This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Polymeric IgA (pIgA) transcytosis mediated by the polymeric immunoglobulin receptor (pIgR) plays a key role in the mucosal immune defense against pathogens and allergens. IgA trancytosis occurs in all mucosal epithelium and in hepatocytes. The binding of pIgA to pIgR stimulates transcytosis of the pIgR-pIgA complex and activates several signaling molecules that include the Src-family non-receptor tyrosine kinase, p62yes. Recently p62yes has been found to control pIgA transcytosis in mouse liver. It is not clear how p62yes regulates pIgA transcytosis. Previous data showed that there is no direct interaction between p62yes and pIgR. pIgR is not the substrate of p62yes since p62yes is unable to phosphorylate pIgR and pIgR is not phosphorylated on tyrosine. Most likely, p62yes regulates the pIgR-pIgA transcytosis via its substrates. Identification of the substrates of p62yes is a key step leading to understanding the mechanisms of pIgA transcytosis. By using a novel technique developed by Dr. Shokat, our preliminary data suggest that Epidermal Growth Factor Receptor (EGFR) may be one of the p62yes substrates. EGFR may be activated by p62yes upon pIgA binding to pIgR. In turn it directly activates PLC-gamma1, thereby leading to activation of the entire signaling pathway. In the proposed experiments, the following specific hypotheses will be tested: 1) EGFR is a possible substrate of p62yes and may play a role in the regulation of pIgA transcytosis in epithelial cells and hepatocytes. 2) pIgR-pIgA, p62yes and a substrate of p62yes form a protein complex in an endosomal compartment in rat hepatocytes. 3) Activation of EGFR increases pIgA transcytosis. This proposed research could help us to understand mucosal immunity and the basic mechanisms of protein transport in polarized epithelial cells and hepatocytes.
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