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https://www.readbyqxmd.com/read/28736554/differential-requirements-for-src-family-kinases-in-syk-or-zap70-mediated-slp-76-phosphorylation-in-lymphocytes
#1
Frank Fasbender, Maren Claus, Sabine Wingert, Mina Sandusky, Carsten Watzl
In a synthetic biology approach using Schneider (S2) cells, we show that SLP-76 is directly phosphorylated at tyrosines Y113 and Y128 by SYK in the presence of ITAM-containing adapters such as CD3ζ, DAP12, or FcεRγ. This phosphorylation was dependent on at least one functional ITAM and a functional SH2 domain within SYK. Inhibition of Src-kinases by inhibitors PP1 and PP2 did not reduce SLP-76 phosphorylation in S2 cells, suggesting an ITAM and SYK dependent, but Src-kinase independent signaling pathway...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28736076/suppression-of-ige-mediated-mast-cell-activation-and-mouse-anaphylaxis-via-inhibition-of-syk-activation-by-8-formyl-7-hydroxy-4-methylcoumarin-4%C3%AE-8c
#2
Seung Taek Nam, Young Hwan Park, Hyun Woo Kim, Hyuk Soon Kim, Dajeong Lee, Min Bum Lee, Young Mi Kim, Wahn Soo Choi
Mast cells trigger IgE-mediated allergic reactions by releasing various allergic mediators. 8-Formyl-7-hydroxy-4-methylcoumarin, also called 4μ8C, was originally known as an inositol-requiring enzyme 1 (IRE1) suppressant, but no study has examined its relationship with mast cells and allergic diseases. Therefore, the purpose of this study was to determine whether 4μ8C is effective in suppressing allergic reactions in mast cells and in IgE-mediated allergic animal model. 4μ8C suppressed the degranulation of IgE-mediated mast cells (IC50=3...
July 20, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28717031/phagocytic-receptors-activate-syk-and-src-signaling-during-borrelia-burgdorferi-phagocytosis
#3
Tess L Killpack, Maria Ballesteros, Stephen C Bunnell, Alice Bedugnis, Lester Kobzik, Linden T Hu, Tanja Petnicki-Ocwieja
Phagocytosis of the Lyme disease causing pathogen Borrelia burgdorferi has been shown to be important in generating an inflammatory response to the pathogen. As a result, understanding the mechanisms of phagocytosis has been an area of great interest in the field of Lyme disease. Several cell surface receptors that participate in B. burgdorferi phagocytosis have been reported, including scavenger receptor MARCO and integrin α3β1. We sought to define the mechanisms by which these receptors mediated phagocytosis and to identify signaling pathways activated downstream of these receptors upon contact with B...
July 17, 2017: Infection and Immunity
https://www.readbyqxmd.com/read/28716125/mercury-alters-endogenous-phosphorylation-profiles-of-syk-in-murine-b-cells
#4
Joseph A Caruso, Nicholas Carruthers, Namhee Shin, Randal Gill, Paul M Stemmer, Allen Rosenspire
BACKGROUND: Epidemiological evidence and animal models suggest that exposure to low and non-neurotoxic concentrations of mercury may contribute to idiosyncratic autoimmune disease. Since defects in function and signaling in B cells are often associated with autoimmunity, we investigated whether mercury exposure might alter B cell responsiveness to self-antigens by interfering with B cell receptor (BCR) signal transduction. In this study we determined the effects of mercury on the protein tyrosine kinase SYK, a critical protein involved in regulation of the BCR signaling pathway...
July 17, 2017: BMC Immunology
https://www.readbyqxmd.com/read/28706459/beauvericin-a-cyclic-peptide-inhibits-inflammatory-responses-in-macrophages-by-inhibiting-the-nf-%C3%AE%C2%BAb-pathway
#5
Sulgi Yoo, Mi-Yeon Kim, Jae Youl Cho
Beauvericin (BEA), a cyclic hexadepsipeptide produced by the fungus Beauveria bassiana, is known to have anti-cancer, anti-inflammatory, and anti-microbial actions. However, how BEA suppresses macrophage-induced inflammatory responses has not been fully elucidated. In this study, we explored the anti-inflammatory properties of BEA and the underlying molecular mechanisms using lipopolysaccharide (LPS)-treated macrophage-like RAW264.7 cells. Levels of nitric oxide (NO), mRNA levels of transcription factors and the inflammatory genes inducible NO synthase (iNOS) and interleukin (IL)-1, and protein levels of activated intracellular signaling molecules were determined by Griess assay, semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), luciferase reporter gene assay, and immunoblotting analysis...
July 2017: Korean Journal of Physiology & Pharmacology
https://www.readbyqxmd.com/read/28706155/characterization-of-midostaurin-as-a-dual-inhibitor-of-flt3-and-syk-and-potentiation-of-flt3-inhibition-against-flt3-itd-driven-leukemia-harboring-activated-syk-kinase
#6
Ellen L Weisberg, Alexandre Puissant, Richard Stone, Martin Sattler, Sara J Buhrlage, Jing Yang, Paul W Manley, Chengcheng Meng, Michael Buonopane, John F Daley, Suzan Lazo, Renee Wright, David M Weinstock, Amanda L Christie, Kimberly Stegmaier, James D Griffin
Oncogenic FLT3 kinase is a clinically validated target in acute myeloid leukemia (AML), and both multi-targeted and selective FLT3 inhibitors have been developed. Spleen tyrosine kinase (SYK) has been shown to be activated and increased in FLT3-ITD-positive AML patients, and has further been shown to be critical for transformation and maintenance of the leukemic clone in these patients. Further, over-expression of constitutively activated SYK causes resistance to highly selective FLT3 tyrosine kinase inhibitors (TKI)...
July 6, 2017: Oncotarget
https://www.readbyqxmd.com/read/28688804/crotoxin-a-rattlesnake-toxin-down-modulates-functions-of-bone-marrow-neutrophils-and-impairs-the-syk-gtpase-pathway
#7
Tatiane S Lima, Camila L Neves, Vanessa O Zambelli, Flávia S R Lopes, Sandra C Sampaio, Maria Cristina Cirillo
Neutrophils have a critical role in the innate immune response; these cells represent the primary line of defense against invading pathogens or tissue injury. Crotoxin (CTX), the major toxin of the South American rattlesnake (Crotalus durissus terrificus) venom, presents longstanding anti-inflammatory properties, inhibiting neutrophil migration and phagocytosis by peritoneal neutrophils for 14 days. Herein, to elucidate these sustained inhibitory effects induced by CTX, we performed in vitro and in vivo studies evaluating the functionality of bone marrow neutrophils and possible molecular mechanisms associated with these effects...
July 5, 2017: Toxicon: Official Journal of the International Society on Toxinology
https://www.readbyqxmd.com/read/28680194/syk-plays-a-critical-role-in-the-expression-and-activation-of-irak1-in-lps-treated-macrophages
#8
Jae Gwang Park, Young-Jin Son, Byong Chul Yoo, Woo Seok Yang, Ji Hye Kim, Jong-Hoon Kim, Jae Youl Cho
To address how interleukin-1 receptor-associated kinase 1 (IRAK1) is controlled by other enzymes activated by toll-like receptor (TLR) 4, we investigated the possibility that spleen tyrosine kinase (Syk), a protein tyrosine kinase that is activated at an earlier stage during TLR4 activation, plays a central role in regulating the functional activation of IRAK1. Indeed, we found that overexpression of myeloid differentiation primary response gene 88 (MyD88), an adaptor molecule that drives TLR signaling, induced IRAK1 expression and that piceatannol, a Syk inhibitor, successfully suppressed the MyD88-dependent upregulation of IRAK1 under LPS treatment conditions...
2017: Mediators of Inflammation
https://www.readbyqxmd.com/read/28674449/dexamethasone-induced-inhibition-of-dectin-1-activation-of-antigen-presenting-cells-is-mediated-via-stat-3-and-nf-%C3%AE%C2%BAb-signaling-pathways
#9
Philipp Kotthoff, Annkristin Heine, Stefanie Andrea Erika Held, Peter Brossart
Treatment of patients with glucocorticoids can result in an increased risk of infection with pathogens such as fungi. Dectin-1 is a member of the C-type lectin receptor superfamily and was shown to be one of the major receptors for fungal beta-glucans. Activation of Dectin-1 increases the production of cytokines and chemokines and T-cell stimulatory capacity of DC and mediates resolution of fungal infections. Here we show that antigen-presenting cells generated in the presence of dexamethasone (Dex-DC) have a reduced capacity to stimulate T-cell proliferation and decreased expression of costimulatory molecules, that can not be enhanced upon stimulation with Dectin-1 ligands...
July 3, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28671985/dectin-2-is-a-primary-receptor-for-nlrp3-inflammasome-activation-in-dendritic-cell-response-to-histoplasma-capsulatum
#10
Tzu-Hsuan Chang, Juin-Hua Huang, Hsiu-Chao Lin, Wen-Yu Chen, Yu-Hsiang Lee, Li-Chung Hsu, Mihai G Netea, Jenny P-Y Ting, Betty A Wu-Hsieh
Inflammasome is an intracellular protein complex that serves as cytosolic pattern recognition receptor (PRR) to engage with pathogens and to process cytokines of the interleukin-1 (IL-1) family into bioactive molecules. It has been established that interleukin-1β (IL-1β) is important to host defense against Histoplasma capsulatum infection. However, the detailed mechanism of how H. capsulatum induces inflammasome activation leading to IL-1β production has not been studied. Here, we showed in dendritic cells (DCs) that H...
July 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28663280/megakaryocytic-smad4-regulates-platelet-function-through-syk-and-rock2-expression
#11
Yanhua Wang, Lirong Jiang, Xi Mo, Yu Lan, Xiao Yang, Xinyi Liu, Jian Zhang, Li Zhu, Junling Liu, Xiaolin Wu
Smad4, a key transcription factor in the TGF-β signaling pathway, is involved in a variety of cell physiological and pathological processes. Here, we characterized megakaryocyte/platelet-specific Smad4 deficiency in mice to elucidate its effect on platelet function. We found that megakaryocyte/platelet-specific loss of Smad4 caused mild thrombocytopenia and significantly extended first occlusion time and tail bleeding time in mice. Smad4-deficient platelets showed reduced agonist-induced platelet aggregation...
June 29, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28661042/cd11b-promotes-the-differentiation-of-osteoclasts-induced-by-rankl-through-the-spleen-tyrosine-kinase-signalling-pathway
#12
Guoxi Yang, Xiaoyong Chen, Zhao Yan, Qingsheng Zhu, Chongfei Yang
Macrophage surface antigen-1 (Mac-1, CD11b/CD18) has been implicated in the regulation of osteoclastogenesis. In the synovial tissues of patients with aseptic loosening after total hip replacement, CD11b was up-regulated, which indicated that CD11b is closely involved in osteolysis around the prosthesis. We found that CD11b, but not CD18, promoted osteoclast (OC) maturation. Here, we show CD11b up-regulated the levels of spleen tyrosine kinase (Syk), c-Fos and nuclear factor of activated T cells, cytoplasmic-1 (NFATc1), as well as the activity of extracellular-regulated kinase (Erk), and as a result, osteoclast precursors (OCPs) differentiated and became tartrate-resistant acid phosphatase (TRAP)-positive...
June 29, 2017: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/28650106/dok3-modulates-bone-remodeling-by-negatively-regulating-osteoclastogenesis-and-positively-regulating-osteoblastogenesis
#13
Xiaofeng Cai, Junjie Xing, Courtney L Long, Qisheng Peng, Mary Beth Humphrey
Osteoclastogenesis is essential for bone remodeling and normal skeletal maintenance. RANKL promotes osteoclast differentiation and function but requires costimulation of immunoreceptor tyrosine-based activation motif (ITAM)-coupled immunoreceptors. Triggering receptor expressed on myeloid cells-2 (TREM2) coupled to ITAM-adaptor protein DNAX activation protein 12kDA (DAP12) provides costimulation of intracellular calcium signaling during osteoclastogenesis. Previously, we found that downstream of kinase-3 (DOK3) physically associates with DAP12 to inhibit toll-like receptor (TLR)-induced inflammatory signaling in macrophages...
June 26, 2017: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
https://www.readbyqxmd.com/read/28646116/tonic-b-cell-receptor-signaling-in-diffuse-large-b-cell-lymphoma
#14
Ondrej Havranek, Jingda Xu, Stefan Köhrer, Zhiqiang Wang, Lisa Becker, Justin M Comer, Jared Henderson, Wencai Ma, John Man Chun Ma, Jason R Westin, Dipanjan Ghosh, Nicholas Shinners, Luhong Sun, Allen F Yi, Anusha R Karri, Jan A Burger, Tomasz Zal, R Eric Davis
We used CRISPR/Cas9-mediated genomic modification to investigate B-cell receptor (BCR) signaling in cell lines of diffuse large B-cell lymphoma (DLBCL). Three manipulations that altered BCR genes without affecting surface BCR levels showed that BCR signaling differs between the germinal center B-cell (GCB) subtype, which is insensitive to BTK inhibition by ibrutinib, and the activated B-cell (ABC) subtype. Replacing antigen-binding BCR regions had no effect on BCR signaling in GCB-DLBCL lines, reflecting this subtype's exclusive use of tonic BCR signaling...
June 23, 2017: Blood
https://www.readbyqxmd.com/read/28644734/high-throughput-phenotypic-screening-of-kinase-inhibitors-to-identify-drug-targets-for-polycystic-kidney-disease
#15
Tijmen H Booij, Hester Bange, Wouter N Leonhard, Kuan Yan, Michiel Fokkelman, Steven J Kunnen, Johannes G Dauwerse, Yu Qin, Bob van de Water, Gerard J P van Westen, Dorien J M Peters, Leo S Price
Polycystic kidney disease (PKD) is a prevalent disorder characterized by renal cysts that lead to kidney failure. Various signaling pathways have been targeted to stop disease progression, but most interventions still focus on alleviating PKD-associated symptoms. The mechanistic complexity of the disease, as well as the lack of functional in vitro assays for compound testing, has made drug discovery for PKD challenging. To identify modulators of PKD, Pkd1(-/-) kidney tubule epithelial cells were applied to a scalable and automated 3D cyst culture model for compound screening, followed by phenotypic profiling to determine compound efficacy...
June 1, 2017: SLAS Discovery
https://www.readbyqxmd.com/read/28634183/syk-inhibitors-interfere-with-erythrocyte-membrane-modification-during-p-falciparum-growth-and-suppress-parasite-egress
#16
Antonella Pantaleo, Kristina R Kesely, Maria Carmina Pau, Ioannis Tsamesidis, Evelin Schwarzer, Oleksii A Skorokhod, Huynh D Chien, Marta Ponzi, Lucia Bertuccini, Philip S Low, Francesco M Turrini
Band 3 (a.k.a. the anion exchanger, SLCA1, AE1) constitutes the major attachment site of the spectrin-based cytoskeleton to the erythrocyte's lipid bilayer and thereby contributes critically to the stability of the red cell membrane. During the intra-erythrocytic stage of Plasmodium falciparum's life cycle, band 3 becomes tyrosine phosphorylated in response to oxidative stress, leading to a decrease in its affinity for the spectrin/actin cytoskeleton and causing global membrane destabilization. Because this membrane weakening is hypothesized to facilitate parasite egress and the consequent dissemination of released merozoites throughout the bloodstream, we decided to explore which tyrosine kinase inhibitors might block the kinase-induced membrane destabilization...
June 20, 2017: Blood
https://www.readbyqxmd.com/read/28624575/intestinal-fungal-dysbiosis-associates-with-visceral-hypersensitivity-in-patients-with-irritable-bowel-syndrome-and-rats
#17
Sara Botschuijver, Guus Roeselers, Evgeni Levin, Daisy M Jonkers, Olaf Welting, Sigrid Em Heinsbroek, Heleen H de Weerd, Teun Boekhout, Matteo Fornai, Ad A Masclee, Frank H J Schuren, Wouter J de Jonge, Jurgen Seppen, Rene M van den Wijngaard
BACKGROUND & AIMS: Visceral hypersensitivity is one feature of irritable bowel syndrome (IBS). Bacterial dysbiosis might be involved in activation of nociceptive sensory pathways, but there have been few studies of the role of the mycobiome (the fungal microbiome) in development of IBS. We analyzed intestinal mycobiomes of patients with IBS and a rat model of visceral hypersensitivity. METHODS: We used internal transcribed spacer 1-based metabarcoding to compare fecal mycobiomes of 18 healthy volunteers with those of 39 patients with IBS (with visceral hypersensitivity or normal levels of sensitivity)...
June 14, 2017: Gastroenterology
https://www.readbyqxmd.com/read/28614370/the-hemagglutinin-neuramidinase-protein-of-newcastle-disease-virus-upregulates-expression-of-the-trail-gene-in-murine-natural-killer-cells-through-the-activation-of-syk-and-nf-%C3%AE%C2%BAb
#18
Ying Liang, De-Zhi Song, Shuang Liang, Zeng-Feng Zhang, Ling-Xi Gao, Xiao-Hui Fan
Newcastle disease virus (NDV) is responsible for tumoricidal activity in vitro and in vivo. However, the mechanisms that lead to this activity are unclear. Natural killer cells are able to induce apoptosis of tumor cells through multiple pathways, including the tumor necrosis factor-related apoptosis-inducing ligand-death receptor pathway. We previously showed that exposure of NK and T cells to NDV resulted in enhanced tumoricidal activity that was mediated by upregulated expression of the TRAIL gene, via an interferon gamma -dependent pathway...
2017: PloS One
https://www.readbyqxmd.com/read/28594748/inhibition-of-spleen-tyrosine-kinase-reduces-renal-allograft-injury-in-a-rat-model-of-acute-antibody-mediated-rejection-in-sensitized-recipients
#19
Sharmila Ramessur Chandran, Yingjie Han, Greg H Tesch, Julie Di Paolo, William R Mulley, John Kanellis, Frank Y Ma, David J Nikolic-Paterson
BACKGROUND: Organ transplantation into sensitized patients with preexisting donor-specific antibodies (DSA) is very challenging. Spleen tyrosine kinase (Syk) promotes leukocyte recruitment and activation via signalling through various cell surface receptors. We investigated whether a selective Syk inhibitor (GS-492429) could suppress antibody-mediated rejection (AMR) in a rat model of AMR in sensitized recipients. METHODS: Recipient Lewis rats (RT1) were immunized with donor (Dark Agouti, RT1) spleen cells (day -5)...
June 7, 2017: Transplantation
https://www.readbyqxmd.com/read/28536300/receptor-cooperation-in-b-cells
#20
John F Foley
TLR4-stimulated B cell activation is mediated by the tyrosine kinase Syk and depends on the B cell receptor.
May 23, 2017: Science Signaling
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