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Science Signaling

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https://www.readbyqxmd.com/read/28900044/regulation-of-autophagy-nf-%C3%AE%C2%BAb-signaling-and-cell-viability-by-mir-124-in-kras-mutant-mesenchymal-like-nsclc-cells
#1
Anita K Mehta, Kevin Hua, William Whipple, Minh-Thuy Nguyen, Ching-Ti Liu, Johannes Haybaeck, Joanne Weidhaas, Jeff Settleman, Anurag Singh
KRAS mutant non-small cell lung cancer (NSCLC) may be classified into epithelial or mesenchymal subtypes. Despite having the same "driver" mutation, mesenchymal NSCLCs are less responsive than are epithelial NSCLCs to inhibition of the RAS pathway. Identifying alternative networks that promote survival specifically in mesenchymal NSCLC may lead to more effective treatments for this subtype. Through their numerous targets in cellular signaling pathways, noncoding microRNAs (miRNAs) often function as tumor suppressors or oncogenes...
September 12, 2017: Science Signaling
https://www.readbyqxmd.com/read/28900043/a-natural-ligand-for-the-orphan-receptor-gpr15-modulates-lymphocyte-recruitment-to-epithelia
#2
Thomas Suply, Sébastien Hannedouche, Nathalie Carte, Jianping Li, Bianka Grosshans, Michael Schaefer, Layla Raad, Valérie Beck, Solange Vidal, Agnès Hiou-Feige, Noémie Beluch, Samuel Barbieri, Johann Wirsching, Nadine Lageyre, Frank Hillger, Corinne Debon, Janet Dawson, Philip Smith, Vincent Lannoy, Michel Detheux, Francis Bitsch, Rocco Falchetto, Tewis Bouwmeester, Jeffrey Porter, Birgit Baumgarten, Keith Mansfield, José M Carballido, Klaus Seuwen, Frédéric Bassilana
GPR15 is an orphan G protein-coupled receptor (GPCR) that is found in lymphocytes. It functions as a co-receptor of simian immunodeficiency virus and HIV-2 and plays a role in the trafficking of T cells to the lamina propria in the colon and to the skin. We describe the purification from porcine colonic tissue extracts of an agonistic ligand for GPR15 and its functional characterization. In humans, this ligand, which we named GPR15L, is encoded by the gene C10ORF99 and has some features similar to the CC family of chemokines...
September 12, 2017: Science Signaling
https://www.readbyqxmd.com/read/28874606/bacterial-d-amino-acids-suppress-sinonasal-innate-immunity-through-sweet-taste-receptors-in-solitary-chemosensory-cells
#3
Robert J Lee, Benjamin M Hariri, Derek B McMahon, Bei Chen, Laurel Doghramji, Nithin D Adappa, James N Palmer, David W Kennedy, Peihua Jiang, Robert F Margolskee, Noam A Cohen
In the upper respiratory epithelium, bitter and sweet taste receptors present in solitary chemosensory cells influence antimicrobial innate immune defense responses. Whereas activation of bitter taste receptors (T2Rs) stimulates surrounding epithelial cells to release antimicrobial peptides, activation of the sweet taste receptor (T1R) in the same cells inhibits this response. This mechanism is thought to control the magnitude of antimicrobial peptide release based on the sugar content of airway surface liquid...
September 5, 2017: Science Signaling
https://www.readbyqxmd.com/read/28874605/ca-2-and-mitochondrial-ros-both-hero-and-villain-in-membrane-repair
#4
REVIEW
Sandra T Cooper
Membrane repair is a symphony of signaling, conducted principally by the steep influx of Ca(2+) through an injured membrane. In this issue of Science Signaling, Horn et al reveal unique interplay between Ca(2+) influx and mitochondrially generated reactive oxygen species (mtROS) to enhance actin-mediated wound closure for survival of injured mammalian muscle and nonmuscle cells.
September 5, 2017: Science Signaling
https://www.readbyqxmd.com/read/28874604/mitochondrial-redox-signaling-enables-repair-of-injured-skeletal-muscle-cells
#5
Adam Horn, Jack H Van der Meulen, Aurelia Defour, Marshall Hogarth, Sen Chandra Sreetama, Aaron Reed, Luana Scheffer, Navdeep S Chandel, Jyoti K Jaiswal
Strain and physical trauma to mechanically active cells, such as skeletal muscle myofibers, injures their plasma membranes, and mitochondrial function is required for their repair. We found that mitochondrial function was also needed for plasma membrane repair in myoblasts as well as nonmuscle cells, which depended on mitochondrial uptake of calcium through the mitochondrial calcium uniporter (MCU). Calcium uptake transiently increased the mitochondrial production of reactive oxygen species (ROS), which locally activated the guanosine triphosphatase (GTPase) RhoA, triggering F-actin accumulation at the site of injury and facilitating membrane repair...
September 5, 2017: Science Signaling
https://www.readbyqxmd.com/read/28874603/cancer-associated-arginine-to-histidine-mutations-confer-a-gain-in-ph-sensing-to-mutant-proteins
#6
Katharine A White, Diego Garrido Ruiz, Zachary A Szpiech, Nicolas B Strauli, Ryan D Hernandez, Matthew P Jacobson, Diane L Barber
The intracellular pH (pHi) of most cancers is constitutively higher than that of normal cells and enhances proliferation and cell survival. We found that increased pHi enabled the tumorigenic behaviors caused by somatic arginine-to-histidine mutations, which are frequent in cancer and confer pH sensing not seen with wild-type proteins. Experimentally raising the pHi increased the activity of R776H mutant epidermal growth factor receptor (EGFR-R776H), thereby increasing proliferation and causing transformation in fibroblasts...
September 5, 2017: Science Signaling
https://www.readbyqxmd.com/read/28851824/blockade-of-surface-bound-tgf-%C3%AE-on-regulatory-t-cells-abrogates-suppression-of-effector-t-cell-function-in-the-tumor-microenvironment
#7
Sadna Budhu, David A Schaer, Yongbiao Li, Ricardo Toledo-Crow, Katherine Panageas, Xia Yang, Hong Zhong, Alan N Houghton, Samuel C Silverstein, Taha Merghoub, Jedd D Wolchok
Regulatory T cells (Tregs) suppress antitumor immunity by inhibiting the killing of tumor cells by antigen-specific CD8(+) T cells. To better understand the mechanisms involved, we used ex vivo three-dimensional collagen-fibrin gel cultures of dissociated B16 melanoma tumors. This system recapitulated the in vivo suppression of antimelanoma immunity, rendering the dissociated tumor cells resistant to killing by cocultured activated, antigen-specific T cells. Immunosuppression was not observed when tumors excised from Treg-depleted mice were cultured in this system...
August 29, 2017: Science Signaling
https://www.readbyqxmd.com/read/28851823/activation-of-master-virulence-regulator-phop-in-acidic-ph-requires-the-salmonella-specific-protein-ugtl
#8
Jeongjoon Choi, Eduardo A Groisman
Acidic conditions, such as those inside phagosomes, stimulate the intracellular pathogen Salmonella enterica to activate virulence genes. The sensor PhoQ responds to a mildly acidic pH by phosphorylating, and thereby activating, the virulence regulator PhoP. This PhoP/PhoQ two-component system is conserved in a subset of Gram-negative bacteria. PhoQ is thought to be sufficient to activate PhoP in mildly acidic pH. However, we found that the Salmonella-specific protein UgtL, which was horizontally acquired by Salmonella before the divergence of S...
August 29, 2017: Science Signaling
https://www.readbyqxmd.com/read/28851822/protein-kinase-n3-promotes-bone-resorption-by-osteoclasts-in-response-to-wnt5a-ror2-signaling
#9
Shunsuke Uehara, Nobuyuki Udagawa, Hideyuki Mukai, Akihiro Ishihara, Kazuhiro Maeda, Teruhito Yamashita, Kohei Murakami, Michiru Nishita, Takashi Nakamura, Shigeaki Kato, Yasuhiro Minami, Naoyuki Takahashi, Yasuhiro Kobayashi
Cytoskeletal reorganization in osteoclasts to form actin rings is necessary for these cells to attach to bone and resorb bone matrices. We delineated the pathway through which Wnt5a signaling through receptor tyrosine kinase-like orphan receptor 2 (Ror2) promoted the bone-resorbing activity of osteoclasts. Wnt5a binding to Ror2 stimulated Rho, a small GTPase involved in cytoskeletal reorganization. Subsequently, the Rho effector kinase Pkn3 bound to and enhanced the activity of c-Src, a nonreceptor tyrosine kinase that is critical for actin ring formation...
August 29, 2017: Science Signaling
https://www.readbyqxmd.com/read/28831022/the-adaptor-molecule-riam-integrates-signaling-events-critical-for-integrin-mediated-control-of-immune-function-and-cancer-progression
#10
REVIEW
Nikolaos Patsoukis, Kankana Bardhan, Jessica D Weaver, Duygu Sari, Alvaro Torres-Gomez, Lequn Li, Laura Strauss, Esther M Lafuente, Vassiliki A Boussiotis
Lymphocyte activation requires adhesion to antigen-presenting cells. This is a critical event linking innate and adaptive immunity. Lymphocyte adhesion is accomplished through LFA-1, which must be activated by a process referred to as inside-out integrin signaling. Among the few signaling molecules that have been implicated in inside-out integrin activation in hematopoietic cells are the small guanosine triphosphatase (GTPase) Rap1 and its downstream effector Rap1-interacting molecule (RIAM), a multidomain protein that defined the Mig10-RIAM-lamellipodin (MRL) class of adaptor molecules...
August 22, 2017: Science Signaling
https://www.readbyqxmd.com/read/28831021/a-systems-approach-for-discovering-linoleic-acid-derivatives-that-potentially-mediate-pain-and-itch
#11
Christopher E Ramsden, Anthony F Domenichiello, Zhi-Xin Yuan, Matthew R Sapio, Gregory S Keyes, Santosh K Mishra, Jacklyn R Gross, Sharon Majchrzak-Hong, Daisy Zamora, Mark S Horowitz, John M Davis, Alexander V Sorokin, Amit Dey, Danielle M LaPaglia, Joshua J Wheeler, Michael R Vasko, Nehal N Mehta, Andrew J Mannes, Michael J Iadarola
Chronic pain and itch are common hypersensitivity syndromes that are affected by endogenous mediators. We applied a systems-based, translational approach to predict, discover, and characterize mediators of pain and itch that are regulated by diet and inflammation. Profiling of tissue-specific precursor abundance and biosynthetic gene expression predicted that inflamed skin would be abundant in four previously unknown 11-hydroxy-epoxy- or 11-keto-epoxy-octadecenoate linoleic acid derivatives and four previously identified 9- or 13-hydroxy-epoxy- or 9- or 13-keto-epoxy-octadecenoate linoleic acid derivatives...
August 22, 2017: Science Signaling
https://www.readbyqxmd.com/read/28831020/niche-derived-laminin-511-promotes-midbrain-dopaminergic-neuron-survival-and-differentiation-through-yap
#12
Dawei Zhang, Shanzheng Yang, Enrique M Toledo, Daniel Gyllborg, Carmen Saltó, J Carlos Villaescusa, Ernest Arenas
Parkinson's disease (PD) is a neurodegenerative disorder in which the loss of dopaminergic neurons in the midbrain (mDA neurons) causes progressive loss of motor control and function. Using embryonic and mDA neurons, midbrain tissue from mice, and differentiated human neural stem cells, we investigated the mechanisms controlling the survival of mDA neurons. We found that the extracellular matrix protein laminin-511 (LM511) promoted the survival and differentiation of mDA neurons. LM511 bound to integrin α3β1 and activated the transcriptional cofactor YAP...
August 22, 2017: Science Signaling
https://www.readbyqxmd.com/read/28831019/multiplex-quantitative-assays-indicate-a-need-for-reevaluating-reported-small-molecule-trkb-agonists
#13
Umed Boltaev, Yves Meyer, Farangis Tolibzoda, Teresa Jacques, Madalee Gassaway, Qihong Xu, Florence Wagner, Yan-Ling Zhang, Michelle Palmer, Edward Holson, Dalibor Sames
Brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin-related kinase B (TrkB), have emerged as key regulators of brain plasticity and represent disease-modifying targets for several brain disorders, including Alzheimer's disease and major depressive disorder. Because of poor pharmacokinetic properties of BDNF, the interest in small-molecule TrkB agonists and modulators is high. Several compounds have been reported to act as TrkB agonists, and their increasing use in various nervous system disorder models creates the perception that these are reliable probes...
August 22, 2017: Science Signaling
https://www.readbyqxmd.com/read/28811384/loss-of-spdef-and-gain-of-tgfbi-activity-after-androgen-deprivation-therapy-promote-emt-and-bone-metastasis-of-prostate-cancer
#14
Wei-Yu Chen, Yuan-Chin Tsai, Hsiu-Lien Yeh, Florent Suau, Kuo-Ching Jiang, Ai-Ning Shao, Jiaoti Huang, Yen-Nien Liu
Androgen deprivation therapy (ADT) targeting the androgen receptor (AR) is a standard therapeutic regimen for treating prostate cancer. However, most tumors progress to metastatic castration-resistant prostate cancer after ADT. We identified the type 1, 2, and 4 collagen-binding protein transforming growth factor-β (TGFβ)-induced protein (TGFBI) as an important factor in the epithelial-to-mesenchymal transition (EMT) and malignant progression of prostate cancer. In prostate cancer cell lines, AR signaling stimulated the activity of the transcription factor SPDEF, which repressed the expression of TGFBI ADT, AR antagonism, or overexpression of TGFBI inhibited the activity of SPDEF and enhanced the proliferation rates of prostate cancer cells...
August 15, 2017: Science Signaling
https://www.readbyqxmd.com/read/28811383/interleukin-36-cytokines-may-overcome-microbial-immune-evasion-strategies-that-inhibit-interleukin-1-family-signaling
#15
REVIEW
Liselotte E Jensen
Pathogens deploy immune evasion strategies to successfully establish infections within their hosts. Naturally, the host responds by acquiring mechanisms to counter these strategies. There is increasing evidence that the three interleukin-36 (IL-36) cytokines, IL-36α, IL-36β and IL-36γ, play important roles in host immunity. With a focus on the skin as a target for microbial and viral invasion, the current knowledge of IL-36 functions is reviewed. Furthermore, the hypothesis that the IL-36s have evolved to counteract virulence factors is presented using viruses as an example...
August 15, 2017: Science Signaling
https://www.readbyqxmd.com/read/28811382/an-engineered-s1p-chaperone-attenuates-hypertension-and-ischemic-injury
#16
Steven L Swendeman, Yuquan Xiong, Anna Cantalupo, Hui Yuan, Nathalie Burg, Yu Hisano, Andreane Cartier, Catherine H Liu, Eric Engelbrecht, Victoria Blaho, Yi Zhang, Keisuke Yanagida, Sylvain Galvani, Hideru Obinata, Jane E Salmon, Teresa Sanchez, Annarita Di Lorenzo, Timothy Hla
Endothelial dysfunction, a hallmark of vascular disease, is restored by plasma high-density lipoprotein (HDL). However, a generalized increase in HDL abundance is not beneficial, suggesting that specific HDL species mediate protective effects. Apolipoprotein M-containing HDL (ApoM(+)HDL), which carries the bioactive lipid sphingosine 1-phosphate (S1P), promotes endothelial function by activating G protein-coupled S1P receptors. Moreover, HDL-bound S1P is limiting in several inflammatory, metabolic, and vascular diseases...
August 15, 2017: Science Signaling
https://www.readbyqxmd.com/read/28790197/breast-tumors-educate-the-proteome-of-stromal-tissue-in-an-individualized-but-coordinated-manner
#17
Xuya Wang, Arshag D Mooradian, Petra Erdmann-Gilmore, Qiang Zhang, Rosa Viner, Sherri R Davies, Kuan-Lin Huang, Ryan Bomgarden, Brian A Van Tine, Jieya Shao, Li Ding, Shunqiang Li, Matthew J Ellis, John C Rogers, R Reid Townsend, David Fenyö, Jason M Held
Cancer forms specialized microenvironmental niches that promote local invasion and colonization. Engrafted patient-derived xenografts (PDXs) locally invade and colonize naïve stroma in mice while enabling unambiguous molecular discrimination of human proteins in the tumor from mouse proteins in the microenvironment. To characterize how patient breast tumors form a niche and educate naïve stroma, subcutaneous breast cancer PDXs were globally profiled by species-specific quantitative proteomics. Regulation of PDX stromal proteins by breast tumors was extensive, with 35% of the stromal proteome altered by tumors consistently across different animals and passages...
August 8, 2017: Science Signaling
https://www.readbyqxmd.com/read/28790196/trif-dependent-toll-like-receptor-signaling-suppresses-scd1-transcription-in-hepatocytes-and-prevents-diet-induced-hepatic-steatosis
#18
Jing Chen, Jin Li, Jensen H C Yiu, Jenny K W Lam, Chi-Ming Wong, Bernhard Dorweiler, Aimin Xu, Connie W Woo
Nonalcoholic fatty liver disease (NAFLD) includes a spectrum of diseases that ranges in severity from hepatic steatosis to steatohepatitis, the latter of which is a major predisposing factor for liver cirrhosis and cancer. Toll-like receptor (TLR) signaling, which is critical for innate immunity, is generally believed to aggravate disease progression by inducing inflammation. Unexpectedly, we found that deficiency in TIR domain-containing adaptor-inducing interferon-β (TRIF), a cytosolic adaptor that transduces some TLR signals, worsened hepatic steatosis induced by a high-fat diet (HFD) and that such exacerbation was independent of myeloid cells...
August 8, 2017: Science Signaling
https://www.readbyqxmd.com/read/28790195/the-tyrosine-phosphatase-shp-1-promotes-t-cell-adhesion-by-activating-the-adaptor-protein-crkii-in-the-immunological-synapse
#19
Inbar Azoulay-Alfaguter, Marianne Strazza, Michael Peled, Hila K Novak, James Muller, Michael L Dustin, Adam Mor
The adaptor protein CrkII regulates T cell adhesion by recruiting the guanine nucleotide exchange factor C3G, an activator of Rap1. Subsequently, Rap1 stimulates the integrin LFA-1, which leads to T cell adhesion and interaction with antigen-presenting cells (APCs). The adhesion of T cells to APCs is critical for their proper function and education. The interface between the T cell and the APC is known as the immunological synapse. It is characterized by the specific organization of proteins that can be divided into central supramolecular activation clusters (c-SMACs) and peripheral SMACs (p-SMACs)...
August 8, 2017: Science Signaling
https://www.readbyqxmd.com/read/28765513/high-glucose-induced-ros-activates-trpm2-to-trigger-lysosomal-membrane-permeabilization-and-zn-2-mediated-mitochondrial-fission
#20
Nada Abuarab, Tim S Munsey, Lin-Hua Jiang, Jing Li, Asipu Sivaprasadarao
Diabetic stress increases the production of reactive oxygen species (ROS), leading to mitochondrial fragmentation and dysfunction. We hypothesized that ROS-sensitive TRPM2 channels mediated diabetic stress-induced mitochondrial fragmentation. We found that chemical inhibitors, RNAi silencing, and genetic knockout of TRPM2 channels abolished the ability of high glucose to cause mitochondrial fission in endothelial cells, a cell type that is particularly vulnerable to diabetic stress. Similar to high glucose, increasing ROS in endothelial cells by applying H2O2 induced mitochondrial fission...
August 1, 2017: Science Signaling
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