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  • A mutant form of ERα associated with estrogen insensitivity affects the coupling between ligand binding and coactivator recruitment
    Sci. Signal. (IF 6.467) Pub Date : 2020-09-22
    Yin Li, Laurel A. Coons, René Houtman, Kathryn E. Carlson, Teresa A. Martin, Christopher G. Mayne, Diana Melchers, Tanner B. Jefferson, J. Tyler Ramsey, John A. Katzenellenbogen, Kenneth S. Korach

    A homozygous missense mutation in the gene encoding the estrogen receptor α (ERα) was previously identified in a female patient with estrogen insensitivity syndrome. We investigated the molecular features underlying the impaired transcriptional response of this mutant (ERα-Q375H) and four other missense mutations at this position designed to query alternative mechanisms. The identity of residue 375

    更新日期:2020-09-23
  • Daily alcohol intake triggers aberrant synaptic pruning leading to synapse loss and anxiety-like behavior
    Sci. Signal. (IF 6.467) Pub Date : 2020-09-22
    Renato Socodato, Joana F. Henriques, Camila C. Portugal, Tiago O. Almeida, Joana Tedim-Moreira, Renata L. Alves, Teresa Canedo, Cátia Silva, Ana Magalhães, Teresa Summavielle, João B. Relvas

    Alcohol abuse adversely affects the lives of millions of people worldwide. Deficits in synaptic transmission and in microglial function are commonly found in human alcohol abusers and in animal models of alcohol intoxication. Here, we found that a protocol simulating chronic binge drinking in male mice resulted in aberrant synaptic pruning and substantial loss of excitatory synapses in the prefrontal

    更新日期:2020-09-23
  • Zika and ubiquitin
    Sci. Signal. (IF 6.467) Pub Date : 2020-09-22
    John F. Foley

    Ubiquitylation of the Zika virus envelope protein drives viral entry and pathogenesis.

    更新日期:2020-09-23
  • Engineered IL-10 variants elicit potent immunomodulatory effects at low ligand doses
    Sci. Signal. (IF 6.467) Pub Date : 2020-09-15
    Claire Gorby, Junel Sotolongo Bellón, Stephan Wilmes, Walid Warda, Elizabeth Pohler, Paul K. Fyfe, Adeline Cozzani, Christophe Ferrand, Mark R. Walter, Suman Mitra, Jacob Piehler, Ignacio Moraga

    Interleukin-10 (IL-10) is a dimeric cytokine with both immunosuppressive and immunostimulatory activities; however, IL-10–based therapies have shown only marginal clinical benefits. Here, we explored whether the stability of the IL-10 receptor complex contributes to the immunomodulatory potency of IL-10. We generated an IL-10 mutant with enhanced affinity for its IL-10Rβ receptor using yeast surface

    更新日期:2020-09-16
  • Linking integrins and EVs in metastasis
    Sci. Signal. (IF 6.467) Pub Date : 2020-09-15
    Leslie K. Ferrarelli

    Integrins mediate the uptake of extracellular vesicles into breast cancer cells.

    更新日期:2020-09-16
  • COVID-19: All the wrong moves in all the wrong places
    Sci. Signal. (IF 6.467) Pub Date : 2020-09-15
    Christopher D. Barrett, Michael B. Yaffe

    In this Editorial, Barrett and Yaffe highlight shortcomings in our collective response to the COVID-19 pandemic and underscore the need for more basic research into this new disease.

    更新日期:2020-09-16
  • PD-1 suppresses the maintenance of cell couples between cytotoxic T cells and target tumor cells within the tumor
    Sci. Signal. (IF 6.467) Pub Date : 2020-09-15
    Rachel Ambler, Grace L. Edmunds, Sin Lih Tan, Silvia Cirillo, Jane I. Pernes, Xiongtao Ruan, Jorge Huete-Carrasco, Carissa C. W. Wong, Jiahe Lu, Juma Ward, Giulia Toti, Alan J. Hedges, Simon J. Dovedi, Robert F. Murphy, David J. Morgan, Christoph Wülfing

    The killing of tumor cells by CD8+ T cells is suppressed by the tumor microenvironment, and increased expression of inhibitory receptors, including programmed cell death protein-1 (PD-1), is associated with tumor-mediated suppression of T cells. To find cellular defects triggered by tumor exposure and associated PD-1 signaling, we established an ex vivo imaging approach to investigate the response

    更新日期:2020-09-16
  • Quantitative genetic screening reveals a Ragulator-FLCN feedback loop that regulates the mTORC1 pathway
    Sci. Signal. (IF 6.467) Pub Date : 2020-09-15
    Erica De Zan, Ruud van Stiphout, Bianca V. Gapp, Vincent A. Blomen, Thijn R. Brummelkamp, Sebastian M.B. Nijman

    Forward genetic screens in mammalian cell lines, such as RNAi and CRISPR-Cas9 screens, have made major contributions to the elucidation of diverse signaling pathways. Here, we exploited human haploid cells as a robust comparative screening platform and report a set of quantitative forward genetic screens for identifying regulatory mechanisms of mTORC1 signaling, a key growth control pathway that senses

    更新日期:2020-09-16
  • Metabolic adaptation to calorie restriction
    Sci. Signal. (IF 6.467) Pub Date : 2020-09-08
    Carlos Guijas, J. Rafael Montenegro-Burke, Rigo Cintron-Colon, Xavier Domingo-Almenara, Manuel Sanchez-Alavez, Carlos A. Aguirre, Kokila Shankar, Erica L.-W. Majumder, Elizabeth Billings, Bruno Conti, Gary Siuzdak

    Calorie restriction (CR) enhances health span (the length of time that an organism remains healthy) and increases longevity across species. In mice, these beneficial effects are partly mediated by the lowering of core body temperature that occurs during CR. Conversely, the favorable effects of CR on health span are mitigated by elevating ambient temperature to thermoneutrality (30°C), a condition in

    更新日期:2020-09-08
  • ssRNA stimulates Piezo1 and serotonin synthesis
    Sci. Signal. (IF 6.467) Pub Date : 2020-09-08
    Wei Wong

    The gut produces serotonin upon activation of the Ca2+ channel Piezo1 by microbiome-derived ssRNA.

    更新日期:2020-09-08
  • Quantitative kinase and phosphatase profiling reveal that CDK1 phosphorylates PP2Ac to promote mitotic entry
    Sci. Signal. (IF 6.467) Pub Date : 2020-09-08
    Isha Nasa, Lauren E. Cressey, Thomas Kruse, Emil P. T. Hertz, Jiang Gui, Lee M. Graves, Jakob Nilsson, Arminja N. Kettenbach

    The reciprocal regulation of phosphoprotein phosphatases (PPPs) by protein kinases is essential to cell cycle progression and control, particularly during mitosis for which the role of kinases has been extensively studied. PPPs perform much of the serine/threonine dephosphorylation in eukaryotic cells and achieve substrate selectivity and specificity through the interaction of distinct regulatory subunits

    更新日期:2020-09-08
  • The hallmarks of cancer are also the hallmarks of wound healing
    Sci. Signal. (IF 6.467) Pub Date : 2020-09-08
    Lucy MacCarthy-Morrogh, Paul Martin

    The Hanahan and Weinberg “hallmarks of cancer” papers provide a useful structure for considering the various mechanisms driving cancer progression, and the same might be useful for wound healing. In this Review, we highlight how tissue repair and cancer share cellular and molecular processes that are regulated in a wound but misregulated in cancer. From sustained proliferative signaling and the activation

    更新日期:2020-09-08
  • µ-Opioid receptor-induced synaptic plasticity in dopamine neurons mediates the rewarding properties of anabolic androgenic steroids.
    Sci. Signal. (IF 6.467) Pub Date : 2020-09-01
    Leonardo Bontempi,Antonello Bonci

    Anabolic androgenic steroids (AAS) have medical utility but are often abused, and the effects of AAS on reward circuits in the brain have been suggested to lead to addiction. We investigated the previously reported correlations between AAS and the endogenous μ-opioid system in the rewarding properties of AAS in mice. We found that a single injection of a supraphysiological dose of natural or synthetic

    更新日期:2020-09-02
  • 14-3-3 binding creates a memory of kinase action by stabilizing the modified state of phospholamban.
    Sci. Signal. (IF 6.467) Pub Date : 2020-09-01
    Julia Menzel,Daniel Kownatzki-Danger,Sergiy Tokar,Alice Ballone,Kirsten Unthan-Fechner,Markus Kilisch,Christof Lenz,Henning Urlaub,Mattia Mori,Christian Ottmann,Michael J Shattock,Stephan E Lehnart,Blanche Schwappach

    The cardiac membrane protein phospholamban (PLN) is targeted by protein kinase A (PKA) at Ser16 and by Ca2+/calmodulin-dependent protein kinase II (CaMKII) at Thr17. β-Adrenergic stimulation and PKA-dependent phosphorylation of Ser16 acutely stimulate the sarcoplasmic reticulum calcium pump (SERCA) by relieving its inhibition by PLN. CaMKII-dependent phosphorylation may lead to longer-lasting SERCA

    更新日期:2020-09-02
  • Flipping an exosome switch
    Sci. Signal. (IF 6.467) Pub Date : 2020-09-01
    Annalisa M. VanHook

    Nutrient stress changes the biogenesis and biological activity of exosomes in cancer cells.

    更新日期:2020-09-02
  • Mechanisms of autoregulation of C3G, activator of the GTPase Rap1, and its catalytic deregulation in lymphomas.
    Sci. Signal. (IF 6.467) Pub Date : 2020-09-01
    Arturo Carabias,María Gómez-Hernández,Sergio de Cima,Antonio Rodríguez-Blázquez,Alba Morán-Vaquero,Patricia González-Sáenz,Carmen Guerrero,José M de Pereda

    C3G is a guanine nucleotide exchange factor (GEF) that regulates cell adhesion and migration by activating the GTPase Rap1. The GEF activity of C3G is stimulated by the adaptor proteins Crk and CrkL and by tyrosine phosphorylation. Here, we uncovered mechanisms of C3G autoinhibition and activation. Specifically, we found that two intramolecular interactions regulate the activity of C3G. First, an autoinhibitory

    更新日期:2020-09-02
  • A preview of selected articles.
    Sci. Signal. (IF 6.467) Pub Date : 2020-09-01
    Stuart P Atkinson

    更新日期:2020-09-01
  • An allosteric site on MKP5 reveals a strategy for small-molecule inhibition.
    Sci. Signal. (IF 6.467) Pub Date : 2020-08-25
    Zachary T K Gannam,Kisuk Min,Shanelle R Shillingford,Lei Zhang,James Herrington,Laura Abriola,Peter C Gareiss,Georgios Pantouris,Argyrios Tzouvelekis,Naftali Kaminski,Xinbo Zhang,Jun Yu,Haya Jamali,Jonathan A Ellman,Elias Lolis,Karen S Anderson,Anton M Bennett

    The mitogen-activated protein kinase (MAPK) phosphatases (MKPs) have been considered “undruggable,” but their position as regulators of the MAPKs makes them promising therapeutic targets. MKP5 has been suggested as a potential target for the treatment of dystrophic muscle disease. Here, we identified an inhibitor of MKP5 using a p38α MAPK–derived, phosphopeptide-based small-molecule screen. We solved

    更新日期:2020-08-26
  • Blastocyst-induced ATP release from luminal epithelial cells initiates decidualization through the P2Y2 receptor in mice.
    Sci. Signal. (IF 6.467) Pub Date : 2020-08-25
    Xiao-Wei Gu,Zi-Cong Chen,Zhen-Shan Yang,Yan Yang,Ya-Ping Yan,Yue-Fang Liu,Ji-Min Pan,Ren-Wei Su,Zeng-Ming Yang

    Embryo implantation involves a sterile inflammatory reaction that is required for the invasion of the blastocyst into the decidua. Adenosine triphosphate (ATP) released from stressed or injured cells acts as an important signaling molecule to regulate many key physiological events, including sterile inflammation. We found that the amount of ATP in the uterine luminal fluid of mice increased during

    更新日期:2020-08-26
  • Growth factors and SARS-CoV-2
    Sci. Signal. (IF 6.467) Pub Date : 2020-08-25
    John F. Foley

    Phosphoproteomics analysis reveals that blocking growth factor receptor signaling inhibits SARS-CoV-replication.

    更新日期:2020-08-26
  • GULP1 regulates the NRF2-KEAP1 signaling axis in urothelial carcinoma.
    Sci. Signal. (IF 6.467) Pub Date : 2020-08-18
    Masamichi Hayashi,Elisa Guida,Yoshikuni Inokawa,Rachel Goldberg,Leonardo O Reis,Akira Ooki,Manohar Pilli,Pritam Sadhukhan,Juhyung Woo,Woonyoung Choi,Evgeny Izumchenko,Leonel Maldonado Gonzalez,Luigi Marchionni,Alex Zhavoronkov,Mariana Brait,Trinity Bivalacqua,Alexander Baras,George J Netto,Wayne Koch,Anju Singh,Mohammad O Hoque

    Disruption of the KEAP1-NRF2 pathway results in the transactivation of NRF2 target genes, consequently inducing cell proliferation and other phenotypic changes in cancer cells. Here, we demonstrated that GULP1 was a KEAP1-binding protein that maintained actin cytoskeleton architecture and helped KEAP1 to sequester NRF2 in the cytoplasm. In urothelial carcinoma of the bladder (UCB), silencing of GULP1

    更新日期:2020-08-19
  • A prosocial neuroligin
    Sci. Signal. (IF 6.467) Pub Date : 2020-08-18
    Leslie K. Ferrarelli

    NLGN3 links oxytocin signaling, protein synthesis, and social behavior in a mouse model of autism.

    更新日期:2020-08-19
  • Kinetics of receptor tyrosine kinase activation define ERK signaling dynamics.
    Sci. Signal. (IF 6.467) Pub Date : 2020-08-18
    Anatoly Kiyatkin,Iris K van Alderwerelt van Rosenburgh,Daryl E Klein,Mark A Lemmon

    In responses to activation of receptor tyrosine kinases (RTKs), crucial cell fate decisions depend on the duration and dynamics of ERK signaling. In PC12 cells, epidermal growth factor (EGF) induces transient ERK activation that leads to cell proliferation, whereas nerve growth factor (NGF) promotes sustained ERK activation and cell differentiation. These differences have typically been assumed to

    更新日期:2020-08-19
  • Degradation of 5hmC-marked stalled replication forks by APE1 causes genomic instability.
    Sci. Signal. (IF 6.467) Pub Date : 2020-08-18
    Suhas S Kharat,Xia Ding,Divya Swaminathan,Akshey Suresh,Manish Singh,Satheesh K Sengodan,Sandra Burkett,Hanna Marks,Chinmayi Pamala,Yafeng He,Stephen D Fox,Eugen C Buehler,Kathrin Muegge,Scott E Martin,Shyam K Sharan

    Synthetic lethality between poly(ADP-ribose) polymerase (PARP) inhibition and BRCA deficiency is exploited to treat breast and ovarian tumors. However, resistance to PARP inhibitors (PARPis) is common. To identify potential resistance mechanisms, we performed a genome-wide RNAi screen in BRCA2-deficient mouse embryonic stem cells and validation in KB2P1.21 mouse mammary tumor cells. We found that resistance

    更新日期:2020-08-19
  • A better workout without PHD3
    Sci. Signal. (IF 6.467) Pub Date : 2020-08-11
    Wei Wong

    PHD3 deficiency increases fatty acid oxidation in skeletal muscle and improves endurance exercise performance.

    更新日期:2020-08-12
  • Oxidative cross-linking of fibronectin confers protease resistance and inhibits cellular migration.
    Sci. Signal. (IF 6.467) Pub Date : 2020-08-11
    Morgan L Locy,Sunad Rangarajan,Sufen Yang,Mark R Johnson,Karen Bernard,Ashish Kurundkar,Nathaniel B Bone,Jaroslaw W Zmijewski,Jaeman Byun,Subramaniam Pennathur,Yong Zhou,Victor J Thannickal

    The oxidation of tyrosine residues to generate o,o′-dityrosine cross-links in extracellular proteins is necessary for the proper function of the extracellular matrix (ECM) in various contexts in invertebrates. Tyrosine oxidation is also required for the biosynthesis of thyroid hormone in vertebrates, and there is evidence for oxidative cross-linking reactions occurring in extracellular proteins secreted

    更新日期:2020-08-12
  • Bacterial invaders drive CRC progression.
    Sci. Signal. (IF 6.467) Pub Date : 2020-08-11
    Matthew Meyerson

    The oral bacterium Fusobacterium nucleatum is often found in colorectal cancer (CRC). In the 21 July 2020 issue of Science Signaling, Casasanta et al. show that CRC cell–resident F. nucleatum promotes cytokine secretion that may potentiate tumor growth and metastatic progression in patients.

    更新日期:2020-08-12
  • Targeting the kinase insert loop of PERK selectively modulates PERK signaling without systemic toxicity in mice.
    Sci. Signal. (IF 6.467) Pub Date : 2020-08-11
    Daniel T Hughes,Mark Halliday,Heather L Smith,Nicholas C Verity,Colin Molloy,Helois Radford,Adrian J Butcher,Giovanna R Mallucci

    Chronic activation of the unfolded protein response (UPR), notably the branch comprising the kinase PERK and the translation initiation factor eIF2α, is a pathological feature of many neurodegenerative diseases caused by protein misfolding. Partial reduction of UPR signaling at the level of phosphorylated eIF2α is neuroprotective and avoids the pancreatic toxicity caused by full inhibition of PERK

    更新日期:2020-08-12
  • Coordinating a neutrophil swarm
    Sci. Signal. (IF 6.467) Pub Date : 2020-08-04
    Annalisa M. VanHook

    Ca2+ and ATP signaling control the self-organized, collective behaviors of neutrophils at wound sites.

    更新日期:2020-08-05
  • Structural insights into the signal transduction mechanism of the K+-sensing two-component system KdpDE.
    Sci. Signal. (IF 6.467) Pub Date : 2020-08-04
    Mingquan Xie,Mengyuan Wu,Aidong Han

    Two-component systems (TCSs), which consist of a histidine kinase (HK) sensor and a response regulator (RR), are important for bacteria to quickly sense and respond to various environmental signals. HKs and RRs typically function as a cognate pair, interacting only with one another to transduce signaling. Precise signal transduction in a TCS depends on the specific interactions between the receiver

    更新日期:2020-08-05
  • An interspecies translation model implicates integrin signaling in infliximab-resistant inflammatory bowel disease.
    Sci. Signal. (IF 6.467) Pub Date : 2020-08-04
    Douglas K Brubaker,Manu P Kumar,Evan L Chiswick,Cecil Gregg,Alina Starchenko,Paige N Vega,Austin N Southard-Smith,Alan J Simmons,Elizabeth A Scoville,Lori A Coburn,Keith T Wilson,Ken S Lau,Douglas A Lauffenburger

    Anti–tumor necrosis factor (anti-TNF) therapy resistance is a major clinical challenge in inflammatory bowel disease (IBD), due, in part, to insufficient understanding of disease-site, protein-level mechanisms. Although proteomics data from IBD mouse models exist, data and phenotype discrepancies contribute to confounding translation from preclinical animal models of disease to clinical cohorts. We

    更新日期:2020-08-05
  • The collagen receptor glycoprotein VI promotes platelet-mediated aggregation of β-amyloid.
    Sci. Signal. (IF 6.467) Pub Date : 2020-08-04
    Lili Donner,Laura Mara Toska,Irena Krüger,Sandra Gröniger,Ruben Barroso,Alice Burleigh,Diego Mezzano,Susanne Pfeiler,Malte Kelm,Norbert Gerdes,Steve P Watson,Yi Sun,Margitta Elvers

    Cerebral amyloid angiopathy (CAA) and β-amyloid (Aβ) deposition in the brain parenchyma are hallmarks of Alzheimer’s disease (AD). We previously reported that platelets contribute to Aβ aggregation in cerebral vessels by secreting the factor clusterin upon binding of Aβ40 to the fibrinogen receptor integrin αIIbβ3. Here, we investigated the contribution of the collagen receptor GPVI (glycoprotein VI)

    更新日期:2020-08-05
  • A dynamic mouse peptidome landscape reveals probiotic modulation of the gut-brain axis.
    Sci. Signal. (IF 6.467) Pub Date : 2020-07-28
    Pei Zhang,Xiaoli Wu,Shan Liang,Xianfeng Shao,Qianqian Wang,Ruibing Chen,Weimin Zhu,Chen Shao,Feng Jin,Chenxi Jia

    Certain probiotics have beneficial effects on the function of the central nervous system through modulation of the gut-brain axis. Here, we describe a dynamic landscape of the peptidome across multiple brain regions, modulated by oral administration of different probiotic species over various times. The spatiotemporal and strain-specific changes of the brain peptidome correlated with the composition

    更新日期:2020-07-29
  • The mitophagy effector FUNDC1 controls mitochondrial reprogramming and cellular plasticity in cancer cells.
    Sci. Signal. (IF 6.467) Pub Date : 2020-07-28
    Jie Li,Ekta Agarwal,Irene Bertolini,Jae Ho Seo,M Cecilia Caino,Jagadish C Ghosh,Andrew V Kossenkov,Qin Liu,Hsin-Yao Tang,Aaron R Goldman,Lucia R Languino,David W Speicher,Dario C Altieri

    Mitochondria are signaling hubs in eukaryotic cells. Here, we showed that the mitochondrial FUN14 domain–containing protein-1 (FUNDC1), an effector of Parkin-independent mitophagy, also participates in cellular plasticity by sustaining oxidative bioenergetics, buffering ROS production, and supporting cell proliferation. Targeting this pathway in cancer cells suppressed tumor growth but rendered transformed

    更新日期:2020-07-29
  • Facilitating RSV entry
    Sci. Signal. (IF 6.467) Pub Date : 2020-07-28
    John F. Foley

    Binding of respiratory syncytial virus to the receptor IGF-1R stimulates viral entry in a PKCζ-dependent manner.

    更新日期:2020-07-29
  • Fusobacterium nucleatum host-cell binding and invasion induces IL-8 and CXCL1 secretion that drives colorectal cancer cell migration.
    Sci. Signal. (IF 6.467) Pub Date : 2020-07-21
    Michael A Casasanta,Christopher C Yoo,Barath Udayasuryan,Blake E Sanders,Ariana Umaña,Yao Zhang,Huaiyao Peng,Alison J Duncan,Yueying Wang,Liwu Li,Scott S Verbridge,Daniel J Slade

    Fusobacterium nucleatum is implicated in accelerating colorectal cancer (CRC) and is found within metastatic CRC cells in patient biopsies. Here, we found that bacterial invasion of CRC cells and cocultured immune cells induced a differential cytokine secretion that may contribute to CRC metastasis. We used a modified galactose kinase markerless gene deletion approach and found that F. nucleatum invaded

    更新日期:2020-07-22
  • New connections: Redox regulation of kinases
    Sci. Signal. (IF 6.467) Pub Date : 2020-07-21
    Leslie K. Ferrarelli

    Several studies glean insight into how kinases are structurally regulated by reversible oxidation.

    更新日期:2020-07-22
  • Redox priming promotes Aurora A activation during mitosis.
    Sci. Signal. (IF 6.467) Pub Date : 2020-07-21
    Daniel C Lim,Vladimir Joukov,T Justin Rettenmaier,Akiko Kumagai,William G Dunphy,James A Wells,Michael B Yaffe

    Cell cycle–dependent redox changes can mediate transient covalent modifications of cysteine thiols to modulate the activities of regulatory kinases and phosphatases. Our previously reported finding that protein cysteine oxidation is increased during mitosis relative to other cell cycle phases suggests that redox modifications could play prominent roles in regulating mitotic processes. The Aurora family

    更新日期:2020-07-22
  • Heterogeneity in human hippocampal CaMKII transcripts reveals allosteric hub-dependent regulation.
    Sci. Signal. (IF 6.467) Pub Date : 2020-07-21
    Roman Sloutsky,Noelle Dziedzic,Matthew J Dunn,Rachel M Bates,Ana P Torres-Ocampo,Sivakumar Boopathy,Brendan Page,John G Weeks,Luke H Chao,Margaret M Stratton

    Calcium/calmodulin-dependent protein kinase II (CaMKII) plays a central role in Ca2+ signaling throughout the body. In the hippocampus, CaMKII is required for learning and memory. Vertebrate genomes encode four CaMKII homologs: CaMKIIα, CaMKIIβ, CaMKIIγ, and CaMKIIδ. All CaMKIIs consist of a kinase domain, a regulatory segment, a variable linker region, and a hub domain, which is responsible for oligomerization

    更新日期:2020-07-22
  • Untangling the ties that bind different systemic signals in plants.
    Sci. Signal. (IF 6.467) Pub Date : 2020-07-14
    Yosef Fichman,Sara I Zandalinas,Ron Mittler

    Systemic signaling in plants is orchestrated by a complex network of interconnected systemic signals and cell types. In this issue of Science Signaling, Shao et al. unveil how different wound-induced signals integrate into a well-regulated systemic response.

    更新日期:2020-07-14
  • New connections: Flux and distance in Ca2+ signaling
    Sci. Signal. (IF 6.467) Pub Date : 2020-07-14
    Wei Wong

    Understanding ER-to-mitochondrial Ca2+ flux may provide ways to correct mitochondrial dysfunction in various diseases.

    更新日期:2020-07-14
  • Functional anatomy of the full-length CXCR4-CXCL12 complex systematically dissected by quantitative model-guided mutagenesis.
    Sci. Signal. (IF 6.467) Pub Date : 2020-07-14
    Bryan S Stephens,Tony Ngo,Irina Kufareva,Tracy M Handel

    Because of their prominent roles in development, cancer, and HIV, the chemokine receptor CXCR4 and its ligand CXCL12 have been the subject of numerous structural and functional studies, but the determinants of ligand binding, selectivity, and signaling are still poorly understood. Here, building on our latest structural model, we used a systematic mutagenesis strategy to dissect the functional anatomy

    更新日期:2020-07-14
  • Two glutamate- and pH-regulated Ca2+ channels are required for systemic wound signaling in Arabidopsis.
    Sci. Signal. (IF 6.467) Pub Date : 2020-07-14
    Qiaolin Shao,Qifei Gao,Dhondup Lhamo,Hongsheng Zhang,Sheng Luan

    Plants defend against herbivores and nematodes by rapidly sending signals from the wounded sites to the whole plant. We investigated how plants generate and transduce these rapidly moving, long-distance signals referred to as systemic wound signals. We developed a system for measuring systemic responses to root wounding in Arabidopsis thaliana. We found that root wounding or the application of glutamate

    更新日期:2020-07-14
  • Cancer cells with defective oxidative phosphorylation require endoplasmic reticulum-to-mitochondria Ca2+ transfer for survival.
    Sci. Signal. (IF 6.467) Pub Date : 2020-07-14
    Cesar Cardenas,Alenka Lovy,Eduardo Silva-Pavez,Felix Urra,Craig Mizzoni,Ulises Ahumada-Castro,Galdo Bustos,Fabian Jaňa,Pablo Cruz,Paula Farias,Elizabeth Mendoza,Hernan Huerta,Paola Murgas,Martin Hunter,Melany Rios,Oscar Cerda,Irene Georgakoudi,Armen Zakarian,Jordi Molgó,J Kevin Foskett

    Spontaneous Ca2+ signaling from the InsP3R intracellular Ca2+ release channel to mitochondria is essential for optimal oxidative phosphorylation (OXPHOS) and ATP production. In cells with defective OXPHOS, reductive carboxylation replaces oxidative metabolism to maintain amounts of reducing equivalents and metabolic precursors. To investigate the role of mitochondrial Ca2+ uptake in regulating bioenergetics

    更新日期:2020-07-14
  • A redox-active switch in fructosamine-3-kinases expands the regulatory repertoire of the protein kinase superfamily.
    Sci. Signal. (IF 6.467) Pub Date : 2020-07-07
    Safal Shrestha,Samiksha Katiyar,Carlos E Sanz-Rodriguez,Nolan R Kemppinen,Hyun W Kim,Renuka Kadirvelraj,Charalampos Panagos,Neda Keyhaninejad,Maxwell Colonna,Pradeep Chopra,Dominic P Byrne,Geert J Boons,Esther van der Knaap,Patrick A Eyers,Arthur S Edison,Zachary A Wood,Natarajan Kannan

    Aberrant regulation of metabolic kinases by altered redox homeostasis substantially contributes to aging and various diseases, such as diabetes. We found that the catalytic activity of a conserved family of fructosamine-3-kinases (FN3Ks), which are evolutionarily related to eukaryotic protein kinases, is regulated by redox-sensitive cysteine residues in the kinase domain. The crystal structure of the

    更新日期:2020-07-08
  • Fat cells help wounds heal
    Sci. Signal. (IF 6.467) Pub Date : 2020-07-07
    Annalisa M. VanHook

    Dermal adipocytes promote wound healing by recruiting macrophages and transdifferentiating into myofibroblasts.

    更新日期:2020-07-08
  • BMP-1 disrupts cell adhesion and enhances TGF-β activation through cleavage of the matricellular protein thrombospondin-1.
    Sci. Signal. (IF 6.467) Pub Date : 2020-07-07
    Cyril Anastasi,Patricia Rousselle,Maya Talantikite,Agnès Tessier,Caroline Cluzel,Alice Bachmann,Natacha Mariano,Mélissa Dussoyer,Lindsay B Alcaraz,Laëtitia Fortin,Alexandre Aubert,Frédéric Delolme,Naïma El Kholti,Jean Armengaud,Pierre Fournié,Céline Auxenfans,Ulrich Valcourt,Sandrine Vadon-Le Goff,Catherine Moali

    Bone morphogenetic protein 1 (BMP-1) is an important metalloproteinase that synchronizes growth factor activation with extracellular matrix assembly during morphogenesis and tissue repair. The mechanisms by which BMP-1 exerts these effects are highly context dependent. Because BMP-1 overexpression induces marked phenotypic changes in two human cell lines (HT1080 and 293-EBNA cells), we investigated

    更新日期:2020-07-08
  • Aurora A regulation by reversible cysteine oxidation reveals evolutionarily conserved redox control of Ser/Thr protein kinase activity.
    Sci. Signal. (IF 6.467) Pub Date : 2020-07-07
    Dominic P Byrne,Safal Shrestha,Martin Galler,Min Cao,Leonard A Daly,Amy E Campbell,Claire E Eyers,Elizabeth A Veal,Natarajan Kannan,Patrick A Eyers

    Reactive oxygen species (ROS) are physiological mediators of cellular signaling and play potentially damaging roles in human diseases. In this study, we found that the catalytic activity of the Ser/Thr kinase Aurora A was inhibited by the oxidation of a conserved cysteine residue (Cys290) that lies adjacent to Thr288, a critical phosphorylation site in the activation segment. Cys is present at the

    更新日期:2020-07-08
  • The ER chaperone calnexin controls mitochondrial positioning and respiration.
    Sci. Signal. (IF 6.467) Pub Date : 2020-06-30
    Tomás Gutiérrez,Hong Qi,Megan C Yap,Nasser Tahbaz,Leanne A Milburn,Eliana Lucchinetti,Phing-How Lou,Michael Zaugg,Paul G LaPointe,Pascal Mercier,Michael Overduin,Helmut Bischof,Sandra Burgstaller,Roland Malli,Klaus Ballanyi,Jianwei Shuai,Thomas Simmen

    Chaperones in the endoplasmic reticulum (ER) control the flux of Ca2+ ions into mitochondria, thereby increasing or decreasing the energetic output of the oxidative phosphorylation pathway. An example is the abundant ER lectin calnexin, which interacts with sarco/endoplasmic reticulum Ca2+ ATPase (SERCA). We found that calnexin stimulated the ATPase activity of SERCA by maintaining its redox state

    更新日期:2020-06-30
  • New connections: Neurodevelopmental switches
    Sci. Signal. (IF 6.467) Pub Date : 2020-06-30
    Leslie K. Ferrarelli

    Protein modifications in neurons during early development regulate pain sensation and cognition.

    更新日期:2020-06-30
  • Ubiquitination and functional modification of GluN2B subunit-containing NMDA receptors by Cbl-b in the spinal cord dorsal horn.
    Sci. Signal. (IF 6.467) Pub Date : 2020-06-30
    Zi-Yang Zhang,Hu-Hu Bai,Zhen Guo,Hu-Ling Li,Xin-Tong Diao,Tian-Yu Zhang,Lin Yao,Juan-Juan Ma,Zheng Cao,Yin-Xia Li,Xue Bai,Hai-Kun Chen,Zhan-Wei Suo,Xian Yang,Xiao-Dong Hu

    N-methyl-d-aspartate (NMDA) glutamate receptors (NMDARs) containing GluN2B subunits are prevalent early after birth in most brain regions in rodents. Upon synapse maturation, GluN2B is progressively removed from synapses, which affects NMDAR function and synaptic plasticity. Aberrant recruitment of GluN2B into mature synapses has been implicated in several neuropathologies that afflict adults. We found

    更新日期:2020-06-30
  • A PI3K- and GTPase-independent Rac1-mTOR mechanism mediates MET-driven anchorage-independent cell growth but not migration.
    Sci. Signal. (IF 6.467) Pub Date : 2020-06-23
    Alexia Hervieu,Sara Farrah Heuss,Chi Zhang,Rachel Barrow-McGee,Carine Joffre,Ludovic Ménard,Paul Andrew Clarke,Stéphanie Kermorgant

    Receptor tyrosine kinases (RTKs) are often overexpressed or mutated in cancers and drive tumor growth and metastasis. In the current model of RTK signaling, including that of MET, downstream phosphatidylinositol 3-kinase (PI3K) mediates both cell proliferation and cell migration, whereas the small guanosine triphosphatase (GTPase) Rac1 mediates cell migration. However, in cultured NIH3T3 and glioblastoma

    更新日期:2020-06-24
  • Sleepless with ROS
    Sci. Signal. (IF 6.467) Pub Date : 2020-06-23
    Wei Wong

    Sleep deprivation may kill because it induces ROS accumulation and increased oxidative stress in the gut.

    更新日期:2020-06-24
  • TRPML1 channels initiate Ca2+ sparks in vascular smooth muscle cells.
    Sci. Signal. (IF 6.467) Pub Date : 2020-06-23
    Pratish Thakore,Harry A T Pritchard,Caoimhin S Griffin,Evan Yamasaki,Bernard T Drumm,Conor Lane,Kenton M Sanders,Yumei Feng Earley,Scott Earley

    TRPML1 (transient receptor potential mucolipin 1) is a Ca2+-permeable, nonselective cation channel localized to the membranes of endosomes and lysosomes and is not present or functional on the plasma membrane. Ca2+ released from endosomes and lysosomes into the cytosol through TRPML1 channels is vital for trafficking, acidification, and other basic functions of these organelles. Here, we investigated

    更新日期:2020-06-24
  • TRPML1ng on sparks.
    Sci. Signal. (IF 6.467) Pub Date : 2020-06-23
    Madeline Nieves-Cintron,Luis F Santana,Manuel F Navedo

    In this issue of Science Signaling, Thakore et al. report that the Ca2+-permeable channel TRPML1 closely associates with ryanodine receptors to induce Ca2+ sparks in native arterial myocytes. Functional studies revealed a key role for TRPML1 channels in regulation of arterial myocyte contractility and blood pressure.

    更新日期:2020-06-24
  • Crystal structure of the hinge domain of Smchd1 reveals its dimerization mode and nucleic acid-binding residues.
    Sci. Signal. (IF 6.467) Pub Date : 2020-06-16
    Kelan Chen,Richard W Birkinshaw,Alexandra D Gurzau,Iromi Wanigasuriya,Ruoyun Wang,Megan Iminitoff,Jarrod J Sandow,Samuel N Young,Patrick J Hennessy,Tracy A Willson,Denise A Heckmann,Andrew I Webb,Marnie E Blewitt,Peter E Czabotar,James M Murphy

    Structural maintenance of chromosomes flexible hinge domain containing 1 (SMCHD1) is an epigenetic regulator in which polymorphisms cause the human developmental disorder, Bosma arhinia micropthalmia syndrome, and the degenerative disease, facioscapulohumeral muscular dystrophy. SMCHD1 is considered a noncanonical SMC family member because its hinge domain is C-terminal, because it homodimerizes rather

    更新日期:2020-06-16
  • Revealing the plasma membrane in GPCR signaling
    Sci. Signal. (IF 6.467) Pub Date : 2020-06-16
    John F. Foley

    The structure of a membrane-embedded, activated D2 dopamine receptor will help in the development of more selective therapeutics.

    更新日期:2020-06-16
  • High-throughput dynamic BH3 profiling may quickly and accurately predict effective therapies in solid tumors.
    Sci. Signal. (IF 6.467) Pub Date : 2020-06-16
    Patrick D Bhola,Eman Ahmed,Jennifer L Guerriero,Ewa Sicinska,Emily Su,Elizaveta Lavrova,Jing Ni,Otari Chipashvili,Timothy Hagan,Marissa S Pioso,Kelley McQueeney,Kimmie Ng,Andrew J Aguirre,James M Cleary,David Cocozziello,Alaba Sotayo,Jeremy Ryan,Jean J Zhao,Anthony Letai

    Despite decades of effort, the sensitivity of patient tumors to individual drugs is often not predictable on the basis of molecular markers alone. Therefore, unbiased, high-throughput approaches to match patient tumors to effective drugs, without requiring a priori molecular hypotheses, are critically needed. Here, we improved upon a method that we previously reported and developed called high-throughput

    更新日期:2020-06-16
  • The interdependence of renal epithelial and endothelial metabolism and cell state.
    Sci. Signal. (IF 6.467) Pub Date : 2020-06-09
    Michael S Balzer,Katalin Susztak

    In this issue of Science Signaling, Lovisa et al. demonstrate the contribution of endothelial-to-mesenchymal transition (EndMT) to kidney fibrosis development. Their studies reveal the interdependence of endothelial and epithelial metabolism in health and disease.

    更新日期:2020-06-09
  • Molecular alterations in the extracellular matrix in the brains of newborns with congenital Zika syndrome.
    Sci. Signal. (IF 6.467) Pub Date : 2020-06-09
    Renato S Aguiar,Fabio Pohl,Guilherme L Morais,Fabio C S Nogueira,Joseane B Carvalho,Letícia Guida,Luis W P Arge,Adriana Melo,Maria E L Moreira,Daniela P Cunha,Leonardo Gomes,Elyzabeth A Portari,Erika Velasquez,Rafael D Melani,Paula Pezzuto,Fernanda L de Castro,Victor E V Geddes,Alexandra L Gerber,Girlene S Azevedo,Bruno L Schamber-Reis,Alessandro L Gonçalves,Inácio Junqueira-de-Azevedo,Milton Y Nishiyama

    Zika virus (ZIKV) infection during pregnancy can cause a set of severe abnormalities in the fetus known as congenital Zika syndrome (CZS). Experiments with animal models and in vitro systems have substantially contributed to our understanding of the pathophysiology of ZIKV infection. Here, to investigate the molecular basis of CZS in humans, we used a systems biology approach to integrate transcriptomic

    更新日期:2020-06-09
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