This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.One of the key cellular processes involved in tumor growth, invasion, and metastasis is the binding of an HMGB1 protein, amphoterin, to the cell surface receptor for advanced glycation end products (RAGE), with subsequent activation of signal transduction pathways. We found that this binding involves novel glycans expressed on RAGE. This proposal explores the structure of the novel glycans and the role of the glycans in RAGE-amphoterin mediated signaling events, including tumor growth and metastasis. Mammalian lectins often bind to anionic glycans containing sialic acid, phosphate, sulfate esters, or uronic acids. We found new carboxylate modifications on endothelial cell N-linked glycans that are completely distinct from selectin ligands. These novel glycans mediate endothelium/leukocyte interaction, intraperitoneal inflammation, and neurite outgrowth. A specific monoclonal antibody against the glycans blocks peritoneal inflammation in the mouse. The carboxylated glycans bind to four proteins: amphoterin, annexin-I, S100A8/A9 and S100A12, which have been variably linked to neurite outgrowth, tumor growth and metastasis, inflammation and septic shock. We also found evidence that these novel glycans are present on RAGE, a well-documented signal-transducing receptor for amphoterin. Based on our findings, we hypothesize that the novel glycans may have an in vivo role in tumor growth and metastasis, and that glycosylation of RAGE could be important in tumor related processes. We therefore propose to:1. Establish the structure of the novel carboxylated glycans on RAGE. 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 leading 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 carbohydrate based adhesion in normal and malignant cells. A novel therapeutic approach may also emerge.
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