Cytoskeletal Signaling Proteins: Complex Regulatory Mechanisms and Roles in Innate Immunity Public Deposited

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  • March 20, 2019
Creator
  • Cai, Xinming
    • Affiliation: School of Medicine, Department of Cell Biology and Physiology
Abstract
  • In animals, most of the tissues are surrendered by extracellular matrix. The extracellular matrix plays multiple roles in maintaining the function of organs. It not only provides physical support to assemble the cells into an intact tissue but also sends signals to surrounding cells to regulate several cellular behaviors, such as proliferation and anti-apoptosis. The major contact between extracellular matrix and cells is mediated by focal adhesions, a transmembrane protein complex working as a hub to convert the matrix/cell interaction into a chemical signaling. Just like a canonical signaling pathway, focal adhesion signaling cascade is composed of receptors, enzymes and scaffolding proteins. The interplay of these elements precisely transmits the extracellular signal into cells to induce downstream effects. The work described here represents a collection of studies to decipher the detail mechanism of adhesion signaling. The activation of FAK is an essential event in adhesion signal transduction. In chapter II, FRET technology was applied to visualize the spatial and temporal activation of FAK in living cells. PIP2 was identified as a FAK binding partner. That also promotes the activation of FAK via conformational change. In addition to the FAK regulation mechanism, a novel paxillin modification was identified in chapter III. Phosphorylation of paxillin on serine 126 and 130, which is mediated by an ERK/GSK-3 dual kinase mechanism, regulates the cytoskeleton reorganization. Adhesion signaling is critical for multiple biological events, such as angiogenesis, neurite extension, and inflammation. Innate immunity works as the first barrier to fight against microbe infection. It not only directly destroys pathogens but also activates the antigen specific adaptive immune system. The roles of adhesion signaling proteins in innate immunity were also investigated in chapter II and III. The paxillin is phosphorylated by ERK and GSK-3 following LPS stimulation in macrophages, which is required for LPS induced macrophage spreading. In Fcγ receptor meditated phagocytosis, Pyk2 is activated and accumulated to phagocytotic cup during phagocytosis. The deletion or inactivation of Pyk2 impairs phagocytosis in macrophage. The work presented here expands our understanding of how focal adhesion proteins regulate multiple singling pathways.
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  • Schaller, Michael D.
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