Regulace signální transdukce leukocytů membránovými adaptorovými proteiny a kinázami

Borna, Šimon

Signaling pathways must be finely tuned to assign a signal of appropriate strength and duration to the receptor stimulation. Their dysregulation can be very harmful. The consequences of dysregulated signaling pathways vary from autoimmunity, immunodeficiency, and autoinflammation to abnormal proliferation and cancer. In my thesis I aimed to characterize the roles of kinases and membrane associated or transmembrane adaptor proteins in signaling pathways downstream of different receptors. First, I was comparing the roles of SRC family kinases (SFK) in the initiation of antigen receptor signaling in B cells and in T cells. This effort resulted in the manuscript where we re-evaluated current data, which suggested that SYK can initiate BCR signaling independently of SFK. We show that much lower SFK activity is required for the initiation of BCR signaling than for TCR signaling, but we did not find any evidence for SFK-independent signal transduction. We also found that multiple factors are responsible for setting the higher threshold for SFK activity required to initiate signaling by TCR, including differences between SYK and ZAP-70, structure of the antigen receptor itself and separation of the receptor from transmembrane adaptor LAT, which is a major hub coordinating the formation of TCR signalosome....

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