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.
journal_name
Oncogenejournal_title
Oncogeneauthors
Cork SM,Kaur B,Devi NS,Cooper L,Saltz JH,Sandberg EM,Kaluz S,Van Meir EGdoi
10.1038/onc.2012.1subject
Has Abstractpub_date
2012-12-13 00:00:00pages
5144-52issue
50eissn
0950-9232issn
1476-5594pii
onc20121journal_volume
31pub_type
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