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  • Airway relaxation mechanisms and structural basis of osthole for improving lung function in asthma
    Sci. Signal. (IF 6.467) Pub Date : 2020-11-24
    Sheng Wang, Yan Xie, Yan-Wu Huo, Yan Li, Peter W. Abel, Haihong Jiang, Xiaohan Zou, Hai-Zhan Jiao, Xiaolin Kuang, Dennis W. Wolff, You-Guo Huang, Thomas B. Casale, Reynold A. Panettieri, Taotao Wei, Zhengyu Cao, Yaping Tu

    Overuse of β2-adrenoceptor agonist bronchodilators evokes receptor desensitization, decreased efficacy, and an increased risk of death in asthma patients. Bronchodilators that do not target β2-adrenoceptors represent a critical unmet need for asthma management. Here, we characterize the utility of osthole, a coumarin derived from a traditional Chinese medicine, in preclinical models of asthma. In mouse

    更新日期:2020-11-25
  • A more rhythmic heartbeat with calcitonin
    Sci. Signal. (IF 6.467) Pub Date : 2020-11-24
    Wei Wong

    Cardiomyocyte-released calcitonin acts on fibroblasts to limit atrial fibrosis and arrhythmia.

    更新日期:2020-11-25
  • Kallikrein 13 serves as a priming protease during infection by the human coronavirus HKU1
    Sci. Signal. (IF 6.467) Pub Date : 2020-11-24
    Aleksandra Milewska, Katherine Falkowski, Magdalena Kulczycka, Ewa Bielecka, Antonina Naskalska, Pawel Mak, Adam Lesner, Marek Ochman, Maciej Urlik, Elftherios Diamandis, Ioannis Prassas, Jan Potempa, Tomasz Kantyka, Krzysztof Pyrc

    Human coronavirus HKU1 (HCoV-HKU1) is associated with respiratory disease and is prevalent worldwide, but an in vitro model for viral replication is lacking. An interaction between the coronaviral spike (S) protein and its receptor is the primary determinant of tissue and host specificity; however, viral entry is a complex process requiring the concerted action of multiple cellular elements. Here,

    更新日期:2020-11-25
  • MAPping PI3K signaling to endosomes
    Sci. Signal. (IF 6.467) Pub Date : 2020-11-17
    John F. Foley

    The microtubule-associated protein MAP4 recruits PI3Kα from the plasma membrane to endosomes to activate Akt signaling.

    更新日期:2020-11-18
  • NF-κB activation persists into the remodeling phase of tendon healing and promotes myofibroblast survival
    Sci. Signal. (IF 6.467) Pub Date : 2020-11-17
    Katherine T. Best, Anne E. C. Nichols, Emma Knapp, Warren C. Hammert, Constantinos Ketonis, Jennifer H. Jonason, Hani A. Awad, Alayna E. Loiselle

    Although inflammation is necessary during the early phases of tissue repair, persistent inflammation contributes to fibrosis. Acute tendon injuries often heal through a fibrotic mechanism, which impedes regeneration and functional recovery. Because inflammation mediated by nuclear factor κB (NF-κB) signaling is implicated in this process, we examined the spatial, temporal, and cell type–specific activation

    更新日期:2020-11-18
  • ELP-dependent expression of MCL1 promotes resistance to EGFR inhibition in triple-negative breast cancer cells
    Sci. Signal. (IF 6.467) Pub Date : 2020-11-17
    Peter Cruz-Gordillo, Megan E. Honeywell, Nicholas W. Harper, Thomas Leete, Michael J. Lee

    Targeted therapeutics for cancer generally exploit “oncogene addiction,” a phenomenon in which the growth and survival of tumor cells depend on the activity of a particular protein. However, the efficacy of oncogene-targeted therapies varies substantially. For instance, targeting epidermal growth factor receptor (EGFR) signaling is effective in some non–small cell lung cancer (NSCLC) but not in triple-negative

    更新日期:2020-11-18
  • Engineered chemotaxis core signaling units indicate a constrained kinase-off state
    Sci. Signal. (IF 6.467) Pub Date : 2020-11-10
    Alise R. Muok, Teck Khiang Chua, Madhur Srivastava, Wen Yang, Zach Maschmann, Petr P. Borbat, Jenna Chong, Sheng Zhang, Jack H. Freed, Ariane Briegel, Brian R. Crane

    Bacterial chemoreceptors, the histidine kinase CheA, and the coupling protein CheW form transmembrane molecular arrays with remarkable sensing properties. The receptors inhibit or stimulate CheA kinase activity depending on the presence of attractants or repellants, respectively. We engineered chemoreceptor cytoplasmic regions to assume a trimer of receptor dimers configuration that formed well-defined

    更新日期:2020-11-12
  • In PDAC, “bad” cholesterol is good
    Sci. Signal. (IF 6.467) Pub Date : 2020-11-10
    Leslie K. Ferrarelli

    LDL-lowering statins can promote the development of an aggressive subtype of pancreatic cancer.

    更新日期:2020-11-12
  • EGF promotes DKK1 transcription in hepatocellular carcinoma by enhancing the phosphorylation and acetylation of histone H3
    Sci. Signal. (IF 6.467) Pub Date : 2020-11-10
    Jie Niu, Wei Li, Chao Liang, Xiao Wang, Xin Yao, Ruo-Han Yang, Zhan-Sheng Zhang, Han-Fang Liu, Fan-Ye Liu, Shu-Hua Pei, Wen-Qi Li, Hua Sun, Dong Fang, Song-Qiang Xie

    The protein Dickkopf-1 (DKK1) is frequently overexpressed at the transcript level in hepatocellular carcinoma (HCC) and promotes metastatic progression through the induction of β-catenin, a Wnt signaling effector. We investigated how DKK1 expression is induced in HCC and found that activation of the epidermal growth factor receptor (EGFR) promoted parallel MEK-ERK and PI3K-Akt pathway signaling that

    更新日期:2020-11-12
  • Mutation-induced remodeling of the BfmRS two-component system in Pseudomonas aeruginosa clinical isolates
    Sci. Signal. (IF 6.467) Pub Date : 2020-11-03
    Qiao Cao, Nana Yang, Yanhui Wang, Chenchen Xu, Xue Zhang, Ke Fan, Feifei Chen, Haihua Liang, Yingchao Zhang, Xin Deng, Youjun Feng, Cai-Guang Yang, Min Wu, Taeok Bae, Lefu Lan

    Genetic mutations are a primary driving force behind the adaptive evolution of bacterial pathogens. Multiple clinical isolates of Pseudomonas aeruginosa, an important human pathogen, have naturally evolved one or more missense mutations in bfmS, which encodes the sensor histidine kinase of the BfmRS two-component system (TCS). A mutant BfmS protein containing both the L181P and E376Q substitutions

    更新日期:2020-11-04
  • Gβγ is a direct regulator of endogenous p101/p110γ and p84/p110γ PI3Kγ complexes in mouse neutrophils
    Sci. Signal. (IF 6.467) Pub Date : 2020-11-03
    Natalie K. Rynkiewicz, Karen E. Anderson, Sabine Suire, Daniel M. Collins, Eleftherios Karanasios, Oscar Vadas, Roger Williams, David Oxley, Jonathan Clark, Len R. Stephens, Phillip T. Hawkins

    The PI3Kγ isoform is activated by Gi-coupled GPCRs in myeloid cells, but the extent to which the two endogenous complexes of PI3Kγ, p101/p110γ and p84/p110γ, receive direct regulation through Gβγ or indirect regulation through RAS and the sufficiency of those inputs is controversial or unclear. We generated mice with point mutations that prevent Gβγ binding to p110γ (RK552DD) or to p101 (VVKR777AAAA)

    更新日期:2020-11-04
  • MTORC1-dependent reprogramming
    Sci. Signal. (IF 6.467) Pub Date : 2020-11-03
    Annalisa M. VanHook

    DDIT4 and IFRD1 trigger the inhibition and reactivation of MTORC1 during regenerative repair.

    更新日期:2020-11-04
  • Emerging roles for angiomotin in the nervous system
    Sci. Signal. (IF 6.467) Pub Date : 2020-10-27
    Michael Wigerius, Dylan Quinn, James P. Fawcett

    Angiomotins are a family of molecular scaffolding proteins that function to organize contact points (called tight junctions in vertebrates) between adjacent cells. Some angiomotin isoforms bind to the actin cytoskeleton and are part of signaling pathways that influence cell morphology and migration. Others cooperate with components of the Hippo signaling pathway and the associated networks to control

    更新日期:2020-10-28
  • Spatial heterogeneities shape the collective behavior of signaling amoeboid cells
    Sci. Signal. (IF 6.467) Pub Date : 2020-10-27
    Torsten F. Eckstein, Estefania Vidal-Henriquez, Albert J. Bae, Azam Gholami

    In its natural habitat in the forest soil, the cellular slime mold Dictyostelium discoideum is exposed to obstacles. Starving Dictyostelium cells secrete cAMP, which is the key extracellular signaling molecule that promotes the aggregation process required for their long-term survival. Here, we investigated the influence of environmental inhomogeneities on the signaling and pattern formation of Dictyostelium

    更新日期:2020-10-28
  • A checkpoint for pyroptosis
    Sci. Signal. (IF 6.467) Pub Date : 2020-10-27
    Wei Wong

    The nuclear pool of an immune checkpoint protein promotes pyroptosis and tumor necrosis downstream of TNFα.

    更新日期:2020-10-28
  • Modulation of PKM activity affects the differentiation of TH17 cells
    Sci. Signal. (IF 6.467) Pub Date : 2020-10-27
    Scott M. Seki, Kacper Posyniak, Rebecca McCloud, Dorian A. Rosen, Anthony Fernández-Castañeda, Rebecca M. Beiter, Vlad Serbulea, Sarah C. Nanziri, Nikolas Hayes, Charles Spivey, Lelisa Gemta, Timothy N. J. Bullock, Ku-Lung Hsu, Alban Gaultier

    Small molecules that promote the metabolic activity of the pyruvate kinase isoform PKM2, such as TEPP-46 and DASA-58, limit tumorigenesis and inflammation. To understand how these compounds alter T cell function, we assessed their therapeutic activity in a mouse model of T cell–mediated autoimmunity that mimics multiple sclerosis (MS). TH17 cells are believed to orchestrate MS pathology, in part, through

    更新日期:2020-10-28
  • Palmitoylation and colitis
    Sci. Signal. (IF 6.467) Pub Date : 2020-10-20
    John F. Foley

    Interrupting the palmitoylation-depalmitoylation cycle of the transcriptional regulator STAT3 relieves IBD symptoms in mice.

    更新日期:2020-10-20
  • Interclass GPCR heteromerization affects localization and trafficking
    Sci. Signal. (IF 6.467) Pub Date : 2020-10-20
    Rudy Toneatti, Jong M. Shin, Urjita H. Shah, Carl R. Mayer, Justin M. Saunders, Miguel Fribourg, Paul T. Arsenovic, William G. Janssen, Stuart C. Sealfon, Juan F. López-Giménez, Deanna L. Benson, Daniel E. Conway, Javier González-Maeso

    Membrane trafficking processes regulate G protein–coupled receptor (GPCR) activity. Although class A GPCRs are capable of activating G proteins in a monomeric form, they can also potentially assemble into functional GPCR heteromers. Here, we showed that the class A serotonin 5-HT2A receptors (5-HT2ARs) affected the localization and trafficking of class C metabotropic glutamate receptor 2 (mGluR2) through

    更新日期:2020-10-20
  • SMAR1 repression by pluripotency factors and consequent chemoresistance in breast cancer stem-like cells is reversed by aspirin
    Sci. Signal. (IF 6.467) Pub Date : 2020-10-20
    Apoorva Bhattacharya, Shravanti Mukherjee, Poulami Khan, Shruti Banerjee, Apratim Dutta, Nilanjan Banerjee, Debomita Sengupta, Udit Basak, Sourio Chakraborty, Abhishek Dutta, Samit Chattopadhyay, Kuladip Jana, Diptendra K. Sarkar, Subhrangsu Chatterjee, Tanya Das

    The high abundance of drug efflux pumps in cancer stem cells (CSCs) contributes to chemotherapy resistance. The transcriptional regulator SMAR1 suppresses CSC expansion in colorectal cancer, and increased abundance of SMAR1 is associated with better prognosis. Here, we found in breast tumors that the expression of SMAR1 was decreased in CSCs through the cooperative interaction of the pluripotency factors

    更新日期:2020-10-20
  • Dimerization regulates the human APC/C-associated ubiquitin-conjugating enzyme UBE2S
    Sci. Signal. (IF 6.467) Pub Date : 2020-10-20
    Anna K. L. Liess, Alena Kucerova, Kristian Schweimer, Dörte Schlesinger, Olexandr Dybkov, Henning Urlaub, Jörg Mansfeld, Sonja Lorenz

    At the heart of protein ubiquitination cascades, ubiquitin-conjugating enzymes (E2s) form reactive ubiquitin-thioester intermediates to enable efficient transfer of ubiquitin to cellular substrates. The precise regulation of E2s is thus crucial for cellular homeostasis, and their deregulation is frequently associated with tumorigenesis. In addition to driving substrate ubiquitination together with

    更新日期:2020-10-20
  • Hug and hold tight: Dimerization controls the turnover of the ubiquitin-conjugating enzyme UBE2S
    Sci. Signal. (IF 6.467) Pub Date : 2020-10-20
    Anja Bremm

    Precise control of the activity and abundance of ubiquitin-conjugating enzymes (E2s) ensures fidelity in ubiquitin chain synthesis. In this issue of Science Signaling, Liess et al. demonstrate that the human anaphase-promoting complex (APC/C)–associated E2 UBE2S adopts an autoinhibited dimeric state that increases the half-life of UBE2S by preventing its autoubiquitination-driven turnover.

    更新日期:2020-10-20
  • A healthy dose of fear
    Sci. Signal. (IF 6.467) Pub Date : 2020-10-13
    Leslie K. Ferrarelli

    Secretion of IL-17a from meninges-resident T cells promotes anxiety-like behavior in mice.

    更新日期:2020-10-13
  • RASSF effectors couple diverse RAS subfamily GTPases to the Hippo pathway
    Sci. Signal. (IF 6.467) Pub Date : 2020-10-13
    Thillaivillalan Dhanaraman, Swati Singh, Ryan C. Killoran, Anamika Singh, Xingjian Xu, Julia M. Shifman, Matthew J. Smith

    Small guanosine triphosphatases (GTPases) of the RAS superfamily signal by directly binding to multiple downstream effector proteins. Effectors are defined by a folded RAS-association (RA) domain that binds exclusively to GTP-loaded (activated) RAS, but the binding specificities of most RA domains toward more than 160 RAS superfamily GTPases have not been characterized. Ten RA domain family (RASSF)

    更新日期:2020-10-13
  • Mechanical activation of TRPV4 channels controls albumin reabsorption by proximal tubule cells
    Sci. Signal. (IF 6.467) Pub Date : 2020-10-13
    Roberta Gualdani, François Seghers, Xavier Yerna, Olivier Schakman, Nicolas Tajeddine, Younès Achouri, Fadel Tissir, Olivier Devuyst, Philippe Gailly

    Defects in protein reabsorption by the proximal tubule are toxic for epithelial cells in the nephron and may result in nephropathy. In this study, we showed that the ion channel TRPV4 modulated the endocytosis of albumin and low–molecular weight proteins in the proximal tubule. TRPV4 was found at the basolateral side of proximal tubule cells, and its mechanical activation by cell stretching induced

    更新日期:2020-10-13
  • Feeling the warmth in your bones
    Sci. Signal. (IF 6.467) Pub Date : 2020-10-06
    Wei Wong

    Warm ambient temperatures induce gut microbiota to release factors that limit bone loss.

    更新日期:2020-10-07
  • Breast cancer–associated macrophages promote tumorigenesis by suppressing succinate dehydrogenase in tumor cells
    Sci. Signal. (IF 6.467) Pub Date : 2020-10-06
    Valentí Gómez, Thomas R. Eykyn, Rami Mustapha, Fabián Flores-Borja, Victoria Male, Paul R. Barber, Antonia Patsialou, Ryan Green, Fani Panagaki, Chun W. Li, Gilbert O. Fruhwirth, Susana Ros, Kevin M. Brindle, Tony Ng

    Tumor-associated macrophages (TAMs) can exist in pro- and anti-inflammatory states. Anti-inflammatory TAMs (also referred to as M2-polarized) generally suppress antitumor immune responses and enhance the metastatic progression of cancer. To explore the mechanisms behind this phenomenon, we isolated macrophages from mice and humans, polarized them ex vivo, and examined their functional interaction with

    更新日期:2020-10-07
  • Constitutive expression of progesterone receptor isoforms promotes the development of hormone-dependent ovarian neoplasms
    Sci. Signal. (IF 6.467) Pub Date : 2020-10-06
    Margeaux Wetendorf, Rong Li, San-Pin Wu, Jian Liu, Chad J. Creighton, Tianyuan Wang, Kyathanahalli S. Janardhan, Cynthia J. Willson, Rainer B. Lanz, Bruce D. Murphy, John P. Lydon, Francesco J. DeMayo

    Differences in the relative abundances of the progesterone receptor (PGR) isoforms PGRA and PGRB are often observed in women with reproductive tract cancers. To assess the importance of the PGR isoform ratio in the maintenance of the reproductive tract, we generated mice that overexpress PGRA or PGRB in all PGR-positive tissues. Whereas few PGRA-overexpressing mice developed reproductive tract tumors

    更新日期:2020-10-07
  • High-resolution structures of the SARS-CoV-2 2′-O-methyltransferase reveal strategies for structure-based inhibitor design
    Sci. Signal. (IF 6.467) Pub Date : 2020-09-29
    Monica Rosas-Lemus, George Minasov, Ludmilla Shuvalova, Nicole L. Inniss, Olga Kiryukhina, Joseph Brunzelle, Karla J. F. Satchell

    There are currently no antiviral therapies specific for SARS-CoV-2, the virus responsible for the global pandemic disease COVID-19. To facilitate structure-based drug design, we conducted an x-ray crystallographic study of the SARS-CoV-2 nsp16-nsp10 2′-O-methyltransferase complex, which methylates Cap-0 viral mRNAs to improve viral protein translation and to avoid host immune detection. We determined

    更新日期:2020-09-30
  • The purinergic receptor P2Y11 choreographs the polarization, mitochondrial metabolism, and migration of T lymphocytes
    Sci. Signal. (IF 6.467) Pub Date : 2020-09-29
    Carola Ledderose, Sophie Bromberger, Christian J. Slubowski, Koichiro Sueyoshi, Dilan Aytan, Yong Shen, Wolfgang G. Junger

    T cells must migrate to encounter antigen-presenting cells and perform their roles in host defense. Here, we found that autocrine stimulation of the purinergic receptor P2Y11 regulates the migration of human CD4 T cells. P2Y11 receptors redistributed from the front to the back of polarized cells where they triggered intracellular cAMP/PKA signals that attenuated mitochondrial metabolism at the back

    更新日期:2020-09-30
  • Microbial metabolite protects against infection
    Sci. Signal. (IF 6.467) Pub Date : 2020-09-29
    Annalisa M. VanHook

    Commensal-derived d-lactate promotes pathogen capture and clearance by Kupffer cells in the liver.

    更新日期:2020-09-30
  • 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
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