Regulation of vascular endothelial growth factor receptor 2 trafficking and angiogenesis by Golgi localized t-SNARE syntaxin 6.
ABSTRACT Vascular endothelial growth factor receptor 2 (VEGFR2) plays a key role in physiologic and pathologic angiogenesis. Plasma membrane (PM) levels of VEGFR2 are regulated by endocytosis and secretory transport through the Golgi apparatus. To date, the mechanism whereby the VEGFR2 traffics through the Golgi apparatus remains incompletely characterized. We show in human endothelial cells that binding of VEGF to the cell surface localized VEGFR2 stimulates exit of intracellular VEGFR2 from the Golgi apparatus. Brefeldin A treatment reduced the level of surface VEGFR2, confirming that VEGFR2 traffics through the Golgi apparatus en route to the PM. Mechanistically, we show that inhibition of syntaxin 6, a Golgi-localized target membrane-soluble N-ethylmaleimide attachment protein receptor (t-SNARE) protein, interferes with VEGFR2 trafficking to the PM and facilitates lysosomal degradation of the VEGFR2. In cell culture, inhibition of syntaxin 6 also reduced VEGF-induced cell proliferation, cell migration, and vascular tube formation. Furthermore, in a mouse ear model of angiogenesis, an inhibitory form of syntaxin 6 reduced VEGF-induced neovascularization and permeability. Our data demonstrate the importance of syntaxin 6 in the maintenance of cellular VEGFR2 levels, and suggest that the inhibitory form of syntaxin 6 has good potential as an antiangiogenic agent.
- SourceAvailable from: Michel Fausther[Show abstract] [Hide abstract]
ABSTRACT: Portal fibroblasts (PF) are one of the two primary cell types contributing to the myofibroblast population of the liver and are thus essential to the pathogenesis of liver fibrosis. Monocyte chemoattractant protein-1 (MCP-1) is a known profibrogenic chemokine that may be of particular importance in biliary fibrosis. We examined the effect of MCP-1 on release of matrix metalloproteinase-9 (MMP-9) by rat PF. We found that MCP-1 blocks PF release of MMP-9 in a posttranslational fashion. We employed an optical and electron microscopic approach to determine the mechanism of this downregulation. Our data demonstrated that, in the presence of MCP-1, MMP-9-containing vesicles were shunted to a lysosome-like compartment. This is the first report of a secretory protein to be so regulated in fibrogenic cells.Physiological Reports. 11/2014; 2(11).
- [Show abstract] [Hide abstract]
ABSTRACT: A major challenge in muscle-invasive urothelial carcinoma (UC) is to identify biomarkers that can predict disease prognosis and treatment response after cystectomy. Therefore, we analyzed the potential prognostic value of the proteins vascular endothelial growth factor receptor 2 (VEGFR2), S100A4, and S100A6 in UC.Urologic Oncology 05/2014; · 3.36 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: The past5 years have witnessed a significant expansion in our understanding of vascular endothelial growth factor (VEGF) signaling. In particular, the process of canonical activation of VEGF receptor tyrosine kinases by homodimeric VEGF molecules has now been broadened by the realization that heterodimeric ligands and receptors are also active participants in the signaling process. Although heterodimer receptors were described 2 decades ago, their impact, along with the effect of additional cell surface partners and novel autocrine VEGF signaling pathways, are only now starting to be clarified. Furthermore, ligand-independent signaling (noncanonical) has been identified which occurs through galectin and gremlin binding and on rise of intracellular levels of reactive oxygen species. Activation of the VEGF receptors in the absence of ligand holds immediate implications for therapeutic approaches that exclusively target VEGF. The present review provides a concise summary of the recent developments in both canonical and noncanonical VEGF signaling and places these findings in perspective to their potential clinical and biological ramifications.Arteriosclerosis Thrombosis and Vascular Biology 10/2014; · 5.53 Impact Factor