A5012199633- Protein Tyrosine Phosphatases
- T-cell and B-cell Immunology
- Immune Cell Function and Interaction
- Diabetes and associated disorders
- Galectins and Cancer Biology
- Protein Kinase Regulation and GTPase Signaling
- Inflammasome and immune disorders
- Tryptophan and brain disorders
- Receptor Mechanisms and Signaling
- Cell Adhesion Molecules Research
- CAR-T cell therapy research
- Stress Responses and Cortisol
- Signaling Pathways in Disease
- Cytokine Signaling Pathways and Interactions
- Adipokines, Inflammation, and Metabolic Diseases
- Esophageal and GI Pathology
- Schizophrenia research and treatment
- Tracheal and airway disorders
- Ubiquitin and proteasome pathways
- RNA modifications and cancer
- Cancer-related Molecular Pathways
- RNA Research and Splicing
- Toxin Mechanisms and Immunotoxins
- Chronic Myeloid Leukemia Treatments
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
Sykehuset i Vestfold
2014-2023
Glostrup Hospital
2018-2023
Copenhagen University Hospital
2018-2023
Aalborg University Hospital
2014-2017
Aalborg University
2017
University of Oslo
1998-2013
Sanford Burnham Prebys Medical Discovery Institute
2004-2013
Institute for Medical Research
2007-2008
Cancer Research Center
2004
In T cells, cAMP-dependent protein kinase (PKA) type I colocalizes with the cell receptor-CD3 complex (TCR/CD3) and inhibits function via a previously unknown proximal target. Here we examine mechanism for this PKA-mediated immunomodulation. cAMP treatment of Jurkat normal cells reduces Lck-mediated tyrosine phosphorylation TCR/CD3 zeta chain after activation, decreases Lck activity. Phosphorylation residue Y505 in by COOH-terminal Src (Csk), which negatively regulates Lck, is essential...
In resting peripheral T cells, Csk is constitutively present in lipid rafts through an interaction with the SH2-binding protein, PAG, also known as Cbp. Upon triggering of cell antigen receptor (TCR), PAG/Cbp rapidly dephosphorylated leading to dissociation from rafts. However, tyrosine phosphorylation resumes after 3--5 min, at which time reassociates Cells overexpressing a mutant that lacks catalytic domain, but displaces endogenous rafts, have elevated basal levels TCR-zeta-chain and...
Abstract Ligation of the TCR along with coreceptor CD28 is necessary to elicit T cell activation in vivo, whereas triggering alone does not allow a full response. Upon human peripheral blood cells, we found that majority cAMP was generated lipid rafts followed by protein kinase A. However, upon and coligation, β-arrestin complex cAMP-specific phosphodiesterase 4 (PDE4) recruited which down-regulated levels. Whereas inhibition A increased TCR-induced immune responses, PDE4 blunted cytokine...
To uncover signaling system differences between T cell stimuli and subsets, phosphorylation status of 18 proteins at six different time points following TCR triggering CD28/CD2 costimulation was examined in human subsets by phospho-epitope-specific flow cytometry fluorescent barcoded samples, thereby providing a high-resolution map. Compared with effector/memory cells, naive cells displayed stronger activation proximal molecules after alone. Conversely, distal events, like pErk pS6-ribosomal...
Abstract cAMP inhibits biochemical events leading to T cell activation by triggering of an inhibitory protein kinase A (PKA)-C-terminal Src pathway assembled in lipid rafts. In this study, we demonstrate that PKA type I Sp-8-bromo-cAMPS (a agonist) has profound effects on Ag-specific immune responses peripheral effector cells. Activation both cytokine production and proliferative CD4+ CD8+ cells a concentration-dependent manner. The observed appeared occur endogenously were not dependent...
Loss of VHR phosphatase causes cell cycle arrest in HeLa carcinoma cells, suggesting that inhibition may be a useful approach to halt the growth cancer cells. We recently reported is upregulated several cervix lines as well carcinomas uterine cervix. Here we report development multidentate small-molecule inhibitors inhibit its enzymatic activity at nanomolar concentrations and exhibit antiproliferative effects on Chemical library screening was used identify hit compounds, which were further...
Regulation of Src kinase activity is tightly coupled to the phosphorylation status C-terminal regulatory tyrosine Tyr527, which, when phosphorylated by Csk, represses Src. Here, we demonstrate that activation Csk through a prostaglandin E2-cAMP-protein A (PKA) pathway inhibits This inhibitory operative in detergent-resistant membrane fractions where cAMP-elevating agents activate resulting concomitant decrease activity. The effect on depends membrane-anchored and co-localization all...
The lymphoid tyrosine phosphatase (Lyp, PTPN22) is a critical negative regulator of T cell antigen receptor (TCR) signaling. A single-nucleotide polymorphism (SNP) in the ptpn22 gene correlates with incidence various autoimmune diseases, including type 1 diabetes, rheumatoid arthritis, and systemic lupus erythematosus. Since disease-associated allele more potent inhibitor TCR signaling, specific Lyp inhibitors may become valuable treating autoimmunity. Using structure-based approach, we...
Abstract C‐terminal Src kinase (Csk) controls the family Lck, which is essential for T cell antigen receptor (TCR)‐mediated signaling. For first time, we here report effects of acuteelimination Csk in Jurkat cells and primary using short interfering (si) RNA. In both types, 70–85% knockdown was achieved within 48 h. No alterations surface expressionof CD3, CD4 or CD8, Lck protein level were observed. Phosphorylation Y505 markedly reduced a concomitant 4–5‐fold increase Y394 phosphorylation...
Drug-induced eosinophilic myocarditis is a life-threatening and frequently overlooked condition. The prevalence of in clozapine-treated patients may be as high 3 %. An association between olanzapine has not previously been described, but given the chemical similarity clozapine, we hypothesized existence such an association. We searched spontaneous adverse drug reports database Danish Health Medicines Authority for period from October 21, 1996 to – June 03, 2015. identified two fatal cases...
In the present study, we investigate mechanism for protein kinase A (PKA)-mediated activation of C-terminal Src (Csk). Although isolated Csk domain was phosphorylated at Ser(364) by PKA to same stoichiometry as wild-type Csk, significant observed only in presence purified homology 3 (SH3 domain). Furthermore, interaction between SH3 and domains facilitated PKA-mediated phosphorylation domain, evaluated surface plasmon resonance. This suggests that an overall structural organization are...
Src family kinases are suppressed by a "tail bite" mechanism, in which the binding of phosphorylated tyrosine C terminus protein to homology (SH) 2 domain N-terminal half forces catalytic into an inactive conformation stabilized additional SH3 interaction. In addition this intramolecular suppressive function, SH2 also mediates intermolecular interactions, crucial for T cell antigen receptor (TCR) signaling. To better understand relative importance these two opposite functions kinase Lck TCR...
The Csk tyrosine kinase negatively regulates the Src family kinases Lck and Fyn in T cells. Engagement of T-cell antigen receptor results a removal from lipid raft-associated transmembrane protein PAG/Cbp. Instead, becomes associated with an approximately 72-kDa tyrosine-phosphorylated protein, which we identify here as G3BP, phosphoprotein reported to bind SH3 domain Ras GTPase-activating protein. G3BP reduced ability phosphorylate at Y505 by decreasing amount rafts. As consequence,...
Abstract Here, we examined the functional involvement of heterotrimeric G‐proteins in TCR‐induced immune responses. TCR/CD3 crosslinking resulted activation both Gαq and Gαs, but not Gαi‐2. Targeting Gαi‐2 using siRNA demonstrated a specific role TCR signaling. Jurkat TAg T cells with knockdown displayed reduced Lck LAT phosphorylation, paradoxically showed sustained ERK1/2 phosphorylation increased NFAT‐AP‐1‐reporter activity implicating negative control downstream signaling IL‐2‐promoter...