The complex formation of c-Kit and the IL-33R and its influence on SCF- and IL-33-induced mast cell effector functions

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We identified a functionally relevant crosstalk between the activated receptor tyrosine kinase c-Kit and the IL-33R in mast cells. Thereby, activation of c-Kit by its ligand the stem cell factor (SCF) induces interaction of c-Kit with the IL-33R and potentiates the IL-33-induced cytokine production in mast cells. The interaction of activated c-Kit with the unligated IL-33R is not only the precondition for IL-33 to induce its full biological effector functions. Moreover the unligated IL-33R is also essential for activated c-Kit to mediate its complete signaling (e.g. Lyn and STAT activiation). Thererfore the unligated IL-33R establishes the basis for activated c-Kit to mediate SCF-induced and Lyn-dependent signaling pathways and effector functions in mast cells. However, the structural mechanism behind the formation of the c-Kit/IL-33R complex and its impact on SCF and/ or IL-33-induced mast cell effector functions in vitro and in vivo is unknown. Therefore, the overall goal of this study is to investigate the structural requirements for formation of the c-Kit/IL-33R complex and its functional relevance in vitro and in vivo.Therefore the specific aims of this project are:To perform structure/function analysis to identify the extracellular domains of the IL-33R which are critical to mediate complex formation with c-Kit. To investigate the influence of the c-Kit/IL-33R/Lyn complex formation in IL-33-induced and mast cell-dependent allergic reactions in vivo.