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Regulatory roles of PAG and CSK in FcɛRI signaling of mast cells
Potůčková, Lucie ; Dráber, Petr (advisor) ; Šebo, Peter (referee) ; Holáň, Vladimír (referee)
8 1 ABSTRACT (EN) This thesis is focused mainly on understanding mechanisms of regulatory roles of C-terminal Src kinase (CSK) and phosphoprotein associated with glycosphingolipid- enriched microdomains (PAG) in the high-affinity IgE receptor (FcɛRI)-mediated signaling of murine mast cells. FcɛRI activation is initiated by aggregation of the receptor by complexes of multivalent antigen with IgE, followed by activation and enhanced activities of protein tyrosine kinases, phosphatases, adaptor proteins and number of other signal transduction molecules. The signaling events result in mast cell degranulation and release of variety of proinflammatory mediators, responsible for initiation of allergy and other inflammatory diseases. Understanding the function of key regulatory molecules controlling FcεRI-mediated mast cell activation, degranulation, and cytokines production could have therapeutic impact. CSK is a major negative regulator of Src family tyrosine kinases (SFKs) that play a critical role in various immunoreceptor signaling events. However, its function in mast cell activation has not been completely understood. Because of its cytoplasmic localization, CSK was assumed to be brought to the vicinity of the plasma membrane- bound SFKs via binding to membrane-bound adaptors and PAG was a major candidate....
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Regulatory mechanisms of centrosomal microtubule nucleation
Klebanovych, Anastasiya ; Dráber, Pavel (advisor) ; Hašek, Jiří (referee) ; Vomastek, Tomáš (referee)
The spatio-temporal organization and dynamic behavior of microtubules accurately react to cellular needs during intracellular transport, signal transduction, growth, division, and differentiation. The cell generates centrosomal microtubules de novo with the help of γ-tubulin complexes (γTuRCs). The post-translational modifications fine-tune microtubule nucleation by targeting the proteins, interacting with γTuRCs. However, the exact signaling pathways, regulating centrosomal microtubule nucleation, remain mostly unknown. In the presented thesis, we functionally characterized protein tyrosine phosphatase SHP-1 and E3 UFM-protein ligase 1 (UFL1) with its interacting protein CDK5RAP3 (C53) in the regulation of centrosomal microtubule nucleation. We also elucidated the role of actin regulatory protein profilin 1 in this process. We found that SHP-1 formed complexes with γTuRC proteins and negatively regulated microtubule nucleation by modulating the amount of γ-tubulin/γTuRC at the centrosomes in bone marrow-derived mast cells (BMMCs). We suggested a novel mechanism with centrosomal tyrosine-phosphorylated Syk kinase, targeted by SHP-1 during Ag-induced BMMCs activation, regulating microtubules. We showed for the first time that UFL1/C53 protein complex is involved in the regulation of microtubule...
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Regulatory roles of PAG and CSK in FcɛRI signaling of mast cells
Potůčková, Lucie ; Dráber, Petr (advisor) ; Šebo, Peter (referee) ; Holáň, Vladimír (referee)
8 1 ABSTRACT (EN) This thesis is focused mainly on understanding mechanisms of regulatory roles of C-terminal Src kinase (CSK) and phosphoprotein associated with glycosphingolipid- enriched microdomains (PAG) in the high-affinity IgE receptor (FcɛRI)-mediated signaling of murine mast cells. FcɛRI activation is initiated by aggregation of the receptor by complexes of multivalent antigen with IgE, followed by activation and enhanced activities of protein tyrosine kinases, phosphatases, adaptor proteins and number of other signal transduction molecules. The signaling events result in mast cell degranulation and release of variety of proinflammatory mediators, responsible for initiation of allergy and other inflammatory diseases. Understanding the function of key regulatory molecules controlling FcεRI-mediated mast cell activation, degranulation, and cytokines production could have therapeutic impact. CSK is a major negative regulator of Src family tyrosine kinases (SFKs) that play a critical role in various immunoreceptor signaling events. However, its function in mast cell activation has not been completely understood. Because of its cytoplasmic localization, CSK was assumed to be brought to the vicinity of the plasma membrane- bound SFKs via binding to membrane-bound adaptors and PAG was a major candidate....
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