Structural basis for GnT-V therapeutic inhibitors

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DESCRIPTION(provided by applicant): The long-term objective of these experiments is to determine if a particular glycosyltransferase, termed GIcNAc-T V (GnT-V) or Mgat5, regulates N-linked oligosaccharide expression on adhesion proteins that cause changes in cell adhesion and tumor progression. Studies have documented an association between specific changes in N-linked oligosaccharides with b(1,6) branches and oncogenic transformation, increased tumor cell invasiveness, and metastatic potential. Elevation of b(1,6) branches has also been documented in the progression of human mammary and colon carcinomas. The synthesis of this N-linked oligosaccharide branch is catalyzed by GIcNAc-T V, and the activity of this enzyme is selectively increased after transformation of cultured cells with several oncogenes. Transfection of GnT-V cDNA into several cell types causes reduced adhesion to the extracellular matrix glycoproteins fibronectin and collagen type IV, suggesting that b(1,6) branching of integrins can alter integrin ligand binding affinities. Aim I will investigate the mechanisms by which changes in N-linked oligosaccharide 13(1,6) branching regulates integrin ligand binding. Aim II will answer the question: Does elimination of GnT-V activity and expression of the N-linked (1,6) branch on glycoproteins influence MMTV-neu-induced breast carcinoma formation or progression? A transgenic mouse that does not express GnT-V activity, will be crossed with the MMTV-neu mouse and the female offspring analyzed for tumor formation, progression, and metastases. In Aim Ill, the adhesive and signaling properties of these tumor cells, mouse embryo fibroblasts, and cells with over-expressed GnT-V will be studied in detail and compared.