title: Decorin has an appetite for endothelial cell autophagy.
abstract: DCN (decorin), an extracellular matrix constituent and archetypical small leucine-rich proteoglycan (SLRP), acts as a soluble tumor repressor. DCN exerts high-affinity binding interactions with receptor tyrosine kinases and evokes receptor internalization consequent with lysosomal degradation for tumorigenic and angiogenic suppression. In our recent study, we discovered that DCN evokes synthesis of PEG3 (paternally expressed 3), an imprinted gene often silenced in various forms of cancer. Upon DCN stimulation, PEG3 relocalizes to BECN1- and LC3-positive phagophores. Importantly, PEG3 physically associates with BECN1- and LC3-containing supramolecular complexes, in a DCN-inducible manner, and PEG3 is necessary to maintain homeostatic levels of BECN1. Furthermore, DCN evokes a protracted autophagic program via transactivation of the BECN1 and MAPLC3A loci that is critically dependent on PEG3 expression. Mechanistically, DCN directly binds to the Ig domains 3-5 of the KDR/VEGFR2 ectodomain, in a region that partially overlaps with the canonical binding site for VEGFA. Therefore, we have unveiled a novel mechanism for a secreted proteoglycan to induce endothelial cell autophagy in a PEG3-dependent manner. These findings are consistent with earlier preclinical studies focusing on DCN-mediated tumorigenic and angiogenic suppression and may represent the mechanism of action to achieve these effects. Therefore, DCN and perhaps other members of this class of matrix constituents may represent a novel control of autophagy from the outside of the cells.
authors.affiliation: Department of Pathology, Anatomy and Cell Biology and the Cancer Cell Biology and Signaling Program; Kimmel Cancer Center; Thomas Jefferson University; Philadelphia, PA USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Neill
authors.affiliation: Department of Pathology, Anatomy and Cell Biology and the Cancer Cell Biology and Signaling Program; Kimmel Cancer Center; Thomas Jefferson University; Philadelphia, PA USA.
authors.forename: Annabel
authors.initials: A
authors.lastname: Torres
authors.affiliation: Department of Pathology, Anatomy and Cell Biology and the Cancer Cell Biology and Signaling Program; Kimmel Cancer Center; Thomas Jefferson University; Philadelphia, PA USA.
authors.forename: Simone
authors.initials: S
authors.lastname: Buraschi
authors.affiliation: Department of Pathology, Anatomy and Cell Biology and the Cancer Cell Biology and Signaling Program; Kimmel Cancer Center; Thomas Jefferson University; Philadelphia, PA USA.
authors.forename: Renato V
authors.initials: RV
authors.lastname: Iozzo
mesh_terms: D000818:Animals; D001343:Autophagy / Q000502:physiology*; D058575:Decorin / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: C546878:DCN protein, human; D058575:Decorin; D020794:Receptor Protein-Tyrosine Kinases; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: PEG3; VEGFR2; angiogenesis; autophagy; decorin; microenvironment; small leucine-rich proteoglycan