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Browsing by Subject "C-Cbl, Integrin Signaling"

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    Regulation of autoimmunity and integrin signaling by adaptor proteins ADAP, PRAM-1 and C-CBL
    (2008-12) Zou, Liangxing
    To increase our understanding of adaptor proteins in immune responses, we investigated the roles of adaptor protein ADAP in autoimmune diabetes, and PRAM-1 and c-Cbl in integrin signaling in neutrophils. ADAP deficiency introduced into BDC2.5 transgenic background enhances lymphopenia-stimulated proliferation of autoreactive T cells and autoimmune diabetes, which can be relieved by syngeneic transferred T cells. Further studies suggest that impaired thymic selection, but not defective survival of peripheral T cells, contributes to enhanced lymphopenic stimulation in ADAP-deficient BDC2.5 mice. Therefore, we conclude that ADAP suppresses lymphopenia-dependent autoimmune diabetes through the promotion of thymic output. These data reveal a novel mechanism of autoimmunity regulated by adaptor protein ADAP. When we started to explore the molecular mechanisms regulated by PRAM-1 of integrin signaling in neutrophils, we detected coimmunoprecipitation of c-Cbl and PRAM-1 in NB4 cells. Further, we discovered that c-Cbl positively regulates integrin-dependent oxygen burst but negatively regulates Fc receptor-dependent Ca2+ flux in neutrophils. The underlying molecular mechanisms are currently under investigation. Collectively, data presented in this thesis emphasize the essential roles of adaptor proteins in signal transduction and autoimmunity, and will increase our understanding of adaptor proteins in immune responses.