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https://www.readbyqxmd.com/read/28771705/selected-signalling-proteins-recruited-to-the-t-cell-receptor-cd3-complex
#1
REVIEW
Jatuporn Ngoenkam, Wolfgang Schamel, Sutatip Pongcharoen
The T cell receptor (TCR)-CD3 complex, expressed on T cells, determines the outcome of a T cell response. It consists of the TCRαβ heterodimer and the non-covalently associated signalling dimers of CD3εγ, CD3εδ and CD3ζζ. TCRαβ binds specifically to a cognate peptide antigen bound to a major histocompatibility complex (MHC) molecule, whereas the CD3 subunits transmit the signal into the cytosol to activate signalling events. Recruitment of proteins to specialized localizations is one mechanism to regulate activation and termination of signalling...
August 3, 2017: Immunology
https://www.readbyqxmd.com/read/28768156/the-syk-kinases-orchestrate-cerebellar-granule-cell-tangential-migration
#2
Aurélien Benon, Choua Ya, Laurent Martin, Chantal Watrin, Naura Chounlamountri, Iness Jaaoini, Jérôme Honnorat, Véronique Pellier-Monnin, Nelly Noraz
The tyrosine kinases of the Syk family are essential components of the well-characterized immunoreceptor ITAM-based signaling pathway. However, ITAM-based signaling typically does not function in isolation. Instead, it is enmeshed in the molecular network controlling cellular adhesion and chemotaxis. Consistent with the increasing number of data involving ITAM-bearing molecules in neuronal functions, we previously depicted a role for Syk kinases in the establishment of neuronal connectivity. In the developing cerebellum, we found that Syk is essentially expressed in the granule cells (GC) and more importantly, phosphorylated on tyrosine residues representative of an active form of the kinase in tangentially migrating GC...
July 30, 2017: Neuroscience
https://www.readbyqxmd.com/read/28767218/selective-binders-of-the-tandem-sh2-domains-in-syk-and-zap-70-kinases-by-dna-programmed-spatial-screening
#3
Michaela Marczynke, Katharina Groeger, Oliver Seitz
Members of the Syk family of tyrosine kinases arrange Src homology 2 (SH2) domains in tandem to allow firm binding of immunoreceptor tyrosine-based interaction motifs (ITAMs). While the advantages provided by the bivalency enhanced interactions are evident, the impact on binding specificity is less clear. For example, the Spleen tyrosine kinase (Syk) and the Zeta-chain-associated protein kinase (ZAP-70) recognize the consensus sequence pYXXI/L(X)6-8 pYXXI/L with near identical nanomolar affinity. The non-discriminatory recognition on the one hand poses a specificity challenge for the design of sub-type selective protein binders and, on the other hand, raises the question as to how differential activation of Syk and ZAP-70 is ensured when both kinases are co-expressed...
August 2, 2017: Bioconjugate Chemistry
https://www.readbyqxmd.com/read/28759203/structural-and-functional-characterization-of-the-histidine-phosphatase-domains-of-human-sts-1-and-sts-2
#4
Weijie Zhou, Yue Yin, Alexandra S Weinheimer, Neena Kaur, Nick Carpino, Jarrod B French
The suppressor of T-cell signaling (Sts) proteins, Sts-1 and Sts-2, are homologous phosphatases that negatively regulate signaling pathways downstream of the T-cell receptor. Functional inactivation of Sts-1 and Sts-2 in a murine model leads to resistance to systemic infection by the opportunistic pathogen, C. albicans. This suggests that modulation of the host immune response by inhibiting Sts function may be a viable strategy to treat these deadly fungal pathogen infections. To better understand the molecular determinants of function and structure, we characterized the structure and steady-state kinetics of the histidine phosphatase domains of human Sts-1 (Sts-1HP) and Sts-2 (Sts-2HP)...
July 31, 2017: Biochemistry
https://www.readbyqxmd.com/read/28726646/the-prognostic-significance-of-combaind-expression-of-zap-70-and-cd38-in-chronic-lymphocytic-leukemia
#5
T Kirtava, T Vatsadze, E Azrmaiparashili, D Ghirdaladze
Our aim was to assess the inter links of the markers CD38 and ZAP-70 based on our materials, the attitude according to the disease stage, and to document which of them had leading meaning for prognosis and treatmend of the disease. In our study we have used flow cytometry for detection CD38 and ZAP-70+ markers expression. (58 patients to assessments their prognostic value in сhronic lymphocytic leukemia (CLL), Correlation to Rai stages and relationships between this markers and outcome of therapy). We divided all patients in two groups based on level of ZAP-70+ cell and CD38+cells,(I group-patients) ZAP-70+ cells <20% CD38+<30% and ZAP-70+ cells >20% and CD38>30%,(II group) becaus our in investigation shows, that ZAP -70+ is very importance independent prognoctic marker as why in ZAP-70+ cases when its number was <20%, patients had favorable prognosis - the big part of them (13(40...
June 2017: Georgian Medical News
https://www.readbyqxmd.com/read/28710251/role-for-zap-70-signaling-in-the-differential-effector-functions-of-rituximab-and-obinutuzumab-ga101-in-chronic-lymphocytic-leukemia-b-cells
#6
Sladjana Skopelja-Gardner, Jonathan D Jones, B JoNell Hamilton, Alexey V Danilov, William F C Rigby
Rituximab (RTX) has been the hallmark anti-CD20 mAb for the treatment of B cell neoplasms, including B cell chronic lymphocytic leukemia (B-CLL). Recently, a novel humanized anti-CD20 mAb obinutuzumab (GA101) has been implemented as first-line CLL therapy. Treatment of CLL patients with RTX is associated with CD20 loss via an FcγR-mediated process, trogocytosis. RTX-induced trogocytosis has been characterized as both the means of resistance to therapy, via loss of cell surface target proteins (antigenic modulation), as well as a process that alters B cell phenotype and function...
July 14, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28644030/a-plc-%C3%AE-1-feedback-pathway-regulates-lck-substrate-phosphorylation-at-the-t-cell-receptor-and-slp-76-complex
#7
Judson Belmont, Tao Gu, Ashley Mudd, Arthur R Salomon
Phospholipase C gamma 1 (PLC-γ1) occupies a critically important position in the T-cell signaling pathway. While its functions as a regulator of both Ca(2+) signaling and PKC-family kinases are well characterized, PLC-γ1's role in the regulation of early T-cell receptor signaling events is incompletely understood. Activation of the T-cell receptor leads to the formation of a signalosome complex between SLP-76, LAT, PLC-γ1, Itk, and Vav1. Recent studies have revealed the existence of both positive and negative feedback pathways from SLP-76 to the apical kinase in the pathway, Lck...
August 4, 2017: Journal of Proteome Research
https://www.readbyqxmd.com/read/28624782/g-csf-inhibits-lfa-1-mediated-cd4-t-cell-functions-by-inhibiting-lck-and-zap-70
#8
Shasha Zhao, Zhenyang Gu, Li Wang, Lixun Guan, Feiyan Wang, Nan Yang, Lan Luo, Zhe Gao, Yingwei Song, Lili Wang, Daihong Liu, Chunji Gao
In this study, we showed that G-CSF mobilization increased the frequency of T cells, specifically CD3+CD4+ T cells. G-CSF mobilization decreased the secretion of inflammatory cytokines of CD4+ T cells through the LFA-1/ICAM-1 signaling pathway, whereas it did not alter the TH1/TH2 ratio. We found that G-CSF mobilization inhibited LFA-1-mediated CD4+ T cell polarization and motility. In vitro, G-CSF stimulation also attenuated the polarization and adhesiveness of CD4+ T cells through the LFA-1/ICAM-1 interaction...
May 25, 2017: Oncotarget
https://www.readbyqxmd.com/read/28515365/ceramide-synthesis-regulates-t-cell-activity-and-gvhd-development
#9
M Hanief Sofi, Jessica Heinrichs, Mohammed Dany, Hung Nguyen, Min Dai, David Bastian, Steven Schutt, Yongxia Wu, Anusara Daenthanasanmak, Salih Gencer, Aleksandra Zivkovic, Zdzislaw Szulc, Holger Stark, Chen Liu, Ying-Jun Chang, Besim Ogretmen, Xue-Zhong Yu
Allogeneic hematopoietic cell transplantation (allo-HCT) is an effective immunotherapy for a variety of hematologic malignances, yet its efficacy is impeded by the development of graft-versus-host disease (GVHD). GVHD is characterized by activation, expansion, cytokine production, and migration of alloreactive donor T cells. Hence, strategies to limit GVHD are highly desirable. Ceramides are known to contribute to inflammation and autoimmunity. However, their involvement in T-cell responses to alloantigens is undefined...
May 18, 2017: JCI Insight
https://www.readbyqxmd.com/read/28424451/prognostic-impact-of-notch1-myd88-and-sf3b1-mutations-in-polish-population-of-chronic-lymphocytic-leukemia-patients
#10
Maciej Putowski, Marta Podgórniak, Marta Piróg, Joanna Knap, Joanna Zaleska, Joanna Purkot, Jacek Zawiślak, Ewelina Zakrzewska, Agnieszka Karczmarczyk, Paulina Własiuk, Edyta Subocz, Krzysztof Giannopoulos
INTRODUCTION    Currently available prognostic factors determining the course of chronic lymphocytic leukemia (CLL) are not fully efficient especially for newly diagnosed patients. Investigation of molecular changes may help to clarify the reasons of the heterogeneity of the disease. Apart from already confirmed TP53 mutations, novel lesions: NOTCH1, SF3B1 and MYD88 might represent biomarkers of clinical relevance.  OBJECTIVES    The aim was to evaluate mutational status of NOTCH1, MYD88 and SF3B1 and to compare results with confirmed prognostic factors: ZAP-70, CD38 and IGHV mutation...
April 20, 2017: Polish Archives of Internal Medicine
https://www.readbyqxmd.com/read/28395442/-pd-1-pd-l1-expression-and-its-implications-in-patients-with-chronic-lymphocytic-leukemia
#11
J H Li, N N Pang, Z H Zhang, R Zhang, G Chen, J H Qu
Objective: To observe the expression levels of PD-1/PD-L1 costimulatory molecules and explore the clinical significance in patients with chronic lymphocytic leukemia (CLL) . Methods: The expression of PD-1/PD-L1 in peripheral blood CD8(+) T cells, CD4(+)T cells, CD19(+)B, and dendrites cells (DC) was detected by flow cytometry in 57 CLL patients and 20 healthy controls. The correlations of PD-1/PD-L1 expression with disease stage, CD38 expression, ZAP-70 expression, chromosome karyotype abnormality and β(2)-MG expression were analyzed...
March 14, 2017: Zhonghua Xue Ye Xue za Zhi, Zhonghua Xueyexue Zazhi
https://www.readbyqxmd.com/read/28372509/fc%C3%AE-riib-expression-in-early-stage-chronic-lymphocytic-leukemia
#12
Rosa Bosch, Alba Mora, Eva Puy Vicente, Gerardo Ferrer, Sonia Jansà, Rajendra Damle, Sergey Gorlatov, Kanti Rai, Emili Montserrat, Josep Nomdedeu, Marta Pratcorona, Laura Blanco, Silvana Saavedra, Ana Garrido, Albert Esquirol, Irene Garcia, Miquel Granell, Rodrigo Martino, Julio Delgado, Jorge Sierra, Nicholas Chiorazzi, Carol Moreno
In normal B-cells, B-cell antigen receptor (BCR) signaling can be negatively regulated by the low-affinity receptor FcγRIIb (CD32b). To better understand the role of FcγRIIb in chronic lymphocytic leukemia (CLL), we correlated its expression on 155 samples from newly-diagnosed Binet A patients with clinical characteristics and outcome. FcγRIIb expression was similar in normal B-cells and leukemic cells, this being heterogenous among patients and within CLL clones. FcγRIIb expression did not correlate with well known prognostic markers [disease stage, serum beta-2 microglobulin (B2M), IGHV mutational status, expression of ZAP-70 and CD38, and cytogenetics] except for a weak concordance with CD49d...
November 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28337207/gastrointestinal-microbiome-dysbiosis-in-infant-mice-alters-peripheral-cd8-t-cell-receptor-signaling
#13
Gabriela Gonzalez-Perez, Esi S N Lamousé-Smith
We recently reported that maternal antibiotic treatment (MAT) of mice in the last days of pregnancy and during lactation dramatically alters the density and composition of the gastrointestinal microbiota of their infants. MAT infants also exhibited enhanced susceptibility to a systemic viral infection and altered adaptive immune cell activation phenotype and function. CD8(+) effector T cells from MAT infants consistently demonstrate an inability to sustain interferon gamma (IFN-γ) production in vivo following vaccinia virus infection and in vitro upon T cell receptor (TCR) stimulation...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28216435/morpholino-based-correction-of-hypomorphic-zap70-mutation-in-an-adult-with-combined-immunodeficiency
#14
Christina Gavino, Marija Landekic, Jibin Zeng, Ning Wu, Sungmi Jung, Ming-Chao Zhong, Alexis Cohen-Blanchet, Mélanie Langelier, Odile Neyret, Duncan Lejtenyi, Claudia Rochefort, Judith Cotton-Montpetit, Christine McCusker, Bruce Mazer, André Veillette, Donald C Vinh
No abstract text is available yet for this article.
May 2017: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/28209773/mannan-binding-lectin-a-serum-collectin-suppresses-t-cell-proliferation-via-direct-interaction-with-cell-surface-calreticulin-and-inhibition-of-proximal-t-cell-receptor-signaling
#15
Na Zhao, Jie Wu, Simin Xiong, Liyun Zhang, Xiao Lu, Shangliang Chen, Qifeng Wu, Hailan Wang, Ying Liu, Zhengliang Chen, Daming Zuo
Mannan binding lectin (MBL), initially reported to activate the complement pathway, is also known to be involved in the pathogenesis of autoimmune diseases. We report a thus far unknown function of MBL as a suppressor of T-cell activation. MBL markedly inhibited T-cell proliferation induced by anti-CD3 and anti-CD28 antibodies. Moreover, the presence of MBL during T-cell priming interfered with proximal T-cell receptor signaling by decreasing phosphorylation of Lck, ZAP-70, and LAT. MBL bound to T cells through interaction between the collagen-like region of MBL and calreticulin (CRT) expressed on the T-cell surface...
June 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28183684/prognosis-biomarkers-evaluation-in-chronic-lymphocytic-leukemia
#16
Lorena Caixeta Gomes, Fernanda Cristina Gontijo Evangelista, Lirlândia Pires de Sousa, Sergio Schusterschitz da Silva Araujo, Maria das Graças Carvalho, Adriano de Paula Sabino
OBJECTIVE/BACKGROUND: From clinical and biological points of view, chronic lymphocytic leukemia (CLL) is a heterogeneous disease characterized by a progressive accumulation of lymphocytes in the peripheral blood, bone marrow, and lymphoid organs. New prognostic markers in CLL may be useful to clinicians for predicting outcome and in clinical decision-making. The aim of this study was to evaluate the potential prognostic value of the apoptotic/survival-controlling proteins and protein tyrosine kinase ZAP-70 gene expression in CLL patients and control individuals, correlating such findings with patients' clinical data...
February 1, 2017: Hematology/oncology and Stem Cell Therapy
https://www.readbyqxmd.com/read/28164634/cd38-expression-and-variation-as-a-prognostic-factor-chronic-lymphocytic-leukemia
#17
Mesude Falay, Funda Ceran, Ahmet K Gunes, Simten Dagdas, Meltem Ayli, Gulsum Ozet
BACKGROUND: In this study, we aimed to determine a cutoff level for CD38 that would aid us in identifying chronic lymphocytic leukemia patients in need of early therapy and predicting patients at sufficiently low risk who would likely exhibit a rapid improvement; we also aimed to find out if CD38 expression would show variability during disease course and determine the extent of CD38 expression. METHODS: 124 patients were diagnosed with CLL. CD38 and ZAP-70 expression levels were measured with four color flowcytometry...
July 1, 2016: Clinical Laboratory
https://www.readbyqxmd.com/read/28100106/systemic-lupus-erythematosus-in-the-light-of-the-regulatory-effects-of-galectin-1-on-t-cell-function
#18
REVIEW
Á Hornung, É Monostori, L Kovács
Galectin-1 is an endogenous immunoregulatory lectin-type protein. Its most important effects are the inhibition of the differentiation and cytokine production of Th1 and Th17 cells, and the induction of apoptosis of activated T-cells. Galectin-1 has been identified as a key molecule in antitumor immune surveillance, and data are accumulating about the pathogenic role of its deficiency, and the beneficial effects of its administration in various autoimmune disease models. Initial animal and human studies strongly suggest deficiencies in both galectin-1 production and responsiveness in systemic lupus erythematosus (SLE) T-cells...
April 2017: Lupus
https://www.readbyqxmd.com/read/28046066/htlv-1-bzip-factor-enhances-t-cell-proliferation-by-impeding-the-suppressive-signaling-of-co-inhibitory-receptors
#19
Haruka Kinosada, Jun-Ichirou Yasunaga, Kazuya Shimura, Paola Miyazato, Chiho Onishi, Tomonori Iyoda, Kayo Inaba, Masao Matsuoka
Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia-lymphoma (ATL) and inflammatory diseases. To enhance cell-to-cell transmission of HTLV-1, the virus increases the number of infected cells in vivo. HTLV-1 bZIP factor (HBZ) is constitutively expressed in HTLV-1 infected cells and ATL cells and promotes T-cell proliferation. However, the detailed mechanism by which it does so remains unknown. Here, we show that HBZ enhances the proliferation of expressing T cells after stimulation via the T-cell receptor...
January 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28011996/the-kinase-inhibitors-r406-and-gs-9973-impair-t-cell-functions-and-macrophage-mediated-anti-tumor-activity-of-rituximab-in-chronic-lymphocytic-leukemia-patients
#20
Ana Colado, María Belén Almejún, Enrique Podaza, Denise Risnik, Carmen Stanganelli, Esteban Enrique Elías, Patricia Dos Santos, Irma Slavutsky, Horacio Fernández Grecco, María Cabrejo, Raimundo Fernando Bezares, Mirta Giordano, Romina Gamberale, Mercedes Borge
Small molecules targeting kinases involved in B cell receptor signaling are showing encouraging clinical activity in chronic lymphocytic leukemia (CLL) patients. Fostamatinib (R406) and entospletinib (GS-9973) are ATP-competitive inhibitors designed to target spleen tyrosine kinase (Syk) that have shown clinical activity with acceptable toxicity in trials with CLL patients. Preclinical studies with these inhibitors in CLL have focused on their effect in patient-derived leukemic B cells. In this work we show that clinically relevant doses of R406 and GS-9973 impaired the activation and proliferation of T cells from CLL patients...
April 2017: Cancer Immunology, Immunotherapy: CII
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