Protein kinase C (PKC)-induced phosphorylation in macrophages is necessary for a full functional response to bacterial lipopolysaccharides (LPS).
The aim of this research is to investigate the mechanism by which PKC-dependent signaling pathways modulate membrane traffic events related to the immune response to infectious agents. Our focus is the molecular characterization of the MacMARCKS protein, an LPS-inducible PKC substrate, which is associated with vectorial membrane movement in macrophages. We will characterize phagocytosis, endocytosis, and antigen presentation in macrophages isolated from MacMARCKS null (knockout) mice, and from transgenic mice which express a dominant negative MacMARCKS transgene. Parallel studies will done in macrophage-like cell lines which stably express mutant forms of MacMARCKS. PKC-dependent phosphorylation, and LPS, regulate the movement of MacMARCKS between intracellular compartments including phagosomes, lysosomes, and endosomes. We will define the signals which target MacMARCKS to each of these compartments and identify the protein """"""""receptors"""""""" to which they bind. We have identified an LPS response element (LRE) in the 5' upstream region of the MacMARCKS promoter. The LRE will be characterized, and trans-acting factors will be identified with the ultimate goal of reconstructing the LPS signal transduction pathway from the plasma membrane to the nucleus.
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