title: A proprotein convertase/MMP-14 proteolytic cascade releases a novel 40 kDa vasculostatin from tumor suppressor BAI1.
abstract: Brain-specific angiogenesis inhibitor 1 (BAI1), an orphan G protein-coupled receptor-type seven transmembrane protein, was recently found mutated or silenced in multiple human cancers and can interfere with tumor growth when overexpressed. Yet, little is known about its regulation and the molecular mechanisms through which this novel tumor suppressor exerts its anti-cancer effects. Here, we demonstrate that the N terminus of BAI1 is cleaved extracellularly to generate a truncated receptor and a 40-kDa fragment (Vasculostatin-40) that inhibits angiogenesis. We demonstrate that this novel proteolytic processing event depends on a two-step cascade of protease activation: proprotein convertases, primarily furin, activate latent matrix metalloproteinase-14, which then directly cleaves BAI1 to release the bioactive fragment. These findings significantly augment our knowledge of BAI1 by showing a novel post-translational mechanism regulating BAI1 activity through cancer-associated proteases, have important implications for BAI1 function and regulation, and present novel opportunities for therapy of cancer and other vascular diseases.
authors.affiliation: Department of Neurosurgery, Laboratory of Molecular Neuro-Oncology, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Cork
authors.forename: B
authors.initials: B
authors.lastname: Kaur
authors.forename: N S
authors.initials: NS
authors.lastname: Devi
authors.forename: L
authors.initials: L
authors.lastname: Cooper
authors.forename: J H
authors.initials: JH
authors.lastname: Saltz
authors.forename: E M
authors.initials: EM
authors.lastname: Sandberg
authors.forename: S
authors.initials: S
authors.lastname: Kaluz
authors.forename: E G
authors.initials: EG
authors.lastname: Van Meir
mesh_terms: D020533:Angiogenesis Inhibitors / Q000378:metabolism*; D042501:Angiogenic Proteins / Q000235:genetics / Q000378:metabolism*; D001932:Brain Neoplasms / Q000098:blood supply / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D045683:Furin / Q000378:metabolism; D016147:Genes, Tumor Suppressor; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology; D006801:Humans; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000378:metabolism; D010447:Peptide Hydrolases / Q000378:metabolism; D043484:Proprotein Convertases / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D059748:Proteolysis; D043562:Receptors, G-Protein-Coupled
chemical_list: C468226:ADGRB1 protein, human; D020533:Angiogenesis Inhibitors; D042501:Angiogenic Proteins; D043562:Receptors, G-Protein-Coupled; D010447:Peptide Hydrolases; D043484:Proprotein Convertases; D045683:Furin; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14