More

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http://dx.doi.org/10.1126/scisignal.aat6903DOI Listing
December 2018
3 Reads

FZD is a Gα-coupled receptor that exhibits the functional hallmarks of prototypical GPCRs.

Sci Signal 2018 Dec 4;11(559). Epub 2018 Dec 4.

Institute of Pharmacology and Toxicology, University of Würzburg, Versbacher Strasse 9, 97078 Würzburg, Germany.

Frizzleds (FZDs) are a group of seven transmembrane-spanning (7TM) receptors that belong to class F of the G protein-coupled receptor (GPCR) superfamily. FZDs bind WNT proteins to stimulate diverse signaling cascades involved in embryonic development, stem cell regulation, and adult tissue homeostasis. Frizzled 5 (FZD) is one of the most studied class F GPCRs that promote the functional inactivation of the β-catenin destruction complex in response to WNTs. Read More

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http://stke.sciencemag.org/lookup/doi/10.1126/scisignal.aar5
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http://dx.doi.org/10.1126/scisignal.aar5536DOI Listing
December 2018
9 Reads

A division of labor in mTORC1 signaling and autophagy.

Authors:
Sascha Martens

Sci Signal 2018 Dec 4;11(559). Epub 2018 Dec 4.

Department of Biochemistry, Cell Biology and Max F. Perutz Laboratories, Vienna BioCenter, University of Vienna, Dr. Bohr-Gasse 9/3, 1030 Vienna, Austria. Email:

In human cells, the p62 protein acts as an adaptor in various signaling pathways as well as a receptor for selective autophagy. In this issue of , Sanchez-Garrido show that proteolytic cleavage of p62 by caspase-8 determines whether p62 functions as an mTORC1 signaling adaptor or autophagy receptor. Read More

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http://dx.doi.org/10.1126/scisignal.aav3530DOI Listing
December 2018
1 Read

Functional selectivity profiling of the angiotensin II type 1 receptor using pathway-wide BRET signaling sensors.

Sci Signal 2018 Dec 4;11(559). Epub 2018 Dec 4.

Department of Medicine, Research Institute of the McGill University Health Center (RI-MUHC), McGill University, Montréal, QC H4A 3J1, Canada.

G protein-coupled receptors (GPCRs) are important therapeutic targets that exhibit functional selectivity (biased signaling), in which different ligands or receptor variants elicit distinct downstream signaling. Understanding all the signaling events and biases that contribute to both the beneficial and adverse effects of GPCR stimulation by given ligands is important for drug discovery. Here, we report the design, validation, and use of pathway-selective bioluminescence resonance energy transfer (BRET) biosensors that monitor the engagement and activation of signaling effectors downstream of G proteins, including protein kinase C (PKC), phospholipase C (PLC), p63RhoGEF, and Rho. Read More

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http://dx.doi.org/10.1126/scisignal.aat1631DOI Listing
December 2018
3 Reads

Hippocampal mGluR1-dependent long-term potentiation requires NAADP-mediated acidic store Ca signaling.

Sci Signal 2018 Nov 27;11(558). Epub 2018 Nov 27.

Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK.

Acidic organelles, such as endosomes and lysosomes, store Ca that is released in response to intracellular increases in the second messenger nicotinic acid adenine dinucleotide phosphate (NAADP). In neurons, NAADP and Ca signaling contribute to synaptic plasticity, a process of activity-dependent long-term potentiation (LTP) [or, alternatively, long-term depression (LTD)] of synaptic strength and neuronal transmission that is critical for neuronal function and memory formation. We explored the function of and mechanisms regulating acidic Ca store signaling in murine hippocampal neurons. Read More

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http://dx.doi.org/10.1126/scisignal.aat9093DOI Listing
November 2018
1 Read

Aspirin ameliorates experimental autoimmune encephalomyelitis through interleukin-11-mediated protection of regulatory T cells.

Sci Signal 2018 Nov 27;11(558). Epub 2018 Nov 27.

Division of Research and Development, Jesse Brown Veterans Affairs Medical Center, Chicago, IL 60612, USA.

Multiple sclerosis (MS) is a human disease that results from autoimmune T cells targeting myelin protein that is expressed within the central nervous system. In MS, the number of FoxP3-expressing regulatory T cells (T) is reduced, which facilitates the activation of autoreactive T cells. Because aspirin (acetylsalicylic acid) is the most widely used nonsteroidal anti-inflammatory drug, we examined its immunomodulatory effect in mice with experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Read More

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http://dx.doi.org/10.1126/scisignal.aar8278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6325078PMC
November 2018
2 Reads