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https://www.readbyqxmd.com/read/29335257/staphylococcal-superantigens-use-lama2-as-a-coreceptor-to-activate-t-cells
#1
Zhigang Li, Joseph J Zeppa, Mark A Hancock, John K McCormick, Terence M Doherty, Geoffrey N Hendy, Joaquín Madrenas
Canonical Ag-dependent TCR signaling relies on activation of the src-family tyrosine kinase LCK. However, staphylococcal superantigens can trigger TCR signaling by activating an alternative pathway that is independent of LCK and utilizes a Gα11-containing G protein-coupled receptor (GPCR) leading to PLCβ activation. The molecules linking the superantigen to GPCR signaling are unknown. Using the ligand-receptor capture technology LRC-TriCEPS, we identified LAMA2, the α2 subunit of the extracellular matrix protein laminin, as the coreceptor for staphylococcal superantigens...
January 15, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29325713/the-interaction-of-tak1-and-tab1-enhances-lps-induced-cytokine-release-via-modulating-nf-%C3%AE%C2%BAb-activation-larimichthys-crocea
#2
Shi-Yuan Bao, Qing-Xue Sun, Cui-Luan Yao
Transforming growth factor-β-activating kinase 1 (TAK1) is triggered by foreign pathogenic infection and involves in proinflammatory response through the activation of nuclear factor-κB (NF-κB), which is specifically regulated by TAK1-binding protein 1 (TAB1). However, the expression and regulatory characterizations of TAK1 and TAB1 in fish immune response remain largely unknown. In the present study, the cDNA sequences of TAK1 (LcTAK1) and TAB1 (LcTAB1) were identified from large yellow croaker, Larimichthys crocea...
January 8, 2018: Fish & Shellfish Immunology
https://www.readbyqxmd.com/read/29248956/human-c-src-kinase-csk-overexpression-makes-t-cells-dummy
#3
Else Marit Inderberg, Nadia Mensali, Morten P Oksvold, Lars-Egil Fallang, Anne Fåne, Gjertrud Skorstad, Grethe-Elisabeth Stenvik, Cinzia Progida, Oddmund Bakke, Gunnar Kvalheim, June H Myklebust, Sébastien Wälchli
Adoptive cell therapy with T-cell receptor (TCR)-engineered T cells represents a powerful method to redirect the immune system against tumours. However, although TCR recognition is restricted to a specific peptide-MHC (pMHC) complex, increasing numbers of reports have shown cross-reactivity and off-target effects with severe consequences for the patients. This demands further development of strategies to validate TCR safety prior to clinical use. We reasoned that the desired TCR signalling depends on correct pMHC recognition on the outside and a restricted clustering on the inside of the cell...
December 16, 2017: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/29196709/lck-is-a-relevant-target-in-chronic-lymphocytic-leukaemia-cells-whose-expression-variance-is-unrelated-to-disease-outcome
#4
Kathleen J Till, John C Allen, Fatima Talab, Ke Lin, David Allsup, Lynn Cawkwell, Alison Bentley, Ingo Ringshausen, Andrew D Duckworth, Andrew R Pettitt, Nagesh Kalakonda, Joseph R Slupsky
Pathogenesis of chronic lymphocytic leukaemia (CLL) is contingent upon antigen receptor (BCR) expressed by malignant cells of this disease. Studies on somatic hypermutation of the antigen binding region, receptor expression levels and signal capacity have all linked BCR on CLL cells to disease prognosis. Our previous work showed that the src-family kinase Lck is a targetable mediator of BCR signalling in CLL cells, and that variance in Lck expression associated with ability of BCR to induce signal upon engagement...
December 1, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29187853/fine-tuning-of-optimal-tcr-signaling-in-tumor-redirected-cd8-t-cells-by-distinct-tcr-affinity-mediated-mechanisms
#5
Danilo Presotto, Efe Erdes, Minh Ngoc Duong, Mathilde Allard, Pierre-Olivier Regamey, Manfredo Quadroni, Marie-Agnès Doucey, Nathalie Rufer, Michael Hebeisen
Redirecting CD8 T cell immunity with self/tumor-specific affinity-matured T cell receptors (TCRs) is a promising approach for clinical adoptive T cell therapy, with the aim to improve treatment efficacy. Despite numerous functional-based studies, little is known about the characteristics of TCR signaling (i.e., intensity, duration, and amplification) and the regulatory mechanisms underlying optimal therapeutic T cell responses. Using a panel of human SUP-T1 and primary CD8 T cells engineered with incremental affinity TCRs against the cancer-testis antigen NY-ESO-1, we found that upon activation, T cells with optimal-affinity TCRs generated intense and sustained proximal (CD3ζ, LCK) signals associated with distal (ERK1/2) amplification-gain and increased function...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/29175418/src-family-kinase-tyrosine-phosphorylates-toll-like-receptor-4-to-dissociate-myd88-and-mal-tirap-suppressing-lps-induced-inflammatory-responses
#6
Jonathon Mitchell, Su Jin Kim, Alexandra Seelmann, Brendan Veit, Brooke Shepard, Eunok Im, Sang Hoon Rhee
Src family kinases (SFKs) are a family of protein tyrosine kinases containing nine members: Src, Lyn, Fgr, Hck, Lck, Fyn, Blk, Yes, and Ylk. Although SFK activation is a major immediate signaling event in LPS/Toll-like receptor 4 (TLR4) signaling, its precise role has remained elusive due to various contradictory results obtained from a certain SFK member-deficient mice or cells. The observed inconsistencies may be due to the compensation or redundancy by other SFKs upon a SFK deficiency. The chemical rescuing approach was suggested to induce temporal and precise SFK activation in living cells, thereby limiting the chance of cellular adaption to a SFK-deficient condition...
November 23, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/29107425/novel-lck-fms-inhibitors-based-on-phenoxypyrimidine-scaffold-as-potential-treatment-for-inflammatory-disorders
#7
Ahmed Karam Farag, Ahmed Elkamhawy, Ashwini M Londhe, Kyung-Tae Lee, Ae Nim Pae, Eun Joo Roh
Tyrosine kinases including LCK and FMS are involved in inflammatory disorders as well as many types of cancer. Our team has designed and synthesized thirty novel pyrimidine based inhibitors targeting LCK, classified into four different series (amides, ureas, imines (Schiff base) and benzylamines). Twelve of them showed nanomolar IC50 values. Compound 7g showed excellent selectivity profile and was selectively potent over FMS kinase (IC50 value of 4.6 nM). Molecular docking study was performed to help us rationalize the obtained results and predict the possible binding mode for our compounds in both LCK and FMS...
December 1, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29101238/glucocorticoid-resistance-is-reverted-by-lck-inhibition-in-pediatric-t-cell-acute-lymphoblastic-leukemia
#8
Valentina Serafin, Giorgia Capuzzo, Gloria Milani, Sonia Anna Minuzzo, Marica Pinazza, Roberta Bortolozzi, Silvia Bresolin, Elena Porcù, Chiara Frasson, Stefano Indraccolo, Giuseppe Basso, Benedetta Accordi
Pediatric T-acute lymphoblastic leukemia (T-ALL) patients often display resistance to glucocorticoid (GC) treatment. These patients, classified as Prednisone Poor Responders (PPR), have poorer outcome compared to the other pediatric T-ALL patients receiving a high-risk adapted therapy. Since glucocorticoids are administered to ALL patients during all the different phases of therapy, GC resistance represents an important challenge to be addressed in order to improve the outcome for these patients. Mechanisms underlying resistance are not yet fully unraveled, thus our research focused on the identification of deregulated signaling pathways to point out new targeted approaches...
November 3, 2017: Blood
https://www.readbyqxmd.com/read/29099628/murine-cd8-invariant-natural-killer-t-cells-are-negatively-selected-by-cd1d-expressed-on-thymic-epithelial-cells-and-dendritic-cells
#9
Sejin Oh, Hyunji Lee, Jung Hoon Shin, Changwan Hong, Se-Ho Park
BACKGROUND: CD1d-dependent invariant natural killer (iNKT) cells are found as either CD4 single positive (SP) or CD4/CD8 double negative (DN) cells in mice. The size of the CD8(+) iNKT population is extremely small. It is known that CD1d expression on developing thymocytes is sufficient for iNKT development and co-receptor choice, which is driven by Th-POK expression. This study aimed to examine the factors involved in the CD4/CD8 co-receptor choice of iNKT cells in addition to Th-POK-driven silencing of CD8 expression...
November 3, 2017: Immunological Investigations
https://www.readbyqxmd.com/read/29083415/encoding-optical-control-in-lck-kinase-to-quantitatively-investigate-its-activity-in-live-cells
#10
Ardiyanto Liaunardy-Jopeace, Ben L Murton, Mohan Mahesh, Jason W Chin, John R James
LCK is a tyrosine kinase that is essential for initiating T-cell antigen receptor (TCR) signaling. A complete understanding of LCK function is constrained by a paucity of methods to quantitatively study its function within live cells. To address this limitation, we generated LCK*, in which a key active-site lysine is replaced by a photocaged equivalent, using genetic code expansion. This strategy enabled fine temporal and spatial control over kinase activity, thus allowing us to quantify phosphorylation kinetics in situ using biochemical and imaging approaches...
October 30, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/29073235/src-family-kinases-negatively-regulate-nfat-signaling-in-resting-human-t-cells
#11
Alan Baer, Winston Colon-Moran, Jinhua Xiang, Jack T Stapleton, Nirjal Bhattarai
T cell signaling is required for activation of both natural and therapeutic T cells including chimeric antigen receptor (CAR) T cells. Identification of novel factors and pathways regulating T cell signaling may aid in development of effective T cell therapies. In resting human T cells, the majority of Src-family of tyrosine kinases (SFKs) are inactive due to phosphorylation of a conserved carboxy-terminal tyrosine residue. Recently, a pool of enzymatically active SFKs has been identified in resting T cells; however, the significance of these is incompletely understood...
2017: PloS One
https://www.readbyqxmd.com/read/29069290/potent-suppression-of-both-spontaneous-and-carcinogen-induced-colitis-associated-colorectal-cancer-in-mice-by-dietary-celastrol-supplementation
#12
Emily C Barker, Byung-Gyu Kim, Ji Hee Yoon, Gregory P Tochtrop, John J Letterio, Sung Hee Choi
Celastrol is an anti-inflammatory natural triterpenoid, isolated from the herb Tripterygium wilfordii or thunder god vine. Here we define mechanisms mediating anti-inflammatory activity of celastrol and demonstrate efficacy of a dietary celastrol supplement for chemoprevention of inflammation-driven carcinogenesis in mice. Dietary celastrol (31.25 ppm in rodent diet from 8 weeks to 25 weeks of age) is well tolerated and protects against LPS-induced acute inflammation in C57BL/6 mice, potently suppressing LPS-induction of inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2, Interleukin (IL)-6, and IL-1β...
October 21, 2017: Carcinogenesis
https://www.readbyqxmd.com/read/29062038/the-src-family-kinase-lck-cooperates-with-oncogenic-flt3-itd-in-cellular-transformation
#13
Alissa Marhäll, Julhash U Kazi, Lars Rönnstrand
The non-receptor tyrosine kinase LCK belongs to the SRC family of kinases. SRC family kinases are proto-oncogenes that have long been known to play key roles in cell proliferation, motility, morphology and survival. Here we show that LCK regulates the function of the type III receptor tyrosine kinase FLT3 in murine pro-B cells. We observed that expression of LCK significantly enhances the colony forming capacity of the constitutively active FLT3 mutant FLT3-ITD (internal tandem duplication). Furthermore, cells expressing LCK developed tumor earlier compared to cells transfected with empty control vector...
October 23, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29037808/application-of-titration-methods-for-measuring-the-contents-of-ammonium-nitrogen-and-volatile-fatty-acids-in-agricultural-biogas-plants
#14
Michał Piątek, Aleksander Lisowski, Barbara Lisowska
The aim of our research was to assess a relatively new method of estimating ammonium nitrogen concentration in anaerobic digestion of plant substrates. We analysed our own data, received from the anaerobic digestion of maize silage (PM), as well as data published by Purser et al. (2014) who measured energy crops and slurry (ECS), and food waste (FW). In our study, the process was monitored for VFA content that was determined by gas chromatography, and for the content of ammonium nitrogen determined using the HACH LANGE LCK 303 cuvette test...
October 14, 2017: Journal of Biotechnology
https://www.readbyqxmd.com/read/29022919/dcz3301-a-novel-cytotoxic-agent-inhibits-proliferation-in-diffuse-large-b-cell-lymphoma-via-the-stat3-pathway
#15
Xi Sun, Bo Li, Bingqian Xie, Zhijian Xu, Gaomei Chang, Yi Tao, Yong Zhang, Shuaikang Chang, Yingcong Wang, Dandan Yu, Yongsheng Xie, Tingye Li, Houcai Wang, Gege Chen, Liangning Hu, Jun Hou, Yiwen Zhang, Wenqin Xiao, Lu Gao, Jumei Shi, Weiliang Zhu
Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma in adults, characterized by a rapidly increasing painless mass. A novel compound, DCZ3301, was synthesized that exerted direct cytotoxicity against DLBCL cell lines. The effects of DCZ3301 on DLBCL cells in vitro and in vivo and the associated mechanisms were investigated. DCZ3301 inhibited the viability of DLBCL cell lines, even in the presence of protumorigenesis cytokines. Additionally, the compound induced apoptosis and cell cycle arrest at the G2/M phase by reducing mitochondrial membrane potential...
October 12, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28986735/no2-inhalation-enhances-asthma-susceptibility-in-a-rat-model
#16
Ming Han, Xiaotong Ji, Guangke Li, Nan Sang
Nitrogen dioxide (NO2) is a major air pollutant. Epidemiologic studies have found that NO2 exposure is associated with an increased risk of asthma. Nevertheless, the potential molecular mechanisms remain unclear. In this study, we investigated the effect of NO2 inhalation on the occurrence of allergic airway inflammation and its underlying mechanisms. Firstly, male Wistar rats were exposed to 2 and 5 mg/m(3) NO2 (28 days, 5 h/day). The results showed that NO2 exposure could induce pulmonary inflammatory response, mucus formation, and Th1/Th2 imbalance in the lung of normal rats, resulting in allergic asthma-like features...
October 7, 2017: Environmental Science and Pollution Research International
https://www.readbyqxmd.com/read/28970470/nfat2-is-a-critical-regulator-of-the-anergic-phenotype-in-chronic-lymphocytic-leukaemia
#17
Melanie Märklin, Jonas S Heitmann, Alexander R Fuchs, Felicia M Truckenmüller, Michael Gutknecht, Stefanie Bugl, Sebastian J Saur, Juliane Lazarus, Ursula Kohlhofer, Leticia Quintanilla-Martinez, Hans-Georg Rammensee, Helmut R Salih, Hans-Georg Kopp, Michael Haap, Andreas Kirschniak, Lothar Kanz, Anjana Rao, Stefan Wirths, Martin R Müller
Chronic lymphocytic leukaemia (CLL) is a clonal disorder of mature B cells. Most patients are characterised by an indolent disease course and an anergic phenotype of their leukaemia cells, which refers to a state of unresponsiveness to B cell receptor stimulation. Up to 10% of CLL patients transform from an indolent subtype to an aggressive form of B cell lymphoma over time (Richter´s syndrome) and show a significantly worse treatment outcome. Here we show that B cell-specific ablation of Nfat2 leads to the loss of the anergic phenotype culminating in a significantly compromised life expectancy and transformation to aggressive disease...
October 2, 2017: Nature Communications
https://www.readbyqxmd.com/read/28951199/a-t-cell-specific-knockout-reveals-an-important-role-for-protease-activated-receptor-2-in-lymphocyte-development
#18
Nidhish Francis, Alison L Every, Babatunde A Ayodele, Robert N Pike, Eleanor J Mackie, Charles N Pagel
Activation of protease-activated receptor-2 (PAR2) expressed by T cells has been linked to the bone loss associated with periodontitis. We generated PAR2 conditional-null mice and crossed these with mice expressing Cre recombinase under control of the Lck proximal promoter, to produce T cell-specific PAR2-null mice in order to further study the cellular mechanism involved in periodontitis. Here we report that efficient deletion of PAR2 in thymocytes isolated from T cell-specific PAR2-null mice resulted in thymic and splenic hypoplasia and a reduction in the cells of the cortex and a loss of distinction between the cortex and the medulla of the thymus...
September 22, 2017: International Journal of Biochemistry & Cell Biology
https://www.readbyqxmd.com/read/28945083/in-silico-identification-of-a-novel-hinge-binding-scaffold-for-kinase-inhibitor-discovery
#19
Yanli Wang, Yuze Sun, Ran Cao, Dan Liu, Yuting Xie, Li Li, Xiangbing Qi, Niu Huang
To explore novel kinase hinge-binding scaffolds, we carried out structure-based virtual screening against p38α MAPK as a model system. With the assistance of developed kinase-specific structural filters, we identify a novel lead compound that selectively inhibits a panel of kinases with threonine as the gatekeeper residue, including BTK and LCK. These kinases play important roles in lymphocyte activation, which encouraged us to design novel kinase inhibitors as drug candidates for ameliorating inflammatory diseases and cancers...
October 16, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28936799/proteomic-features-of-colorectal-cancer-identify-tumor-subtypes-independent-of-oncogenic-mutations-and-independently-predict-relapse-free-survival
#20
Callisia N Clarke, Michael S Lee, Wei Wei, Ganiraju Manyam, Zhi-Qin Jiang, Yiling Lu, Jeffrey Morris, Bradley Broom, David Menter, Eduardo Vilar-Sanchez, Kanwal Raghav, Cathy Eng, George J Chang, Iris Simon, Rene Bernards, Michael Overman, Gordon B Mills, Dipen Maru, Scott Kopetz
BACKGROUND: The directed study of the functional proteome in colorectal cancer (CRC) has identified critical protein markers and signaling pathways; however, the prognostic relevance of many of these proteins remains unclear. METHODS: We determined the prognostic implications of the functional proteome in 263 CRC tumor samples from patients treated at MD Anderson Cancer Center (MDACC) and 462 patients from The Cancer Genome Atlas (TCGA) to identify patterns of protein expression that drive tumorigenesis...
December 2017: Annals of Surgical Oncology
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