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ZAP-70

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https://www.readbyqxmd.com/read/29547119/fine-tuning-of-substrate-preferences-of-the-src-family-kinase-lck-revealed-through-a-high-throughput-specificity-screen
#1
Neel H Shah, Mark Löbel, Arthur Weiss, John Kuriyan
The specificity of tyrosine kinases is predominantly attributed to localization effects dictated by non-catalytic domains. We developed a method to profile the specificities of tyrosine kinases by combining bacterial surface-display of peptide libraries with next-generation sequencing. Using this, we showed that the tyrosine kinase ZAP-70, which is critical for T cell signaling, discriminates substrates through an electrostatic selection mechanism encoded within its catalytic domain (Shah et al. 2016). Here, we expand this high-throughput platform to analyze the intrinsic specificity of any tyrosine kinase domain against thousands of peptides derived from human tyrosine phosphorylation sites...
March 16, 2018: ELife
https://www.readbyqxmd.com/read/29434598/core-fucosylation-of-the-t-cell-receptor-is-required-for-t-cell-activation
#2
Wei Liang, Shanshan Mao, Shijie Sun, Ming Li, Zhi Li, Rui Yu, Tonghui Ma, Jianguo Gu, Jianing Zhang, Naoyuki Taniguchi, Wenzhe Li
CD4+ T cell activation promotes the pathogenic process of systemic lupus erythematosus (SLE). T cell receptor (TCR) complex are highly core fucosylated glycoproteins, which play important roles in T cell activation. In this study, we found that the core fucosylation of CD4+ T cells was significantly increased in SLE patients. Loss of core fucosyltransferase (Fut8), the sole enzyme for catalyzing the core fucosylation of N-glycan, significantly reduced CD4+ T cell activation and ameliorated the experimental autoimmune encephalomyelitis-induced syndrome in Fut8-/- mice...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29431868/correction-of-t-cell-deficiency-in-zap-70-knockout-mice-by-simple-intraperitoneal-adoptive-transfer-of-thymocytes
#3
Réka Kugyelka, Zoltán Kohl, Katalin Olasz, Lilla Prenek, Tímea Berki, Péter Balogh, Ferenc Boldizsár
The tyrosine kinase ZAP-70 (zeta-chain associated protein of 70 kDa) plays a key role in T cell development and signaling. In the absence of ZAP-70, T cell development is arrested in the CD4+ CD8+ double positive stage, thus ZAP-70 homozygous knockout (ZAP-70-/- ) mice have no mature T cells in their peripheral lymphoid organs and blood, causing severe immunodeficiency. We investigated the early kinetics and long-term effects of wild-type thymocyte transfer on T cell repopulation in ZAP-70-/- mice. We used a single intraperitoneal (ip...
February 12, 2018: Clinical and Experimental Immunology
https://www.readbyqxmd.com/read/29299750/elevated-absolute-nk-cell-counts-in-peripheral-blood-predict-good-prognosis-in-chronic-lymphocytic-leukemia
#4
Wen-Ting Wang, Hua-Yuan Zhu, Yu-Jie Wu, Yi Xia, Jia-Zhu Wu, Wei Wu, Jin-Hua Liang, Li Wang, Lei Fan, Jian-Yong Li, Wei Xu
PURPOSE: The aim of this study was to investigate the prognostic significance of the absolute natural killer (NK) cell counts in peripheral blood in patients with chronic lymphocytic leukemia (CLL). METHODS: A total of 273 previously untreated patients with CLL from April 2004 and October 2015 were enrolled into this retrospective study. We analysed the T cell subsets of all patients and figured out the number of NK cells. Comparisons of NK cell count as continuous parameter in different groups were described using Mann-Whitney U test and the Kruskal-Wallis test...
March 2018: Journal of Cancer Research and Clinical Oncology
https://www.readbyqxmd.com/read/29237129/zap-70-in-signaling-biology-and-disease
#5
Byron B Au-Yeung, Neel H Shah, Lin Shen, Arthur Weiss
T cells possess an array of functional capabilities important for host defense against pathogens and tumors. T cell effector functions require the T cell antigen receptor (TCR). The TCR has no intrinsic enzymatic activity, and thus signal transduction from the receptor relies on additional signaling molecules. One such molecule is the cytoplasmic tyrosine kinase ZAP-70, which associates with the TCR complex and is required for initiating the canonical biochemical signal pathways downstream of the TCR. In this article, we describe recent structure-based insights into the regulation and substrate specificity of ZAP-70, and then we review novel methods for determining the role of ZAP-70 catalytic activity-dependent and -independent signals in developing and mature T cells...
December 13, 2017: Annual Review of Immunology
https://www.readbyqxmd.com/read/29230212/a-novel-function-for-the-streptococcus-pneumoniae-aminopeptidase-n-inhibition-of-t-cell-effector-function-through-regulation-of-tcr-signaling
#6
Lance K Blevins, Derek Parsonage, Melissa B Oliver, Elizabeth Domzalski, W Edward Swords, Martha A Alexander-Miller
Streptococcus pneumoniae ( Spn ) causes a variety of disease states including fatal bacterial pneumonia. Our previous finding that introduction of Spn into an animal with ongoing influenza virus infection resulted in a CD8+ T cell population with reduced effector function gave rise to the possibility of direct regulation by pneumococcal components. Here, we show that treatment of effector T cells with lysate derived from Spn resulted in inhibition of IFNγ and tumor necrosis factor α production as well as of cytolytic granule release...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/29182244/allosteric-modulation-of-grb2-recruitment-to-the-intrinsically-disordered-scaffold-protein-lat-by-remote-site-phosphorylation
#7
William Y C Huang, Jonathon A Ditlev, Han-Kuei Chiang, Michael K Rosen, Jay T Groves
Tyrosine phosphorylation of membrane receptors and scaffold proteins followed by recruitment of SH2 domain-containing adaptor proteins constitutes a central mechanism of intracellular signal transduction. During early T-cell receptor (TCR) activation, phosphorylation of linker for activation of T cells (LAT) leading to recruitment of adaptor proteins, including Grb2, is one prototypical example. LAT contains multiple modifiable sites, and this multivalency may provide additional layers of regulation, although this is not well understood...
December 13, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/29125235/comparison-of-the-mrna-expression-profile-of-b-cell-receptor-components-in-normal-cd5-high-b-lymphocytes-and-chronic-lymphocytic-leukemia-a-key-role-of-zap70
#8
COMPARATIVE STUDY
Aleena A Gladkikh, Daria M Potashnikova, Victor Tatarskiy, Margarita Yastrebova, Alvina Khamidullina, Natasha Barteneva, Ivan Vorobjev
The B-cell receptor (BCR) signaling pathway is of great importance for B-cell survival and proliferation. The BCR expressed on malignant B-CLL cells contributes to the disease pathogenesis, and its signaling pathway is currently the target of several therapeutic strategies. Although various BCR alterations have been described in B-CLL at the protein level, the mRNA expression levels of tyrosine kinases in B-CLL compared to that in normal CD5-high and CD5-low B-lymphocytes remain unknown. In the current study, we measured the mRNA expression levels of CD79A, CD79B, LYN, SYK, SHP1, and ZAP70 in purified populations of CD5-high B-CLL cells, CD5-low B-cells from the peripheral blood of healthy donors, and CD5-high B-cells from human tonsils...
December 2017: Cancer Medicine
https://www.readbyqxmd.com/read/29115891/the-mutational-landscape-of-small-lymphocytic-lymphoma-compared-to-non-early-stage-chronic-lymphocytic-leukemia
#9
Alejandra Martínez-Trillos, Magda Pinyol, Julio Delgado, Marta Aymerich, Maria Rozman, Tycho Baumann, Marcos González-Díaz, Jesus M Hernández, Miguel Alcoceba, Anna Muntañola, Maria José Terol, Blanca Navarro, Eva Giné, Pedro Jares, Sílvia Beà, Alba Navarro, Dolors Colomer, Ferran Nadeu, Enrique Colado, Angel R Payer, Tomás García-Cerecedo, Xosé S Puente, Carlos López-Otin, Elias Campo, Armando López-Guillermo, Neus Villamor
Small lymphocytic lymphoma (SLL) is considered as the non-leukemic form of presentation of chronic lymphocytic leukemia (CLL). We have compared the features, genomic alterations, and outcome of 890 patients with CLL and SLL. One hundred and thirteen patients presented as SLL and more frequently had unmutated-IGHV, CD38(high), ZAP-70(high), CD49d(high), +12, alterations in genes of NOTCH1, cell cycle, RNA metabolism, and NFkB pathways than CLL. During the follow-up, 46% of SLL patients developed CLL. Time to first treatment (TTFT) was shorter in SLL (10-year: 75% vs 62%; p = ...
November 8, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/29091884/advances-in-chronic-lymphocytic-leukemia-pharmacotherapy
#10
REVIEW
Lorena Caixeta Gomes, Aline Lúcia Menezes Ferrão, Fernanda Cristina Gontijo Evangelista, Tâmara Dauare de Almeida, Rayson Carvalho Barbosa, Maria das Graças Carvalho, Adriano de Paula Sabino
Chronic lymphocytic leukemia (CLL) is a lymphoproliferative disease that affects B lymphocytes in most cases. Leukemic lymphocytes have prolonged longevity, defined by resistance to apoptosis. These cells can accumulate in peripheral blood, bone marrow, and solid lymphoid organs. CLL may be indolent or aggressive and has a range of prognostic factors such as expression of CD38 and ZAP-70, immunophenotypic and cytogenetic changes, imbalanced apoptosis proteins, and others. Although CLL has a low mortality rate, this disease is generally not considered curable until today...
January 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/29066254/ci8-short-a-novel-lps-induced-peptide-from-the-ascidian-ciona-intestinalis-modulates-responses-of-the-human-immune-system
#11
Angela Bonura, Aiti Vizzini, Sara Vlah, Francesco Gervasi, Alessandra Longo, Mario R Melis, Frank A Schildberg, Paolo Colombo
The selective modulation of immunity is an emerging concept driven by the vast advances in our understanding of this crucial host defense system. Invertebrates have raised researchers' interest as potential sources of new bioactive molecules owing to their antibacterial, anticancer and immunomodulatory activities. A LipoPolySaccharide (LPS) challenge in the ascidian Ciona intestinalis generates the transcript, Ci8 short, with cis-regulatory elements in the 3' UTR region that are essential for shaping innate immune responses...
October 16, 2017: Immunobiology
https://www.readbyqxmd.com/read/28991187/peptides-from-colochirus-robustus-enhance-immune-function-via-activating-cd3%C3%AE-and-zap-70-mediated-signaling-in-c57bl-6-mice
#12
Xiaogang Du, Fangliang Lian, Yunkun Li, Dong Li, Dayong Wu, Qunli Feng, Zhijiang Feng, Yun Li, Guixian Bu, Fengyan Meng, Xiaohan Cao, Zhiyu Chen, Xianyin Zeng
Colochirus robustus, a species of sea cucumber, has long been used in East and Southeast Asia as nutritious food as well as for certain medicinal purpose. Studies have shown a number of biological functions associated with consumption of sea cucumber, many of which are attributed to its major component, sea cucumber peptides (SCP). However, how SCP impacts immune system, which is critical for host defense, has not been defined. To address this issue, in the present study, we conducted comprehensive analysis of immune function after oral administration of SCP (0, 25, 50, and 75 mg/kg body weigh) for eight weeks in C57BL/6 mice...
October 8, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28947822/microenvironment-regulates-the-expression-of-mir-21-and-tumor-suppressor-genes-pten-pias3-and-pdcd4-through-zap-70-in-chronic-lymphocytic-leukemia
#13
Júlia Carabia, Cecilia Carpio, Pau Abrisqueta, Isabel Jiménez, Noelia Purroy, Eva Calpe, Carles Palacio, Francesc Bosch, Marta Crespo
Chronic lymphocytic leukemia (CLL) cells are highly dependent on microenvironment, being the BCR pathway one key player in this crosstalk. Among proteins participating, ZAP-70 enhances response to microenvironmental stimuli. MicroRNA-21 (miR-21) is overexpressed in diverse neoplasias including CLL, where it has been associated to refractoriness to fludarabine and to shorter time to progression and survival. To further elucidate the role of ZAP-70 in the biology of CLL, we studied its involvement in miR-21 regulation...
September 25, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28884705/cryptochrome-1-gene-expression-is-a-reliable-prognostic-indicator-in-egyptian-patients-with-chronic-lymphocytic-leukemia-a-cohort-prospective-study
#14
Deena Mohamed Habashy, Deena Samir Eissa, Mona Mahmoud Aboelez
Objectives Traditional prognostic factors have proven insufficient to account for the observed heterogeneity in the clinical behavior of chronic lymphocytic leukemia (CLL). Cryptochrome-1 (CRY-1) is a circadian clock gene essential in maintaining circadian rhythm and regulating cell proliferation. We evaluated CRY-1 gene expression in CLL patients, and assessed its putative role as a prognostic indicator for the clinical course of CLL. Materials and Methods Hundred CLL patients at diagnosis were studied for CRY-1 gene expression by qRT-PCR, and were followed up for assessment of time to first treatment (TFT)...
September 8, 2017: Turkish Journal of Haematology: Official Journal of Turkish Society of Haematology
https://www.readbyqxmd.com/read/28881670/g-csf-inhibits-lfa-1-mediated-cd4-t-cell-functions-by-inhibiting-lck-and-zap-70
#15
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...
August 1, 2017: Oncotarget
https://www.readbyqxmd.com/read/28846922/interaction-of-zap70-and-cxcr4-receptor-at-lamellipodia-that-determines-the-directionality-during-jurkat-t-cells-chemotaxis
#16
Chia-Yun Wu, Yi-Ying Tsai, Sheng-Yi Chen, Yu-Ping Lin, Jyh-Wei Shin, Chia-Ching Wu, Bei-Chang Yang
Directional migration of T-lymphocytes is a key process during immune activation and is tightly regulated both temporally and spatially. The initial cell membrane protrusion at a particular site is critical for determining the direction of cell migration. In this study, we found that ZAP-70 protein appeared not only at the margin of the spreading areas of polarized Jurkat T cells but also formed clusters near the center of the cell body on a fibronectin plate. Specifically, some pZAP-70 was located at the lamellipodia/filopodia and was closely associated with the most extended membrane contact...
October 2017: Molecular Immunology
https://www.readbyqxmd.com/read/28833505/aberrant-levels-of-suv39h1-and-suv39h2-methyltransferase-are-associated-with-genomic-instability-in-chronic-lymphocytic-leukemia
#17
Juliana Carvalho Alves-Silva, Doralina do Amaral Rabello, Martha Oliveira Bravo, Antônio Lucena-Araujo, Diego Madureira de Oliveira, Fábio Morato de Oliveira, Eduardo Magalhaes Rego, Fábio Pittella-Silva, Felipe Saldanha-Araujo
Chromosomal alterations are commonly detected in patients with chronic lymphocytic leukemia (CLL) and impact disease pathogenesis, prognosis, and progression. Telomerase expression (hTERT), its activity and the telomere length are other important predictors of survival and multiple outcomes in CLL. SUV39H and SUV420H enzymes are histone methyltransferases (HMTases) involved in several cellular processes, including regulation of telomere length, heterochromatin organization, and genome stability. Here, we investigated whether SUV39H1, SUV39H2, SUV420H1, SUV420H2, and hTERT are associated with genomic instability of CLL...
December 2017: Environmental and Molecular Mutagenesis
https://www.readbyqxmd.com/read/28771705/selected-signalling-proteins-recruited-to-the-t-cell-receptor-cd3-complex
#18
REVIEW
Jatuporn Ngoenkam, Wolfgang W 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 TCR-αβ heterodimer and the non-covalently associated signalling dimers of CD3εγ, CD3εδ and CD3ζζ. TCR-αβ binds specifically to a cognate peptide antigen bound to an 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...
January 2018: Immunology
https://www.readbyqxmd.com/read/28768156/the-syk-kinases-orchestrate-cerebellar-granule-cell-tangential-migration
#19
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-src-homology-2-domains-in-syk-and-zap70-protein-kinases-by-dna-programmed-spatial-screening
#20
Michaela Marczynke, Katharina Gröger, Oliver Seitz
Members of the Syk family of tyrosine kinases arrange Src homology 2 (SH2) domains in tandem to allow the 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 ζ-chain-associated protein kinase (ZAP-70) recognize the consensus sequence pYXXI/L(X)6-8 pYXXI/L with near-identical nanomolar affinity. The nondiscriminatory recognition, on the one hand, poses a specificity challenge for the design of subtype 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...
September 20, 2017: Bioconjugate Chemistry
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