Document Type
Article
Publication Date
8-3-2018
Abstract
Regulation of autophagy by proteolytically cleaved fragments of heparan sulfate proteoglycans is a novel and current research focus in tumor biology. Endorepellin is the C-terminal angiostatic fragment of the heparan sulfate proteoglycan perlecan and induces autophagy in endothelial cells. To further investigate this property, we used NanoString, a digital PCR platform for measuring pre-defined transcripts in biological samples to analyze a custom subset of 95 autophagy-related genes in human umbilical vein endothelial cells treated with ultrapure human recombinant endorepellin. We discovered an endorepellin-evoked pro-autophagic and pro-mitophagic gene expression signatures, which included two coordinately up-regulated mitochondrial-associated genes encoding the E3 ubiquitin protein ligase Parkin and the tumor suppressor mitostatin. Induction of both proteins required the tyrosine kinase activity of vascular endothelial growth factor receptor 2 (VEGFR2). Furthermore, we discovered that endorepellin evoked mitochondrial depolarization in endothelial cells via a specific interaction between its two proximal LG1/2 domains and VEGFR2. We also found that following loss of membrane potential, mitostatin and parkin interact and that mitostatin associates with the established Parkin receptor mitofusin-2. In conclusion, we have identified a critical role for endorepellin in remodeling the autophagic transcriptome and influencing mitochondrial homeostasis.
Recommended Citation
Neill, Thomas; Andreuzzi, Eva; Wang, Zi-Xuan; Peiper, Stephen C.; Mongiat, Maurizo; and Iozzo, Renato V., "Endorepellin remodels the endothelial transcriptome toward a pro-autophagic and pro-mitophagic gene signature." (2018). Department of Pathology, Anatomy, and Cell Biology Faculty Papers. Paper 238.
https://jdc.jefferson.edu/pacbfp/238
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
PubMed ID
29921586
Language
English
Comments
This research was originally published in Journal of Biological Chemistry. Neill, T., Andreuzzi, E., Wang, Z.., Peiper, S. C., Mongiat, M., & Iozzo, R. V.. Endorepellin remodels the endothelial transcriptome toward a pro-autophagic and pro-mitophagic gene signature. Journal of Biological Chemistry. 2018; 193:12137-12148. © the American Society for Biochemistry and Molecular Biology.