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https://www.readbyqxmd.com/read/29677469/multidomain-control-over-tec-kinase-activation-state-tunes-the-t-cell-response
#1
Amy H Andreotti, Raji E Joseph, James M Conley, Janet Iwasa, Leslie J Berg
Signaling through the T cell antigen receptor (TCR) activates a series of tyrosine kinases. Directly associated with the TCR, the SRC family kinase LCK and the SYK family kinase ZAP-70 are essential for all downstream responses to TCR stimulation. In contrast, the TEC family kinase ITK is not an obligate component of the TCR cascade. Instead, ITK functions as a tuning dial, to translate variations in TCR signal strength into differential programs of gene expression. Recent insights into TEC kinase structure have provided a view into the molecular mechanisms that generate different states of kinase activation...
April 26, 2018: Annual Review of Immunology
https://www.readbyqxmd.com/read/29675799/identification-of-the-protocatechuate-transporter-gene-in-sphingobium-sp-strain-syk-6-and-effects-of-overexpression-on-production-of-a-value-added-metabolite
#2
Kosuke Mori, Naofumi Kamimura, Eiji Masai
Sphingobium sp. strain SYK-6 expresses the best characterized catabolic systems for lignin-derived aromatic compounds. However, the uptake systems for these aromatics remain unknown. In this study, we identified and characterized the protocatechuate (PCA) transporter gene SLG_12880 (pcaK) in SYK-6. Sequence comparisons revealed that PcaK belongs to the aromatic acid/H+ symporter family of major facilitator superfamily transporters. Further, pcaK was highly conserved among Sphingomonadales possessing catabolic genes for vanillate and PCA...
April 19, 2018: Applied Microbiology and Biotechnology
https://www.readbyqxmd.com/read/29673901/the-role-of-syk-in-peripheral-t-cells
#3
Jeoung-Eun Park, Sirshendu Majumdar, David D Brand, Edward F Rosloniec, Ae-Kyung Yi, John M Stuart, Andrew H Kang, Linda K Myers
The aim of this study was to understand how Syk affects peripheral T cell function. T cells from Syk-/- chimeric mice and DR1 Sykfl/fl CD4cre conditional mice gave strong CD3-induced Th1, Th2, and Th17 cytokine responses. However, an altered peptide ligand (APL) of human CII (256-276) with two substitutions (F263N, E266D), also called A12, elicited only Th2 cytokine responses from Sykfl/fl T cells but not Sykfl/fl- CD4cre T cells. Western blots revealed a marked increase in the phosphorylation of Syk, JNK and p38 upon A12/DR1 activation in WT or Sykfl/fl T cells but not in Sykfl/fl CD4-cre cells...
April 16, 2018: Clinical Immunology: the Official Journal of the Clinical Immunology Society
https://www.readbyqxmd.com/read/29670076/cathelicidins-prime-platelets-to-mediate-arterial-thrombosis-and-tissue-inflammation
#4
Joachim Pircher, Thomas Czermak, Andreas Ehrlich, Clemens Eberle, Erik Gaitzsch, Andreas Margraf, Jochen Grommes, Prakash Saha, Anna Titova, Hellen Ishikawa-Ankerhold, Konstantin Stark, Tobias Petzold, Thomas Stocker, Ludwig T Weckbach, Julia Novotny, Markus Sperandio, Bernhard Nieswandt, Alberto Smith, Hanna Mannell, Barbara Walzog, David Horst, Oliver Soehnlein, Steffen Massberg, Christian Schulz
Leukocyte-released antimicrobial peptides contribute to pathogen elimination and activation of the immune system. Their role in thrombosis is incompletely understood. Here we show that the cathelicidin LL-37 is abundant in thrombi from patients with acute myocardial infarction. Its mouse homologue, CRAMP, is present in mouse arterial thrombi following vascular injury, and derives mainly from circulating neutrophils. Absence of hematopoietic CRAMP in bone marrow chimeric mice reduces platelet recruitment and thrombus formation...
April 18, 2018: Nature Communications
https://www.readbyqxmd.com/read/29669391/translational-biomarkers-and-ex-vivo-models-of-joint-tissues-as-a-tool-for-drug-development-in-rheumatoid-arthritis
#5
Cecilie F Kjelgaard-Petersen, Adam Platt, Martin Braddock, Martin A Jenkins, Kishwar Musa, Emma Graham, Thorbjørn Gantzel, Gillian Slynn, Michael E Weinblatt, Morten A Karsdal, Christian S Thudium, Anne-C Bay-Jensen
OBJECTIVE: Rheumatoid arthritis (RA) is a chronic, autoimmune and degenerative joint disease leading to disability, reduced life quality, and increased mortality. Although several synthetic and biological disease modifying anti-rheumatic drugs (DMARDs) are available, there is still a medical need for novel drugs controlling disease progression. As only 10% of RA drug candidates that enter phase I trials are eventually FDA registered, there is an immediate requirement for translational drug development tools to facilitate early drug development decision making...
April 18, 2018: Arthritis & Rheumatology
https://www.readbyqxmd.com/read/29669390/editorial-title-lessons-learned-from-a-failed-clinical-trial
#6
EDITORIAL
E F A Leijten, T R D J Radstake, K A Reedquist
Spleen tyrosine kinase (Syk), through its capacity to promote the pathogenic activation of B lymphocytes, myeloid cells, osteoclasts, and stromal fibroblast-like synoviocytes, has been subject to intense translational and clinical scrutiny as a potential therapeutic target in rheumatoid arthritis (RA) (1). Initial phase II clinical trials with the Syk inhibitor fostamatinib showed promising effectivity in treating RA patients that had displayed inadequate responses to methotrexate (2,3). However, concerns were raised of drug-dependent adverse effects in these studies, and fostamatinib did not improve disease in RA patients failing other biologic agents (4)...
April 18, 2018: Arthritis & Rheumatology
https://www.readbyqxmd.com/read/29669173/second-generation-syk-inhibitor-entospletinib-ameliorates-fully-established-inflammation-and-bone-destruction-in-the-cherubism-mouse-model
#7
Tetsuya Yoshimoto, Tatsuhide Hayashi, Toshio Kondo, Mizuho Kittaka, Ernst J Reichenberger, Yasuyoshi Ueki
Cherubism is a craniofacial disorder characterized by maxillary and mandibular bone destruction. Gain-of-function mutations in the SH3-domain binding protein 2 (SH3BP2) are responsible for the excessive bone resorption caused by fibrous inflammatory lesions. A homozygous knock-in (KI) mouse model for cherubism (Sh3bp2KI/KI ) develops autoinflammation resulting in systemic bone destruction. While administration of the TNF-α blocker etanercept to neonatal Sh3bp2KI/KI mice prevented the disease onset, this therapy was not effective for adult Sh3bp2KI/KI mice or human cherubism patients who already had lesions...
April 18, 2018: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
https://www.readbyqxmd.com/read/29668708/dectin-1-2-induced-autocrine-pge2-signaling-licenses-dendritic-cells-to-prime-th2-responses
#8
Maria M M Kaisar, Manuel Ritter, Carlos Del Fresno, Hulda S Jónasdóttir, Alwin J van der Ham, Leonard R Pelgrom, Gabriele Schramm, Laura E Layland, David Sancho, Clarissa Prazeres da Costa, Martin Giera, Maria Yazdanbakhsh, Bart Everts
The molecular mechanisms through which dendritic cells (DCs) prime T helper 2 (Th2) responses, including those elicited by parasitic helminths, remain incompletely understood. Here, we report that soluble egg antigen (SEA) from Schistosoma mansoni, which is well known to drive potent Th2 responses, triggers DCs to produce prostaglandin E2 (PGE2), which subsequently-in an autocrine manner-induces OX40 ligand (OX40L) expression to license these DCs to drive Th2 responses. Mechanistically, SEA was found to promote PGE2 synthesis through Dectin-1 and Dectin-2, and via a downstream signaling cascade involving spleen tyrosine kinase (Syk), extracellular signal-regulated kinase (ERK), cytosolic phospholipase A2 (cPLA2), and cyclooxygenase 1 and 2 (COX-1 and COX-2)...
April 18, 2018: PLoS Biology
https://www.readbyqxmd.com/read/29666621/the-role-of-aire-in-the-immunity-against-candida-albicans-in-a-model-of-human-macrophages
#9
Jose Antonio Tavares de Albuquerque, Pinaki Prosad Banerjee, Angela Castoldi, Royce Ma, Nuria Bengala Zurro, Leandro Hideki Ynoue, Christina Arslanian, Marina Uchoa Wall Barbosa-Carvalho, Joya Emilie de Menezes Correia-Deur, Fernanda Guimarães Weiler, Magnus Regios Dias-da-Silva, Marise Lazaretti-Castro, Luis Alberto Pedroza, Niels Olsen Saraiva Câmara, Emily Mace, Jordan Scott Orange, Antonio Condino-Neto
Autoimmune-polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a primary immunodeficiency caused by mutations in the autoimmune regulator gene ( AIRE ). Patients with AIRE mutations are susceptible to Candida albicans infection and present with autoimmune disorders. We previously demonstrated that cytoplasmic AIRE regulates the Syk-dependent Dectin-1 pathway. In this study, we further evaluated direct contact with fungal elements, synapse formation, and the response of macrophage-like THP-1 cells to C...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29662845/suppressive-effects-of-vaccinium-angustifolium-root-extract-via-down-regulation-of-activation-of-syk-lyn-and-nf-%C3%AE%C2%BAb-in-fc%C3%A9-ri-mediated-allergic-reactions
#10
Sun-Yup Shim
Vaccinium angustifolium , reported as the lowbush blueberry, has a rich polyphenolic content with which biological activities have been closely associated. In this study, the effects of V. angustifolium root extract (VAE) on the anti-FcɛRI α chain antibody (CRA-1)-induced FcɛRI-mediated signaling factors, protein tyrosine kinases (PTK), Lyn, Syk, and nuclear factor kappa-B cells (NF-κB) in KU812F cells were investigated. The total phenolic content of VAE was found to be 170±1.9 mg gallic acid equivalents/g...
March 2018: Preventive Nutrition and Food Science
https://www.readbyqxmd.com/read/29658701/functional-annotation-of-ligu-as-a-1-3-allylic-isomerase-during-the-degradation-of-lignin-in-the-protocatechuate-4-5-cleavage-pathway-from-the-soil-bacterium-sphingobium-sp-syk-6
#11
Tessily N Hogancamp, Frank M Raushel
Sphingobium sp. SYK-6 is a Gram-negative soil bacterium that contributes to the degradation of lignin. Lignin provides structural support and protection to plants as a complex aromatic heteropolymer. The lignin degradation pathway of guaiacyl moieties leads to the intermediate, protocatechuate (PCA), which is further degraded via the 4,5-cleavage pathway where PCA is ultimately metabolized to pyruvate and oxaloacetate. In this pathway, LigI has been shown to catalyze the hydrolysis of 2-pyrone-4,6-dicarboxylate (PDC) to (4E)-oxalomesaconate (OMA)...
April 16, 2018: Biochemistry
https://www.readbyqxmd.com/read/29643476/inhibition-of-ovarian-tumor-cell-invasiveness-by-targeting-syk-in-the-tyrosine-kinase-signaling-pathway
#12
Yu Yu, Yohan Suryo Rahmanto, Meng-Horng Lee, Pei-Hsun Wu, Jude M Phillip, Chuan-Hsiang Huang, Michele I Vitolo, Stephanie Gaillard, Stuart S Martin, Denis Wirtz, Ie-Ming Shih, Tian-Li Wang
Cell motility and invasiveness are prerequisites for dissemination, and largely account for cancer mortality. We have identified an actionable kinase, spleen tyrosine kinase (SYK), which is keenly tightly associated with tumor progression in ovarian cancer. Here, we report that active recombinant SYK directly phosphorylates cortactin and cofilin, which are critically involved in assembly and dynamics of actin filament through phosphorylation signaling. Enhancing SYK activity by inducing expression of a constitutively active SYK mutant, SYK130E , increased growth factor-stimulated migration and invasion of ovarian cancer cells, which was abrogated by cortactin knockdown...
April 11, 2018: Oncogene
https://www.readbyqxmd.com/read/29629899/ask1-2-signaling-promotes-inflammation-in-a-mouse-model-of-neutrophilic-dermatosis
#13
Sarang Tartey, Prajwal Gurung, Tejasvi Krishna Dasari, Amanda Burton, Thirumala-Devi Kanneganti
Mice homozygous for the Tyr208Asn amino acid substitution in the carboxy terminus of Src homology region 2 (SH2) domain-containing phosphatase 1 (SHP-1) (referred to as Ptpn6spin mice) spontaneously develop a severe inflammatory disease resembling neutrophilic dermatosis in humans. Disease in Ptpn6spin mice is characterized by persistent footpad swelling and suppurative inflammation. Recently, in addition to IL-1α and IL-1R signaling, we demonstrated a pivotal role for several kinases such as SYK, RIPK1, and TAK1 in promoting inflammatory disease in Ptpn6spin mice...
April 9, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29625466/narrow-spectrum-kinase-inhibitors-demonstrate-promise-for-the-treatment-of-dry-eye-disease-and-other-ocular-inflammatory-disorders
#14
Suzanne Hagan, Matthew C T Fyfe, Boatemaa Ofori-Frimpong, Katherine Oliver, Martyn R Foster, Sameer Sirohi, Yemisi Solanke, Michael Doughty, Adele Rowley, Mike Taylor, Steve Webber, Claire A Walshe
Purpose: The purpose of this study is to determine the potential of narrow spectrum kinase inhibitors (NSKIs) to treat inflammatory eye disorders. Methods: Human conjunctival epithelial (HCE) cells were retrieved from subjects via impression cytology. Real-time quantitative PCR (qPCR) was performed on HCE cells to determine gene expression of NSKI kinase targets and proinflammatory cytokines in dry eye disease (DED) patients versus healthy controls. qPCR also assessed p38α expression in hyperosmolar-treated Chang conjunctival epithelial cells...
March 1, 2018: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/29623489/bi1-is-associated-with-microvascular-protection-in-cardiac-ischemia-reperfusion-injury-via-repressing-syk-nox2-drp1-mitochondrial-fission-pathways
#15
Hao Zhou, Chen Shi, Shunying Hu, Hong Zhu, Jun Ren, Yundai Chen
BACKGROUND: Mitochondrial fission has been identified as the pathogenesis underlying the development of cardiac microvascular ischemia reperfusion (IR) injury, although the regulatory signaling upstream from fission is far from clear. Bax inhibitor is a novel anti-apoptotic factor, and, however, its role of cardiac microvascular IR injury and mitochondrial homeostasis remains unclear. METHODS: The cardiac microvascular IR injury was performed in WT mice and BI1 transgenic (BITG ) mice...
April 6, 2018: Angiogenesis
https://www.readbyqxmd.com/read/29618939/-syk-expression-level-distinguishes-control-from-brca1-mutated-lymphocytes
#16
Tamar Zahavi, Amir Sonnenblick, Yael Shimshon, Luna Kadouri, Tamar Peretz, Asher Y Salmon, Mali Salmon-Divon
Background: About 5%-10% of breast cancer and 10%-15% of ovarian cancer are hereditary. BRCA1 and BRCA2 are the most common germline mutations found in both inherited breast and ovarian cancers. Once these mutations are identified and classified, a course of action to reduce the risk of developing either ovarian or breast cancer - including surveillance and surgery - is carried out. Purpose: The purpose of the current research is to characterize the gene expression differences between healthy cells harboring a mutation in BRCA1 /2 genes and normal cells...
2018: Cancer Management and Research
https://www.readbyqxmd.com/read/29616043/lineage-specific-analysis-of-syk-function-in-autoantibody-induced-arthritis
#17
Tamás Németh, Krisztina Futosi, Kata Szilveszter, Olivér Vilinovszki, Levente Kiss-Pápai, Attila Mócsai
Autoantibody production and autoantibody-mediated inflammation are hallmarks of a number of autoimmune diseases. The K/BxN serum-transfer arthritis is one of the most widely used models of the effector phase of autoantibody-induced pathology. Several hematopoietic lineages including neutrophils, platelets, and mast cells have been proposed to contribute to inflammation and tissue damage in this model. We have previously shown that the Syk tyrosine kinase is critically involved in the development in K/BxN serum-transfer arthritis and bone marrow chimeric experiments indicated that Syk is likely involved in one or more hematopoietic lineages during the disease course...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29616021/adaptive-reconfiguration-of-natural-killer-cells-in-hiv-1-infection
#18
Dimitra Peppa, Isabela Pedroza-Pacheco, Pierre Pellegrino, Ian Williams, Mala K Maini, Persephone Borrow
Human cytomegalovirus (HCMV) co-infection is highly prevalent within HIV-1 cohorts and is an important cofactor in driving ongoing immune activation, even during effective antiretroviral treatment. HCMV infection has recently been associated with expansion of adaptive-like natural killer (NK) cells, which harbor epigenetic alterations that impact on their cellular function and phenotype. The influence of HCMV co-infection on the considerable heterogeneity among NK cells and their functional responses to different stimuli was assessed in a cohort of HIV-1-infected individuals sampled during different stages of infection, compared with healthy subjects stratified according to HCMV serostatus...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29616019/the-syk-coupled-c-type-lectin-receptors-dectin-2-and-dectin-3-are-involved-in-paracoccidioides-brasiliensis-recognition-by-human-plasmacytoid-dendritic-cells
#19
Nycolas Willian Preite, Claudia Feriotti, Dhêmerson Souza de Lima, Bruno Borges da Silva, Antônio Condino-Neto, Alessandra Pontillo, Vera Lúcia Garcia Calich, Flávio Vieira Loures
Plasmacytoid dendritic cells (pDCs), which have been extensively studied in the context of the immune response to viruses, have recently been implicated in host defense mechanisms against fungal infections. Nevertheless, the involvement of human pDCs during paracoccidioidomycosis (PCM), a fungal infection endemic to Latin America, has been scarcely studied. However, pDCs were found in the cutaneous lesions of PCM patients, and in pulmonary model of murine PCM these cells were shown to control disease severity...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29611449/splenic-tyrosine-kinase-syk-inhibitors-and-their-possible-use-in-acute-myeloid-leukemia
#20
Sushma Bartaula-Brevik, Marte Karen Lindstad Brattås, Tor Henrik Anderson Tvedt, Håkon Reikvam, Øystein Bruserud
Splenic tyrosine kinase (SYK) is a non-receptor tyrosine kinase. It is important for downstream signaling from several cell surface receptors, including Fc receptors, complement receptors and integrins. SYK can have either oncogenic or tumor suppressor activity in human malignancies. Recent studies suggest that SYK inhibition may have an antileukemic effect in human acute myeloid leukemia (AML). Areas covered: Relevant publications were identified through literature searches in the PubMed database. We searched for (i) original articles describing the results from clinical studies of SYK inhibition; (ii) published articles describing the importance of SYK in human malignancies, especially AML...
April 4, 2018: Expert Opinion on Investigational Drugs
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