Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 291, Issue 37, Pages 19245-19256Publisher
ELSEVIER
DOI: 10.1074/jbc.M116.740266
Keywords
AMP-activated kinase (AMPK); angiogenesis; atomic force microscopy (AFM); Beclin-1 (BECN1); perlecan; proteoglycan
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Funding
- National Institutes of Health [RO1 CA39481, RO1 CA47282, RO1 CA164462, T32 AA07463]
- Department of Education GAANN Program
- Drexel Interdisciplinary Collaboration and Research Enterprise (iCARE)
- Drexel
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Endorepellin, the C-terminal domain of perlecan, is an angiostatic molecule that acts as a potent inducer of autophagy via its interaction with VEGFR2. In this study, we examined the effect of endorepellin on endothelial cells using atomic force microscopy. Soluble endorepellin caused morphological and biophysical changes such as an increase in cell surface roughness and cell height. Surprisingly, these changes were not accompanied by alterations in the endothelial cell elastic modulus. We discovered that endorepellin-induced autophagic flux led to co-localization of mammalian target of rapamycin with LC3-positive autophagosomes. Endorepellin functioned upstream of AMP-activated kinase , as compound C, an inhibitor of AMP-activated kinase , abrogated endorepellin-mediated activation and co-localization of Beclin 1 and LC3, thereby reducing autophagic progression. Functionally, we discovered that both endorepellin and Torin 1, a canonical autophagic inducer, blunted ex vivo angiogenesis. We conclude that autophagy is a novel mechanism by which endorepellin promotes angiostasis independent of nutrient deprivation.
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