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ZAP-70

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https://www.readbyqxmd.com/read/29895969/inhibition-of-maternal-embryonic-leucine-zipper-kinase-with-otssp167-displays-potent-anti-leukemic-effects-in-chronic-lymphocytic-leukemia
#1
Ya Zhang, Xiangxiang Zhou, Ying Li, Yangyang Xu, Kang Lu, Peipei Li, Xin Wang
TP53 pathway defects contributed to therapy resistance and adverse clinical outcome in chronic lymphocytic leukemia (CLL), which represents an unmet clinical need with few therapeutic options. Maternal embryonic leucine zipper kinase (MELK) is a novel oncogene, which plays crucial roles in mitotic progression and stem cell maintenance. OTSSP167, an orally administrated inhibitor targeting MELK, is currently in a phase I/II clinical trial in patients with advanced breast cancer and acute myeloid leukemia. Yet, no investigation has been elucidated to date regarding the oncogenic role of MELK and effects of OTSSP167 in chronic lymphocytic leukemia (CLL)...
June 12, 2018: Oncogene
https://www.readbyqxmd.com/read/29893517/relationship-between-the-expression-of-cd25-and-cd69-on-the-surface-of-lymphocytes-t-and-b-from-peripheral-blood-and-bone-marrow-of-patients-with-chronic-lymphocytic-leukemia-and-established-prognostic-factors-of-this-disease
#2
Ewelina Grywalska, Małgorzata Bartkowiak-Emeryk, Marcin Pasiarski, Karolina Olszewska-Bożek, Michał Mielnik, Martyna Podgajna, Monika Pieczykolan, Anna Hymos, Elżbieta Fitas, Agata Surdacka, Stanisław Góźdź, Jacek Roliński
BACKGROUND: Chronic lymphocytic leukemia (CLL) is a condition characterized by the accumulation of morphologically mature monoclonal lymphocytes B with the CD19+/CD5+/CD23+ phenotype in lymphoid tissue, peripheral blood and bone marrow. The clinical course of patients with CLL is heterogeneous, ranging from indolent to aggressive. The role of lymphocyte activation in the natural history of CLL is still a matter of discussion. OBJECTIVES: The aim of this study was to determine the percentages and absolute numbers of lymphocytes B and T in peripheral blood and bone marrow of CLL patients...
June 12, 2018: Advances in Clinical and Experimental Medicine: Official Organ Wroclaw Medical University
https://www.readbyqxmd.com/read/29789296/tuning-itam-multiplicity-on-t-cell-receptors-can-control-potency-and-selectivity-to-ligand-density
#3
John R James
The T cell antigen receptor (TCR) recognizes peptides from pathogenic proteins bound in the major histocompatibility complex (MHC). To convert this binding event into downstream signaling, the TCR complex contains immunoreceptor tyrosine-based activation motifs (ITAMs) that act as docking sites for the cytoplasmic tyrosine kinase ZAP-70. Unique among antigen receptors, the TCR complex uses 10 ITAMs to transduce peptide-MHC binding to the cell interior. Using synthetic, drug-inducible receptor-ligand pairs, it was found that greater ITAM multiplicity primarily enhanced the efficiency with which ligand binding was converted into an intracellular signal...
May 22, 2018: Science Signaling
https://www.readbyqxmd.com/read/29748447/morphological-immunophenotypic-and-genetic-features-of-chronic-lymphocytic-leukemia-with-trisomy-12-a-comprehensive-review
#4
REVIEW
Francesco Autore, Paolo Strati, Luca Laurenti, Alessandra Ferrajoli
Chronic lymphocytic leukemia is an extremely heterogeneous disease and prognostic factors such as chromosomal abnormalities are important predictors of time to first treatment and survival. Trisomy 12 is the second most frequent aberration detected by fluorescence in situ hybridization at the time of diagnosis (10-25%), and it confers an intermediate prognostic risk, with a median time to first treatment of 33 months and a median overall survival of 114 months. Here, we review the unique morphological, immunophenotypic, and genetic characteristics of patients with chronic lymphocytic leukemia and trisomy 12...
June 2018: Haematologica
https://www.readbyqxmd.com/read/29720981/the-neutral-sphingomyelinase-2-is-required-to-polarize-and-sustain-t-cell-receptor-signaling
#5
Charlene Börtlein, Annette Draeger, Roman Schoenauer, Alexander Kuhlemann, Markus Sauer, Sibylle Schneider-Schaulies, Elita Avota
By promoting ceramide release at the cytosolic membrane leaflet, the neutral sphingomyelinase 2 (NSM) is capable of organizing receptor and signalosome segregation. Its role in T cell receptor (TCR) signaling remained so far unknown. We now show that TCR-driven NSM activation is dispensable for TCR clustering and initial phosphorylation, but of crucial importance for further signal amplification. In particular, at low doses of TCR stimulatory antibodies, NSM is required for Ca2+ mobilization and T cell proliferation...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29680229/zap-70-in-chronic-lymphocytic-leukemia-a-meta-analysis
#6
REVIEW
Yini Liu, Yangfeng Wang, Jule Yang, Yongyi Bi, Hong Wang
BACKGROUND: Recent studies have reported that zeta-chain-associated protein kinase 70 (ZAP-70) expression plays a prognostic role in chronic lymphocytic leukemia (CLL). However, these results remain controversial. Thus, we performed a meta-analysis to clarify the prognostic value of ZAP-70 expression in CLL. MATERIALS AND METHODS: Relevant studies were searched in PubMed, Embase, Cochrane library, and Web of Science up to January 2018. Clinicopathological features and prognostic data were extracted from the studies...
August 2018: Clinica Chimica Acta; International Journal of Clinical Chemistry
https://www.readbyqxmd.com/read/29677469/multidomain-control-over-tec-kinase-activation-state-tunes-the-t-cell-response
#7
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/29547119/fine-tuning-of-substrate-preferences-of-the-src-family-kinase-lck-revealed-through-a-high-throughput-specificity-screen
#8
Neel H Shah, Mark Löbel, Arthur Weiss, John Kuriyan
The specificity of tyrosine kinases is attributed predominantly 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
#9
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-knock-out-mice-by-simple-intraperitoneal-adoptive-transfer-of-thymocytes
#10
R Kugyelka, Z Kohl, K Olasz, L Prenek, T Berki, P Balogh, F Boldizsár
The tyrosine kinase zeta chain-associated protein of 70 kDa (ZAP-70) plays a key role in T cell development and signalling. 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 (i...
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
#11
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
#12
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...
April 26, 2018: 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
#13
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
#14
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
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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
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