Developmental partitioning of SYK and ZAP70 prevents autoimmunity and cancer
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PROVIDER: PRJNA625737 | ENA |
REPOSITORIES: ENA
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Project description:Even though SYK and ZAP70 kinases share high sequence homology and serve analogous functions, their expression in B and T cells is strictly segregated throughout evolution. Here, we identified aberrant ZAP70 expression as a common feature in a broad range of B cell malignancies. We validated SYK as the kinase that sets the thresholds for negative selection of autoreactive and premalignant clones. When aberrantly expressed in B cells, ZAP70 competes with SYK at the BCR signalosome and redirects SYK from negative selection to tonic PI3K signaling, thereby promoting B cell survival. In genetic mouse models for B-ALL and B-CLL, conditional expression of Zap70 accelerated disease onset, while genetic deletion impaired malignant transformation. Inducible activation of Zap70 during B cell development compromised negative selection of autoreactive B cells, resulting in pervasive autoantibody production. Strict segregation of the two kinases is critical for normal B cell selection and represents a central safeguard against the development of autoimmune disease and B cell malignancies.
2021-05-21 | GSE148797 | GEO
Project description: Not available
| S-EPMC8239336 | biostudies-literature
Project description:Lack of NFATc1 SUMOylation prevents autoimmunity and alloreactivity
| PRJNA623120 | ENA
Project description:T cell antigen receptor (TCR) signaling depends upon the kinases Lck and Zap70. Lck phosphorylates the TCR, facilitating Zap70 recruitment to the stimulated TCR. Lck also phosphorylates Zap70, relieving its auto-inhibition and activating its catalytic domain. Zap70 then phosphorylates the critical adaptors LAT and SLP76 which serve to nucleate key effector molecules required for downstream responses. However, mechanisms facilitating the interaction of Zap70 with its substrates have not been described. We report an evolutionarily conserved proline-rich motif in LAT is important for Zap70-induced phosphorylation of LAT and downstream signaling. This LAT proline-rich motif associated with the Lck SH3 domain, thereby facilitating Zap70-mediated phosphorylation of LAT and downstream functions. Our results suggest Lck orchestrates multiple steps in TCR signaling including the newly described facilitation of the interaction of Zap70 with its substrate LAT. This previously unrecognized feature of TCR proximal signaling may contribute to the development of more immunomodulatory therapies.
2019-11-12 | PXD008258 | Pride
Project description: Not available
| S-EPMC3977572 | biostudies-literature
Project description:The progression of periodontitis is closely associated with Th17 cells, yet the functional differences of Th17 cells under periodontitis conditions remain poorly understood. Therefore, we established an experimental periodontitis model using IL-17GFP/+ transgenic mice, isolated Th17 cells via flow cytometry, and performed RNA sequencing. Results showed that periodontitis induced significant changes in Th17 cells, including a marked increase in cell proportion, as well as upregulated expression of Th17-associated immunoinflammatory signaling pathways and inflammatory cytokines (IL-17, IL-23, and GM-CSF). Within Th17 differentiation-related pathways, Zap70 expression was significantly upregulated and exhibited a positive correlation with IL-17. Local silencing of Zap70 via AAV-sh-Zap70 significantly reduced the expression of IL-17, IL-23/IL-23r, and GM-CSF, while alleviating alveolar bone resorption. In conclusion, periodontitis significantly enhances the proinflammatory capacity of Th17 cells, and this change is associated with Zap70, which indicates that Zap70 holds promise as a potential therapeutic target for periodontitis.
2026-02-20 | GSE319621 | GEO
Project description:Comparison of Chronic Lymphocytic Leukemia patients expressing high or low levels of ZAP70 mRNA: prognostic factors and interaction with the microenvironment. Zeta-associated protein 70 (ZAP70) is a widely recognized prognostic factor in chronic lymphocytic leukemia (CLL), but mechanisms by which its higher expression leads to a poor outcome remain to be fully explained. In an attempt to unveil unfavorable cellular properties linked to high ZAP70 expression, we used gene expression profiling to identify genes associated with disparities in B-cells from CLL patients expressing high versus low ZAP70 mRNA, measured by quantitative real-time PCR. Keywords: comparison of poor and good prognosis CLL patient transcriptome regarding ZAP70 expression
2009-04-18 | GSE12734 | GEO
Project description:Comparison of Chronic Lymphocytic Leukemia patients expressing high or low levels of ZAP70 mRNA: prognostic factors and interaction with the microenvironment. Zeta-associated protein 70 (ZAP70) is a widely recognized prognostic factor in chronic lymphocytic leukemia (CLL), but mechanisms by which its higher expression leads to a poor outcome remain to be fully explained. In an attempt to unveil unfavorable cellular properties linked to high ZAP70 expression, we used gene expression profiling to identify genes associated with disparities in B-cells from CLL patients expressing high versus low ZAP70 mRNA, measured by quantitative real-time PCR. Experiment Overall Design: Two groups of seven CLL patients were compared, selected on the basis of either high or low ZAP70 mRNA expression. Total RNA from CD19+ purified cells was exctracted and hybidyzed on Affymetrix GeneChipî Human Genome U133 Plus 2.0 Array. Amplification, hybridization and scanning were done according to standard Affymetrix protocols (www.affymetrix.com). CEL files were ,normalized with RMA method.
2009-04-25 | E-GEOD-12734 | biostudies-arrayexpress