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 I ll, 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.
|Lee, Jin Kyu; Matthews, Russell T; Lim, Jae-Min et al. (2012) Developmental expression of the neuron-specific N-acetylglucosaminyltransferase Vb (GnT-Vb/IX) and identification of its in vivo glycan products in comparison with those of its paralog, GnT-V. J Biol Chem 287:28526-36|
|Abbott, Karen L; Pierce, J Michael (2010) Lectin-based glycoproteomic techniques for the enrichment and identification of potential biomarkers. Methods Enzymol 480:461-76|
|Guo, Hua-Bei; Johnson, Heather; Randolph, Matthew et al. (2010) Specific posttranslational modification regulates early events in mammary carcinoma formation. Proc Natl Acad Sci U S A 107:21116-21|
|Abbott, Karen L; Lim, Jae-Min; Wells, Lance et al. (2010) Identification of candidate biomarkers with cancer-specific glycosylation in the tissue and serum of endometrioid ovarian cancer patients by glycoproteomic analysis. Proteomics 10:470-81|
|Alvarez-Manilla, Gerardo; Troupe, Karolyn; Fleming, Maria et al. (2010) Comparison of the substrate specificities and catalytic properties of the sister N-acetylglucosaminyltransferases, GnT-V and GnT-Vb (IX). Glycobiology 20:166-74|
|Guo, Hua-Bei; Johnson, Heather; Randolph, Matthew et al. (2009) Knockdown of GnT-Va expression inhibits ligand-induced downregulation of the epidermal growth factor receptor and intracellular signaling by inhibiting receptor endocytosis. Glycobiology 19:547-59|
|Guo, Hua-Bei; Johnson, Heather; Randolph, Matthew et al. (2009) Regulation of homotypic cell-cell adhesion by branched N-glycosylation of N-cadherin extracellular EC2 and EC3 domains. J Biol Chem 284:34986-97|
|Abbott, Karen L; Matthews, Russell T; Pierce, Michael (2008) Receptor tyrosine phosphatase beta (RPTPbeta) activity and signaling are attenuated by glycosylation and subsequent cell surface galectin-1 binding. J Biol Chem 283:33026-35|
|Abbott, Karen L; Nairn, Alison V; Hall, Erica M et al. (2008) Focused glycomic analysis of the N-linked glycan biosynthetic pathway in ovarian cancer. Proteomics 8:3210-20|
|Abbott, Karen L; Aoki, Kazuhiro; Lim, Jae-Min et al. (2008) Targeted glycoproteomic identification of biomarkers for human breast carcinoma. J Proteome Res 7:1470-80|
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