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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.

While G-protein-coupled receptors (GPCRs) have received considerable attention for their biological activity in a diversity of physiological functions and have become targets for therapeutic intervention in many diseases, the function of the cell adhesion subfamily of GPCRs remains poorly understood. Within this group, the family of brain angiogenesis inhibitor molecules (BAI1-3) has become increasingly appreciated for their diverse roles in biology and disease. In particular, recent findings suggest emerging roles for BAI1 in the regulation of phenomena including phagocytosis, synaptogenesis, and the inhibition of tumor growth and angiogenesis via the processing of its extracellular domain into secreted vasculostatins. Here we summarize the known biological features of the BAI proteins, including their structure, proteolysis events, and interacting partners, and their recently identified ability to regulate certain signaling pathways. Finally, we discuss the potential of the BAIs as therapeutics or targets for diseases as varied as cancer, stroke, and schizophrenia.

Angiogenesis is a critical physiologic process that is appropriated during tumorigenesis. Little is known about how this process is specifically regulated in the brain. Brain angiogenesis inhibitor-1 (BAI1) is a brain-predominant seven-transmembrane protein that contains five antiangiogenic thrombospondin type-1 repeats (TSR). We recently showed that BAI1 is cleaved at a conserved proteolytic cleavage site releasing a soluble, 120 kDa antiangiogenic factor called vasculostatin (Vstat120). Vstat120 has been shown to inhibit in vitro angiogenesis and suppress subcutaneous tumor growth. Here, we examine its effect on the intracranial growth of malignant gliomas and further study its antitumor mechanism. First, we show that expression of Vstat120 strongly suppresses the intracranial growth of malignant gliomas, even in the presence of the strong proangiogenic stimulus mediated by the oncoprotein epidermal growth factor receptor variant III (EGFRvIII). This tumor-suppressive effect is accompanied by a decrease in tumor vascular density, suggesting a potent antiangiogenic effect in the brain. Second, and consistent with this interpretation, we find that treatment with Vstat120 reduces the migration of cultured microvascular endothelial cells in vitro and inhibits corneal angiogenesis in vivo. Third, we show that these antivascular effects critically depend on the presence of the cell surface receptor CD36 on endothelial cells in vitro and in vivo, supporting the role of Vstat120 TSRs in mediating these effects. These results advance the understanding of brain-specific angiogenic regulation, and suggest that Vstat120 has therapeutic potential in the treatment of brain tumors and other intracerebral vasculopathies.