The polarization of epithelial cells is of crucial importance in normal renal function. TO achieve this polarization, proteins must be targeted to the basolateral or apical surface of epithelial cells. Recent work has suggested a role for protein-protein interaction domains in the targeting of proteins to specific cell surfaces. One family of proteins that is likely to be involved in such targeting are the X11 proteins. X11 family members have multiple protein-protein interaction motifs including a phosphotyrosine binding (PTB) domain. PTB domains bind to beta turn peptide motifs in a phosphotyrosine dependent and independent fashion. X11 family members also have two PDZ domains. Proteins with PDZ domains can target and aggregate cell surface proteins by binding short peptide sequences present in the carboxy-terminal tail of these surface proteins. Recent work has indicated that the C. Elegans homologue of X11 may target growth factor receptors to the basolateral surface of epithelial cells. We have recently identified a mammalian isoform of X11 in epithelial cells and hypothesize that this form of X11 has a role in protein targeting to the basolateral membranes of epithelial cells. Protein interaction domains may also be important for the apical targeting of proteins. Podocalyxin is localized to the apical surface of renal podocytes and is thought to play an important role in the glomerular filtration apparatus. While the extracellular domain of podocalyxin is poorly conserved between main and rabbit, the intracellular domain is 96% identical. The intracellular domain of podocalyxin contains a sequence highly related to motifs that bind PDZ domains. We hypothesize that this motif is important for the retention and aggregation of podocalyxin at the apical surface of epithelial cells. To test these hypotheses we plan to examine the localization of X11 isoforms within epithelial cells and to identify the role of the specific protein-protein-protein interaction domains in this localization. We will also examine the role of the podocalyxin intracellular domain, specifically the PDZ binding motif, in podocalyxin localization and protein interactions.
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