Malignancy involves cellular growth, movement, and metastasis. One of the key cellular check-points regulating these features is the binding of a secreted cytosolic molecule called amphoterin to the cell surface receptor for advanced glycation end products (RAGE). We found that this binding involves novel glycans that we discovered. This proposal explores the structure and function of the glycans that mediate these interactions. We have identified a new type of carboxylated N-linked oligosaccharide that is especially enriched in endothelial cells, embryonic neurons and cancer cells. Our biochemical and immunological evidence indicates that the antigen contains di-carboxylated amino acids amide-linked to the sugar chains. These novel glycans mediate endothelium/leukocyte binding, and intraperitoneal inflammation in vivo and neurite outgrowth in vitro. The carboxylated glycans directly bind to four proteins: amphoterin, annexin-I and S 100A8/A9, and S100A12, which have been linked in various ways to inflammation, septic shock, tumor growth or metastasis. We found that RAGE N-linked sugar chains contain the carboxylates and that they mediate amphoterin-RAGE binding and some of the multiple intracellular signaling events they ignite. To understand the role of the carboxylated glycans in this complex process, we propose to: 1. Establish the detailed structure of the carboxylated glycans on bovine RAGE and in neuroblastoma cells. 2. Determine the significance of carboxylated glycans in defining the pathophysiological functions of RAGE, in terms of ligand binding and intracellular signaling. 3. Assess the role of carboxylated glycans in mediating amphoterin-RAGE interactions in vitro and in vivo that lead to tumor growth, invasion, and metastasis.The fundamental understanding of the structure of these novel glycans together with their effects on tumor growth and metastasis are likely to add an important dimension to the understanding of these pathologies and may lead to novel therapeutic approaches to block them.
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