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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 to the activation of integrins such as LFA-1 is poorly understood. Here, we identify a novel role of the protein tyrosine phosphatase SHP-1 in the regulation of murine LFA-1-mediated adhesion in an allograft setting...
October 3, 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
Meng Xu, Chengfeng Cai, Xuli Sun, Wanze Chen, Qinxi Li, Huamin Zhou
Clnk, as a third member of the Blnk/SLP-76 adapter family, is involved in the positive regulation of immunoreceptor signaling. Here we provide findings that Clnk may be is required for TNF induced cell death, it functions downstream of RIP3 and promotes TNF- induced ROS generation and MLKL tetramer formation and subsequent necrosis of L929 cells. Therefore, Clnk, as an adaptor protein, may take part in the other cellular processes.
July 31, 2015: Biochemical and Biophysical Research Communications
Kristin Lampe, Mehari Endale, Siobhan Cashman, Hao Fang, Jochen Mattner, David Hildeman, Kasper Hoebe
Absence of MHC class I expression is an important mechanism by which NK cells recognize a variety of target cells, yet the pathways underlying "missing-self" recognition, including the involvement of activating receptors, remain poorly understood. Using ethyl-N-nitrosourea mutagenesis in mice, we identified a germline mutant, designated Ace, with a marked defect in NK cell mediated recognition and elimination of "missing-self" targets. The causative mutation was linked to chromosome 11 and identified as a missense mutation (Thr428Ile) in the SH2 domain of Slp-76-a critical adapter molecule downstream of ITAM-containing surface receptors...
July 2015: European Journal of Immunology
Sujan Devkota, Raji E Joseph, Lie Min, D Bruce Fulton, Amy H Andreotti
Activation of the phospholipase, PLCγ1, is critical for proper T cell signaling following antigen receptor engagement. In T cells, the Tec family kinase, interleukin-2-induced tyrosine kinase (ITK), phosphorylates PLCγ1 at tyrosine 783 (Y783) leading to activation of phospholipase function and subsequent production of the second messengers inositol 1,4,5-trisphosphate and diacylglycerol. In this work, we demonstrate that PLCγ1 can be primed for ITK-mediated phosphorylation on Y783 by a specific region of the adaptor protein, SLP-76...
August 28, 2015: Journal of Molecular Biology
Qing Zhang, Huilin Zhang
Mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1, also called hematopoietic progenitor kinase 1, HPK1) is a serine/threonine kinase. As a member of the MAP4K family, MAP4K1 is closely associated with various adaptor proteins such as caspase recruitment domain family member 11 (CARD11), hematopoietic cell-specific protein 1 (HS1), HPK1-interacting protein of 55 kD (HIP-55), growth factor receptor-bound protein 2 (GRB2) family, the linker for activated T-cells (LAT), SH2 domain containing leukocyte protein of 76 kD (SLP-76) family, homologues of the v-crk oncogene product (CRK) family, the B-cell adaptor molecule of 32 kD (BAM32), etc...
March 2015: Zhong Nan da Xue Xue Bao. Yi Xue Ban, Journal of Central South University. Medical Sciences
Amanda M Schmidt, Wen Lu, Vishal J Sindhava, Yanping Huang, Janis K Burkhardt, Enjun Yang, Matthew J Riese, Jonathan S Maltzman, Martha S Jordan, Taku Kambayashi
Regulatory T cells (Tregs) are a subset of CD4(+) T cells that maintain immune tolerance in part by their ability to inhibit the proliferation of conventional CD4(+) T cells (Tconvs). The role of the TCR and the downstream signaling pathways required for this suppressive function of Tregs are not fully understood. To yield insight into how TCR-mediated signals influence Treg suppressive function, we assessed the ability of Tregs with altered TCR-mediated signaling capacity to inhibit Tconv proliferation. Mature Tregs deficient in Src homology 2 domain containing leukocyte protein of 76 kDa (SLP-76), an adaptor protein that nucleates the proximal signaling complex downstream of the TCR, were unable to inhibit Tconv proliferation, suggesting that TCR signaling is required for Treg suppressive function...
May 1, 2015: Journal of Immunology: Official Journal of the American Association of Immunologists
Kristina M Hillen, Ruth Gather, Anselm Enders, Hanspeter Pircher, Peter Aichele, Paul Fisch, Britta Blumenthal, Wolfgang W Schamel, Tobias Straub, Christopher C Goodnow, Stephan Ehl
Defining the minimal thresholds for effective antiviral T cell immunity is important for clinical decisions in immunodeficient patients. TCR signaling is critical for T cell development, activation, and effector functions. In this article, we analyzed which of these TCR-mediated processes is limiting for antiviral immunity in a mouse strain with reduced expression of SLP-76 (twp mice). Despite severe T cell activation defects in vitro, twp mice generated a normal proportion of antiviral effector T cells postinfection with lymphocytic choriomeningitis virus (LCMV)...
March 15, 2015: Journal of Immunology: Official Journal of the American Association of Immunologists
Owen M Siggs, Lisa A Miosge, Stephen R Daley, Kelly Asquith, Paul S Foster, Adrian Liston, Christopher C Goodnow
Gene variants that disrupt TCR signaling can cause severe immune deficiency, yet less disruptive variants are sometimes associated with immune pathology. Null mutations of the gene encoding the scaffold protein Src homology 2 domain-containing leukocyte protein of 76 kDa (SLP-76), for example, cause an arrest of T cell positive selection, whereas a synthetic membrane-targeted allele allows limited positive selection but is associated with proinflammatory cytokine production and autoantibodies. Whether these and other enigmatic outcomes are due to a biochemical uncoupling of tolerogenic signaling, or simply a quantitative reduction of protein activity, remains to be determined...
March 15, 2015: Journal of Immunology: Official Journal of the American Association of Immunologists
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