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Cédric Poyet, Linto Thomas, Tobias M Benoit, David Aquino Delmo, Laura Luberto, Irina Banzola, Michèle S Günthart, Giovanni Sais, Daniel Eberli, Tullio Sulser, Maurizio Provenzano
Several lymphangiogenic factors, such as vascular endothelial growth factors (VEGFs), have been found to drive the development of lymphatic metastasis in bladder cancer (BCa).Here, we have analyzed the gene expression of lymphangiogenic factors in tissue specimens from 12 non-muscle invasive bladder cancers (NMIBC) and 11 muscle invasive bladder cancers (MIBC), considering tumor and tumor-adjacent normal bladder areas obtained from the same organs. We then compared the results observed in patients with those obtained after treating human primary bladder microvascular endothelial cells (MEC) with either direct stimulation with VEGF-A or VEGF-C or by co-culturing (trans-well assay) MEC with bladder cancer cell lines varying in VEGF-A and VEGF-C production based on tumor grade...
March 28, 2017: Oncotarget
Lavanya Mokada-Gopal, Alexander Boeser, Christian H K Lehmann, Friedel Drepper, Diana Dudziak, Bettina Warscheid, David Voehringer
The transcription factor STAT6 plays a key role in mediating signaling downstream of the receptors for IL-4 and IL-13. In B cells, STAT6 is required for class switch recombination to IgE and for germinal center formation during type 2 immune responses directed against allergens or helminths. In this study, we compared the transcriptomes and proteomes of primary mouse B cells from wild-type and STAT6-deficient mice cultured for 4 d in the presence or absence of IL-4. Microarray analysis revealed that 214 mRNAs were upregulated and 149 were downregulated >3-fold by IL-4 in a STAT6-dependent manner...
March 27, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
Johannes Breuning, Marion H Brown
The cell surface receptor, CD6 regulates T cell activation in both an activating and inhibitory manner. The adaptor protein SLP-76 is recruited to the CD6 cytoplasmic phosphorylated Y662 residue during T cell activation, providing an activating signal to T cells. In this study, a biochemical approach identified the SH2 domain-containing adaptor protein GADS as the dominant interaction partner for the CD6 cytoplasmic Y629 residue. Functional experiments in human Jurkat and primary T cells showed that mutation of both Y629F and Y662F abolished costimulation by CD6...
March 13, 2017: Molecular and Cellular Biology
Youg R Thaker, Asha Recino, Monika Raab, Asma Jabeen, Maja Wallberg, Nelson Fernandez, Christopher E Rudd
The adaptor protein Src homology 2 domain-containing leukocyte phosphoprotein of 76 kDa (SLP-76) plays a crucial role in T cell activation by linking antigen receptor (T cell receptor, TCR) signals to downstream pathways. At its N terminus, SLP-76 has three key tyrosines (Tyr-113, Tyr-128, and Tyr-145, "3Y") as well as a sterile α motif (SAM) domain whose function is unclear. We showed previously that the SAM domain has two binding regions that mediate dimer and oligomer formation. In this study, we have identified SAM domain-carrying non-receptor tyrosine kinase, activated Cdc42-associated tyrosine kinase 1 (ACK1; also known as Tnk2, tyrosine kinase non-receptor 2) as a novel binding partner of SLP-76...
April 14, 2017: Journal of Biological Chemistry
Paula Vélez, Raymundo Ocaranza-Sánchez, Diego López-Otero, Lilian Grigorian-Shamagian, Isaac Rosa, Esteban Guitián, José María García-Acuña, José Ramón González-Juanatey, Ángel García
The platelet-specific collagen receptor glycoprotein VI (GPVI) is critical for the formation of arterial thrombosis in vivo. We analyzed GPVI-activated platelets from ST-elevation myocardial infarction (STEMI) patients and matched stable coronary artery disease (SCAD) controls in order to provide novel clues on the degree of involvement of GPVI signaling in the acute event. Firstly, platelets were isolated from systemic venous blood and activated with the GPVI specific agonist CRP (collagen-related peptide)...
December 22, 2016: Scientific Reports
Yannan Zhang, Sifei Yu, Xiaomin Li, Binyan Yang, Changyou Wu
The translocator protein (TSPO) ligands impacted inflammatory and immune responses. However, the exact effects of TSPO ligands on Th1 responses in vitro and in vivo are still unclear. In the current study, we found that TSPO ligands, FGIN1-27 and Ro5-4864, suppressed the cytokine production in a dose- dependent manner by purified human CD4(+) T cells from PBMCs after stimulation. TSPO ligands inhibited the production of IFN-γ by memory CD4(+) T cells and the differentiation of naïve CD4(+) T cells into Th1 cells via  suppressing the activity of the corresponding transcription factors as indicated by reduced expression of T-bet and downregulation of STAT1, STAT4 and STAT5 phosphorylation...
December 6, 2016: Clinical Science (1979-)
Valarie A Barr, Eilon Sherman, Jason Yi, Itoro Akpan, Alexandre K Rouquette-Jazdanian, Lawrence E Samelson
The adapter molecule linker for activation of T cells (LAT) plays a crucial role in forming signaling complexes induced by stimulation of the T cell receptor (TCR). These multi-molecular complexes are dynamic structures that activate highly regulated signaling pathways. Previously, we have demonstrated nanoscale structure in LAT-based complexes where the adapter SLP-76 (also known as LCP2) localizes to the periphery of LAT clusters. In this study, we show that initially LAT and SLP-76 are randomly dispersed throughout the clusters that form upon TCR engagement...
December 15, 2016: Journal of Cell Science
Neel H Shah, Qi Wang, Qingrong Yan, Deepti Karandur, Theresa A Kadlecek, Ian R Fallahee, William P Russ, Rama Ranganathan, Arthur Weiss, John Kuriyan
The sequence of events that initiates T cell signaling is dictated by the specificities and order of activation of the tyrosine kinases that signal downstream of the T cell receptor. Using a platform that combines exhaustive point-mutagenesis of peptide substrates, bacterial surface-display, cell sorting, and deep sequencing, we have defined the specificities of the first two kinases in this pathway, Lck and ZAP-70, for the T cell receptor ζ chain and the scaffold proteins LAT and SLP-76. We find that ZAP-70 selects its substrates by utilizing an electrostatic mechanism that excludes substrates with positively-charged residues and favors LAT and SLP-76 phosphosites that are surrounded by negatively-charged residues...
October 4, 2016: ELife
Martin G Sauer, Jessica Herbst, Ulf Diekmann, Christopher E Rudd, Christian Kardinal
The clinical potential of transplantation is often reduced by T cell-mediated alloresponses that cause graft rejection or graft-versus-host disease. Integrin-mediated adhesion between alloreactive T cells and antigen-presenting cells is essential for allorejection. The identity of the signaling events needed for the activation of integrins such as LFA-1 is poorly understood. Here, we identified a novel role of the protein tyrosine phosphatase SHP-1 in the regulation of murine LFA-1-mediated adhesion in an allograft setting...
December 15, 2016: Molecular and Cellular Biology
(no author information available yet)
Our cover picture features an H&E staining of liver sections from mice with a mutation in the SH2 domain of the signal transducing adaptor protein slp-76. The application of concanavalin A (Con A) induces milder hepatitis in these mice than in wild-type B6 mice due to a decreased activation of invariant natural killer T (iNKT) cells. The image relates to the article by Danzer et al. (pp. 2121-2136) in which the authors describe a pivotal role of slp-76 in activation and tissue distribution of iNKT cells.
September 2016: European Journal of Immunology
Krisztina Futosi, Attila Mócsai
Neutrophils play a critical role in antimicrobial host defense, but their improper activation also contributes to inflammation-induced tissue damage. Therefore, understanding neutrophil biology is important for the understanding, diagnosis, and therapy of both infectious and inflammatory diseases. Neutrophils express a large number of cell-surface receptors that sense extracellular cues and trigger various functional responses through complex intracellular signaling pathways. During the last several years, we and others have shown that tyrosine kinases play a critical role in those processes...
September 2016: Immunological Reviews
Eilon Sherman, Valarie A Barr, Robert K Merrill, Carole K Regan, Connie L Sommers, Lawrence E Samelson
Signalling complexes are dynamic, multimolecular structures and sites for intracellular signal transduction. Although they play a crucial role in cellular activation, current research techniques fail to resolve their structure in intact cells. Here we present a multicolour, photoactivated localization microscopy approach for imaging multiple types of single molecules in fixed and live cells and statistical tools to determine the nanoscale organization, topology and synergy of molecular interactions in signalling complexes downstream of the T-cell antigen receptor...
2016: Nature Communications
Claudia Danzer, Anna Koller, Julia Baier, Harald Arnold, Claudia Giessler, Robert Opoka, Stephanie Schmidt, Maike Willers, Sidonia Mihai, Hans Parsch, Stefan Wirtz, Christoph Daniel, Annegret Reinhold, Swen Engelmann, Stefanie Kliche, Christian Bogdan, Kasper Hoebe, Jochen Mattner
TCR ligation is critical for the selection, activation, and integrin expression of T lymphocytes. Here, we explored the role of the TCR adaptor protein slp-76 on iNKT-cell biology. Compared to B6 controls, slp-76(ace/ace) mice carrying a missense mutation (Thr428Ile) within the SH2-domain of slp-76 showed an increase in iNKT cells in the thymus and lymph nodes, but a decrease in iNKT cells in spleens and livers, along with reduced ADAP expression and cytokine response. A comparable reduction in iNKT cells was observed in the livers and spleens of ADAP-deficient mice...
September 2016: European Journal of Immunology
Huai-Chia Chuang, Xiaohong Wang, Tse-Hua Tan
MAP kinase kinase kinase kinases (MAP4Ks) belong to the mammalian Ste20-like family of serine/threonine kinases. MAP4Ks including MAP4K1/HPK1, MAP4K2/GCK, MAP4K3/GLK, MAP4K4/HGK, MAP4K5/KHS, and MAP4K6/MINK have been reported to induce JNK activation through activating the MAP3K-MAP2K cascade. The physiological roles of MAP4Ks in immunity and inflammation are largely unknown until recent studies using biochemical approaches and knockout mice. Surprisingly, JNK is not the major target of MAP4Ks in immune cells; MAP4Ks regulate immune responses through novel targets...
2016: Advances in Immunology
Harris Bell-Temin, Ashley E Culver-Cochran, Dale Chaput, Christina M Carlson, Melanie Kuehl, Brant R Burkhardt, Paula C Bickford, Bin Liu, Stanley M Stevens
Microglia, the resident immune cells of the brain, have been shown to display a complex spectrum of roles that span from neurotrophic to neurotoxic depending on their activation status. Microglia can be classified into four stages of activation, M1, which most closely matches the classical (pro-inflammatory) activation stage, and the alternative activation stages M2a, M2b, and M2c. The alternative activation stages have not yet been comprehensively analyzed through unbiased, global-scale protein expression profiling...
December 2015: Molecular & Cellular Proteomics: MCP
Pussadee Paensuwan, Jatuporn Ngoenkam, Boonruang Khamsri, Kanlaya Preechanukul, Donruedee Sanguansermsri, Sutatip Pongcharoen
BACKGROUND: The engagement of the T cell receptor (TCR)-CD3 complex induces the formation of multiple signalling complexes, which are required for actin cytoskeletal rearrangement. The Wiskott-Aldrich syndrome protein (WASp) is a key regulator of actin polymerization that is recruited to the TCR activation site. Since WASp is a binding partner of adaptor protein Nck, which is recruited directly to the TCR CD3? subunit upon TCR ligation, therefore we proposed that the direct recruitment of Nck to TCR-CD3 may also bring WASp directly to TCR-CD3...
September 2015: Asian Pacific Journal of Allergy and Immunology
Hebin Liu, Helga Schneider, Asha Recino, Christine Richardson, Martin W Goldberg, Christopher E Rudd
While immune cell adaptors regulate proximal T cell signaling, direct regulation of the nuclear pore complex (NPC) has not been reported. NPC has cytoplasmic filaments composed of RanGAP1 and RanBP2 with the potential to interact with cytoplasmic mediators. Here, we show that the immune cell adaptor SLP-76 binds directly to SUMO-RanGAP1 of cytoplasmic fibrils of the NPC, and that this interaction is needed for optimal NFATc1 and NF-κB p65 nuclear entry in T cells. Transmission electron microscopy showed anti-SLP-76 cytoplasmic labeling of the majority of NPCs in anti-CD3 activated T cells...
September 3, 2015: Molecular Cell
Cristina Capuano, Maddalena Romanelli, Chiara Pighi, Giuseppe Cimino, Angela Rago, Rosa Molfetta, Rossella Paolini, Angela Santoni, Ricciarda Galandrini
Natural killer (NK) immune cells mediate antibody-dependent cellular cytotoxicity (ADCC) by aggregating FcγRIIIA/CD16, contributing significantly to the therapeutic effect of CD20 monoclonal antibodies (mAb). In this study, we show that CD16 ligation on primary human NK cells by the anti-CD20 mAb rituximab or ofatumumab stably impairs the spontaneous cytotoxic response attributable to cross-tolerance of several unrelated NK-activating receptors (including NKG2D, DNAM-1, NKp46, and 2B4). Similar effects were obtained from NK cells isolated from patients with chronic lymphocytic leukemia in an autologous setting...
October 1, 2015: Cancer Research
Ana Dios-Esponera, Soledad Isern de Val, Silvia Sevilla-Movilla, Rosa García-Verdugo, David García-Bernal, Nohemí Arellano-Sánchez, Carlos Cabañas, Joaquin Teixidó
Stimulation by chemokines of integrin α4β1-dependent T-lymphocyte adhesion is a crucial step for lymphocyte trafficking. The adaptor Vav1 is required for chemokine-activated T-cell adhesion mediated by α4β1. Conceivably, proteins associating with Vav1 could potentially modulate this adhesion. Correlating with activation by the chemokine CXCL12 of T-lymphocyte attachment to α4β1 ligands, a transient stimulation in the association of Vav1 with SLP-76, Pyk2, and ADAP was observed. Using T-cells depleted for SLP-76, ADAP, or Pyk2, or expressing Pyk2 kinase-inactive forms, we show that SLP-76 and ADAP stimulate chemokine-activated, α4β1-mediated adhesion, whereas Pyk2 opposes T-cell attachment...
September 15, 2015: Molecular Biology of the Cell
Cecilie Dahl Hem, Vibeke Sundvold-Gjerstad, Stine Granum, Lise Koll, Greger Abrahamsen, Laszlo Buday, Anne Spurkland
BACKGROUND: The Lck and Src binding adaptor protein TSAd (T cell specific adaptor) regulates actin polymerization in T cells and endothelial cells. The molecular details as to how TSAd regulates this process remain to be elucidated. RESULTS: To identify novel interaction partners for TSAd, we used a scoring matrix-assisted ligand algorithm (SMALI), and found that the Src homology 2 (SH2) domain of the actin regulator Non-catalytic region of tyrosine kinase adaptor protein (Nck) potentially binds to TSAd phosphorylated on Tyr(280) (pTyr(280)) and pTyr(305)...
2015: Cell Communication and Signaling: CCS
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