Impaired Glycosylation of Vascular Endothelial Growth Factor Receptor 2 in Tumor Angiogenesis

肿瘤血管生成中血管内皮生长因子受体 2 的糖基化受损

• 批准号: 8908429
• 负责人: Kevin Brown Chandler
• 金额: $ 5.24万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8908429
• 关键词: Affect; Angiogenic Switch; BAY 54-9085; Binding Proteins; Blood Vessels; Cell membrane; Cell surface; Clathrin; Development; Drug resistance; Endocytosis; Endothelial Cells; Exposure to; Glycopeptides; Goals; Golgi Apparatus; Growth; Hypoxia; Imaging Techniques; Immunoprecipitation; Knowledge; Lead; Ligands; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Membrane; Molecular Biology; Neoplasm Metastasis; Organelles; Pathologic Neovascularization; Pattern; Phosphorylation; Play; Polysaccharides; Population; Process; Protein Glycosylation; Proteins; Proteomics; Receptor Activation; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Recycling; Residencies; Resistance; Role; Signal Transduction; Subcellular Fractions; Tumor Angiogenesis; Tumor Cell Line; UV Radiation Exposure; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factors; Vascularization; Western Blotting; Work; angiogenesis; antiangiogenesis therapy; bevacizumab; cancer therapy; crosslink; endosome membrane; extracellular; glycosylation; inhibitor/antagonist; link protein; molecular imaging; multicatalytic endopeptidase complex; novel; public health relevance; receptor; screening; sugar; therapeutic angiogenesis; therapy development; trafficking; tumor; tumor growth

 DESCRIPTION (provided by applicant): Angiogenesis (the development of new blood vessels from established vasculature) is essential for tumor growth and metastasis. Vascular endothelial growth factor receptor 2 (VEGFR-2) is a receptor tyrosine kinase (RTK) involved in angiogenic signaling in normal and pathological conditions. Tumors frequently express high levels of hypoxia-induced VEGF ligands that target VEGFR-2 to support tumor vascularization and growth. While VEGFR-2 inhibitors including bevacizumab, sorafenib and sunitinib are used for cancer treatment, the development of resistance to these agents poses an obstacle to effective management of cancer. Recently, impaired trafficking and ligand-independent VEGFR-2 activation and signaling in the Golgi have been demonstrated. Intriguingly, disruption of N-glycosylation affects VEGFR-2 trafficking and may play a role in this process. However, the impact of VEGFR-2 glycosylation on trafficking and receptor activation is largely unexplored. We hypothesize that altered protein glycosylation in pathological circumstances contributes to the sustained localization of VEGFR-2 to the Golgi apparatus by affecting trafficking of VEGFR-2 and leads to ligand-independent activation and signaling from the Golgi. Therefore, we propose to study the impact of VEGFR-2 glycosylation on VEGFR-2 trafficking and activation. We plan to explore this hypothesis by (A) establishing the glycosylation status of membrane and subcellular fractions of VEGFR-2 and examining their impact on receptor activation, (B) screening for glycosylation-dependent VEGFR-2 protein interactions in cell membrane and Golgi fractions, and (C) investigating the role of VEGFR-2 glycosylation in protein recycling, turnover and degradation. A major goal of this proposal is to explore the role of glycosylation in VEGFR-2 trafficking, signaling and aberrant tumor angiogenesis. I will analyze VEGFR-2 glycopeptides and released N-glycans and screen for VEGFR-2 glycosylation-dependent protein interactions using UV-activated crosslinking sugars via mass spectrometry. Results from this study will illuminate the role of glycosylation in VEGFR-2 trafficking and signaling, including: characterization of differences in glycosylation between Golgi and extracellular fractions, assessment of changes in receptor activation and signaling associated with changes in glycosylation, identification of glycosylation-specific VEGFR-2 interacting partners that modulate VEGFR-2 trafficking, and determination of the impact of receptor glycosylation on protein recycling and degradation.