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Phosphorylation of the adaptor protein PSTPIP2 and its role in neutrophilic granulocytes
Dvořáček, Tomáš ; Brdička, Tomáš (advisor) ; Ballek, Ondřej (referee)
PSTPIP2 is an adaptor protein of the F-BAR family, which is an important regulator controlling the effector mechanisms of innate immune cells. The regulatory functions of this protein were discovered thanks to the CMO mouse strain, which lost the expression of this protein. As a result of PSTPIP2 deficiency, mice of the CMO strain develop an autoinflammatory disease affecting bone tissue and skin. The main mechanism that drives its pathology is the loss of regulation of the neutrophil granulocyte activity. These cells then produce excessive amounts of the pro-inflammatory cytokine IL-1β and reactive oxygen species. However, the exact molecular mechanism of action of the PSTPIP2 protein is unknown. When the PSTPIP2 protein is activated, it is phosphorylated and interacts with other proteins, which mediate its regulatory function. Interaction partners described so far in neutrophil granulocytes include phosphatases of the PEST family, the lipid phosphatase SHIP1 and the non-receptor tyrosine kinase CSK. In this thesis, we identified kinases from the SRC family as kinases that phosphorylate PSTPIP2. Furthermore, we found that the main phosphorylation sites of PSTPIP2 are tyrosines at positions 323 and 329. Finally, we proved that SHIP1 can bind to the phosphotyrosine motif around the tyrosine at...
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Spatiotemporal regulation of Lck activity in the initiation of TCR signalling
Ballek, Ondřej ; Filipp, Dominik (advisor) ; Černý, Jan (referee) ; Vomastek, Tomáš (referee)
Ph.D. Thesis: Spatiotemporal regulation of Lck aktivity in the TCR signalling Ondřej Ballek Abstract Arguably, the most studied cell types of immune system are T-cells. They are key players of adaptive immunity responsible for targeted action against pathogens or other danger signals. Due to their central importance, any alteration in the regulation of their activity leads often to immunopathology. Thus, the knowledge how to harness their bio-destructive effector functions is of critical importance. Up today, there is only limited consensus on the nature of molecular mechanisms controlling the initiation of T-cell activation. When T-cell receptor (TCR) recognizes its cognate antigen presented on antigen presenting cell (APC), the activation signal is transmitted through the plasma membrane and subsequent phosphorylation of cytoplasmic chains of TCR complex ensues. This is commonly considered as the first biochemical sign of T-cell activation, the process called TCR triggering. How the activation signal gets into the cell and which molecular mechanisms control TCR triggering are two fundamental, yet still unanswered questions. In this study we focused mainly on the latter one. Working within this experimental framework, we investigated three particular problems. The first one concerns the spatiotemporal...
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