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

Oncogene volume 31, pages 5144–5152 (2012)Cite this article

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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.

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Acknowledgements

Paper contributions. SMC performed Vstat40 characterization, angiogenesis, cleavage site detection and furin/MMP-14 protease identification experiments, and SMC and EGVM wrote the manuscript. NSD, BK, EMS and SK performed Vstat40 and protease identification experiments. LC and JHS performed the survival analysis. Experiments were conceived of and planned by the respective authors under the direction of EGVM. We appreciate the helpful advice and assistance of all members of the Laboratory of Molecular Neuro-Oncology. SMC was in the Emory graduate program in Neuroscience and acknowledges project guidance by her thesis committee (Drs Randy Hall, Robert McKeon, Paula Vertino and Wei Zhou). We thank Dr C Dubois (Université de Sherbrooke) for the kind gift of LoVo cells. The US National Institutes of Health (R01 CA86335 to EGVM and contract 29XS193 to JHS), P30 CA138292 (to the Winship Cancer Institute) and the Emory Neurosciences Initiative (to EGVM) contributed to the funding of this research.

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Author notes

  1. B Kaur

    Present address: 5Current address: Dardinger Laboratory for Neuro-oncology and Neurosciences, Department of Neurological Surgery, James Comprehensive Cancer Center, The Ohio State University Medical Center, Columbus, OH 43210, USA.,

Authors and Affiliations

  1. Department of Neurosurgery, Laboratory of Molecular Neuro-Oncology, Emory University School of Medicine, Atlanta, GA, USA

    S M Cork, B Kaur, N S Devi, E M Sandberg, S Kaluz & E G Van Meir

  2. Center for Comprehensive Informatics, Emory University, Atlanta, GA, USA

    L Cooper & J H Saltz

  3. Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA

    E G Van Meir

  4. Winship Cancer Institute, Emory University, Atlanta, GA, USA

    J H Saltz, S Kaluz & E G Van Meir

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Correspondence to E G Van Meir.

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Cork, S., Kaur, B., Devi, N. et al. A proprotein convertase/MMP-14 proteolytic cascade releases a novel 40 kDa vasculostatin from tumor suppressor BAI1. Oncogene 31, 5144–5152 (2012). https://doi.org/10.1038/onc.2012.1

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