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Kelei Li, Zhe Cong, Zhuoying Peng, Ting Chen, Jing Xue, Qiang Wei
CD45 has been reported to regulate the HIV-1 gp120-induced apoptosis of Jurkat cells. Here, we demonstrate that the extracellular domain of CD45 plays an important role in this function. We observed that CD45RO-transfected cells, but not cells transfected with other CD45 isoforms, underwent significant apoptosis induced by gp120. However, a CD45RA-transfected cell line treated with an O-glycan inhibitor was able to undergo apoptosis. The role of the extracellular domain of CD45 was further confirmed using CD45 isoformtransfected cell lines by analyzing the phosphorylation of Lck, which is a direct substrate of CD45 tyrosine phosphatase, and by using an Lck inhibitor...
December 20, 2017: Biological Chemistry
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
Anne Buffière, Théo Accogli, Laetitia Saint-Paul, Géraldine Lucchi, Benjamin Uzan, Paola Ballerini, Jean-Noël Bastie, Laurent Delva, Françoise Pflumio, Ronan Quéré
No abstract text is available yet for this article.
February 28, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Ruth Nussinov, Chung-Jung Tsai, Hyunbum Jang
Ras signaling initiates at the plasma membrane. Thus, Ras behavior at the membrane and how it relates to its interactions with Raf and PI3Kα, are of immense interest. Here we review factors influencing Ras lateral diffusion. We then ask whether oncogenic Ras diffusion speed in the membrane is important for signaling response times and whether it affects ubiquitously all pathways. We suggest that if Ras expression is sufficiently high to dimerize (or form nanoclusters), signaling response of those pathways where dimers (or nanoclusters) are involved corresponds to the speed with which Ras molecules travel in the membrane...
February 27, 2018: Seminars in Cancer Biology
Mikel M Arbulo-Echevarria, Isaac Narbona-Sánchez, Cecilia M Fernandez-Ponce, Inmaculada Vico-Barranco, Mª Dolores Rueda-Ygueravide, Michael L Dustin, Arkadiusz Miazek, Mª Carmen Duran-Ruiz, Francisco García-Cózar, Enrique Aguado
The adaptor protein linker for activation of T cells (LAT) has an essential role transducing activatory intracellular signals coming from the TCR/CD3 complex. Previous reports have shown that upon T-cell activation, LAT interacts with the tyrosine kinase Lck, leading to the inhibition of its kinase activity. LAT-Lck interaction seemed to depend on a stretch of negatively charged amino acids in LAT. Here, we have substituted this segment of LAT between amino acids 113 and 126 with a non-charged segment and expressed the mutant LAT (LAT-NIL) in J...
2018: Frontiers in Immunology
Yingbin Zhong, Qiang Ye, Chengyan Chen, Mingyong Wang, Han Wang
EZH2 is a subunit of polycomb repressive complex 2 (PRC2) that silences gene transcription via H3K27me3 and was shown to be essential for mammalian liver circadian regulation and hematopoiesis through gene silencing. Much less, however, is known about how Ezh2 acts in live zebrafish. Here, we show that zebrafish ezh2 is regulated directly by the circadian clock via both E-box and RORE motif, while core circadian clock genes per1a, per1b, cry1aa and cry1ab are down-regulated in ezh2 null mutant and ezh2 morphant zebrafish, and either knockdown or overexpression of ezh2 alters locomotor rhythms, indicating that Ezh2 is required for zebrafish circadian regulation...
February 13, 2018: Nucleic Acids Research
A J Davenport, R S Cross, K A Watson, Y Liao, W Shi, H M Prince, P A Beavis, J A Trapani, M H Kershaw, D S Ritchie, P K Darcy, P J Neeson, M R Jenkins
Chimeric antigen receptor T (CAR-T) cells are effective serial killers with a faster off-rate from dying tumor cells than CAR-T cells binding target cells through their T cell receptor (TCR). Here we explored the functional consequences of CAR-mediated signaling using a dual-specific CAR-T cell, where the same cell was triggered via TCR (tcrCTL) or CAR (carCTL). The carCTL immune synapse lacked distinct LFA-1 adhesion rings and was less reliant on LFA to form stable conjugates with target cells. carCTL receptors associated with the synapse were found to be disrupted and formed a convoluted multifocal pattern of Lck microclusters...
February 27, 2018: Proceedings of the National Academy of Sciences of the United States of America
Gabriel Santpere, Ana Alcaráz-Sanabria, Verónica Corrales-Sánchez, Atanasio Pandiella, Balázs Győrffy, Alberto Ocaña
In breast cancer, it is unclear the functional modifications at a transcriptomic level that are associated with the evolution from epithelial cells and ductal carcinoma in situ (DCIS) to basal-like tumors. By applying weighted gene co-expression network analysis (WGCNA), we identified 17 gene co-expression modules in normal, DCIS and basal-like tumor samples. We then correlated the expression pattern of these gene modules with disease progression from normal to basal-like tumours and found eight modules exhibiting a high and statistically significant correlation...
January 2, 2018: Oncotarget
Yu-Jing Wu, Heng-Shi Chen, Wen-Sheng Chen, Jin Dong, Xiao-Jie Dong, Xing Dai, Qiong Huang, Wei Wei
Researchers have shown that the level of immunoglobulin D (IgD) is often elevated in patients with autoimmune diseases. The possible roles of IgD on the function of human T cell activation are still unclear. Paeoniflorin-6'-O-benzene sulfonate (code: CP-25), the chemistry structural modifications of paeoniflorin, was a novel drug of anti-inflammation and immunomodulation. The aims of this study were to determine if human CD4+ T cells could be activated by IgD via the IgD receptor (IgDR)-Lck pathway and whether the novel compound CP-25 could affect the activation of T cells by regulating Lck...
2018: Frontiers in Pharmacology
María Barreira, Sonia Rodríguez-Fdez, Xosé R Bustelo
Vav1 is a hematopoietic-specific Rho GDP/GTP exchange factor and signaling adaptor. Although these activities are known to be stimulated by direct Vav1 phosphorylation, little information still exists regarding the regulatory layers that influence the overall Vav1 activation cycle. Using a collection of cell models and activation-mimetic Vav1 mutants, we show here that the dephosphorylated state of Vav1 in nonstimulated T cells requires the presence of a noncatalytic, phospholipase Cγ1-Slp76-mediated inhibitory pathway...
February 1, 2018: Cellular Signalling
Caleb R Glassman, Heather L Parrish, Mark S Lee, Michael S Kuhns
CD4+ T cells convert the time that T cell receptors (TCRs) interact with peptides embedded within class II major histocompatibility complex molecules (pMHCII) into signals that direct cell-fate decisions. In principle, TCRs relay information to intracellular signaling motifs of the associated CD3 subunits, while CD4 recruits the kinase Lck to those motifs upon coincident detection of pMHCII. But the mechanics by which this occurs remain enigmatic. In one model, the TCR and CD4 bind pMHCII independently, while in another, CD4 interacts with a composite surface formed by the TCR-CD3 complex bound to pMHCII...
January 30, 2018: Cell Reports
Qi Li, Xiaohong Peng, Haoran Huang, Jingjing Li, Fan Wang, Jie Wang
This study aimed to identify miRNAs that may contribute to the pathogenesis of sudden sensorineural hearing loss (SSNHL) by RNA-seq (RNA-sequencing).RNA was extracted from SSNHL patients and healthy volunteers, respectively. Sequencing was performed on HiSeq4000 platform. After filtering, clean reads were mapped to the human reference genome hg19. Differential expression analysis of miRNAs between the SSNHL samples and the normal samples was performed using DEseq to identify differentially expressed microRNAs (DEMs)...
November 2017: Medicine (Baltimore)
Andreas Rheinländer, Burkhart Schraven, Ursula Bommhardt
CD45 is an evolutionary highly conserved receptor protein tyrosine phosphatase exclusively expressed on all nucleated cells of the hematopoietic system. It is characterized by the expression of several isoforms, specific to a certain cell type and the developmental or activation status of the cell. CD45 is one of the key players in the initiation of T cell receptor signaling by controlling the activation of the Scr family protein-tyrosine kinases Lck and Fyn. CD45 defiency results in T- and B-lymphocyte dysfunction in the form of severe combined immune deficiency...
January 20, 2018: Immunology Letters
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
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
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
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
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
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...
January 2018: Biochemical Pharmacology
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
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