A proprotein convertase/MMP-14 proteolytic cascade releases a novel 40 kDa vasculostatin from tumor suppressor BAI1

Brain angiogenesis inhibitor 1 (BAI1), an orphan GPCR-type seven transmembrane receptor, was recently found mutated or silenced in multiple human cancers and can interfere with tumor growth when overexpressed. Yet, little is known about 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 that inhibits angiogenesis. We demonstrate that this novel proteolytic processing event depends on a two-step cascade of protease of 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 posttranslational 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.