This project explores the molecular basis for selective targeting of different membrane proteins to different destinations in polarized epithelia. The focus is upon three integral membrane glycoproteins: dipeptidylpeptidase IV, an apical protein; Na,K-ATPase, a basolateral protein; and LEP100, a lysosomal protein that, least in some cells, cycles to the plasma membrane. It is postulated that each membrane protein contains structural information which the cell uses in sorting the protein for delivery to the correct destination. The short-range goal of this project is to identify aspects of structure necessary and sufficient for the targeting of each protein to the correct destination. In the case of the Na,K-ATPase, the interaction with the cytoskeleton may play an essential role in basolateral localization; this will be explored by identifying and eliminating the cytoskeleton-binding site on the ATPase. The second goal is to determine whether the same structural information involved in targeting in one type of epithelium serves this purpose in each of three epithelia (renal, intestinal, and hepatic) which appear to use somewhat different mechanisms to achieve polarity. A third goal is to explore the characteristics of the sorting/targeting mechanism(s), beginning with the question of whether the putative receptor mechanisms for recognizing the individual targeting signals are saturable. A long-term goal is to identify the components of the cellular machinery involved in the sorting and targeting of membrane proteins in polarized epithelia and to understand their individual functions.
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