| Research Abstract |
In this project, we have analyzed the molecular links between vector transport machinery and cell adhesion machinery. Our primary focus is on membrane-associated proteins that interact directly or indirectly with cell adhesion molecules.
We identified novel membrane-associated proteins including PAPIN, ankycorbin, and carom. PAPIN is a multi-PDZ protein and presumably a scaffold protein. Both of ankycorbin and carom indirectly interact with actin. Interestingly, carom interacts with MAGI-1, a tight junction-associated protein, before cell junctions become mature but it comes to bind to CASK, a different membrane-associated protein, in fully polarized epithelial cells. We also clarified how membrane-associated proteins are targeted to epithelial junctions. MAGI-1 is recruited to the lateral membranes through the interaction with beta-catenin. PAPIN and ERBIN interact with p0071, a member of catenin family proteins, but their subcellular localizations are independent of these interactions
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. Likewise, Lin-7, a beta-catenin-interactor, is recruited to the lateral membranes by a cell adhesion molecule, nectin, and its associated protein, afadin, but not by beta-catenin. We also discovered a novel cell adhesion molecule that binds to MAGI-1 and named it JAM4. JAM4 and MAGI-1 co-operate to regulate the intercellular permeability. JAM4 enhances hepatocyte growth factor-mediated signaling putatively by activating Rac. At synapses, a neuronal isoform of MAGI-1 named S-SCAM, which is recruited by beta-catenin to cadherin-based adhesion sites, subsequently induces another cell adhesion mediated by neuroligin and triggers the remodeling of actin cytoskeleton. Similarly, in epithelial cells, nectin induces the cadherin-based adhesion via afadin and the accumulation ofJAM1 that is a component of tight junctions. Moreover, we have found that MAGI-1 links JAM4 and nephrin in kidney glomeruli. All these findings indicate that membrane-associated proteins are important to link different categories of cell adhesion molecules. Finally, we have obtained four novel proteins binding to microtubules. Less
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