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MBC in Press, published online ahead of print September 8, 2004
Mol. Biol. Cell 10.1091/mbc.E04-08-0673

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Submitted on August 6, 2004
Revised on August 27, 2004
Accepted on August 30, 2004

Cleavages within the Prodomain Direct Intracellular Trafficking and Degradation of Mature BMP-4

Catherine Degnin,* François Jean,{dagger}{ddagger} Gary Thomas,{dagger}{sect} and Jan L. Christian{sect}||

*Department of Biochemistry and Molecular Biology, {dagger}Vollum Institute, and {sect}Department of Cell and Developmental Biology, Oregon Health and Science University, School of Medicine, Portland, OR 97239-3098

Monitoring Editor: Carl-Henrik Heldin

ProBMP-4 is initially cleaved at a consensus furin motif adjacent to the mature ligand domain (the S1 site) and this allows for subsequent cleavage at an upstream motif (the S2 site). Previous studies have shown that S2 cleavage regulates the activity and signaling range of mature BMP-4, but the mechanism by which this occurs is unknown. Here we show that the proand mature domains of BMP-4 remain noncovalently associated following S1 cleavage, generating a complex that is targeted for rapid degradation. Degradation requires lysosomal and proteosomal function and is enhanced by interaction with heparin sulfate proteoglycans. Subsequent cleavage at the S2 site liberates mature BMP-4 from the prodomain, thereby stabilizing the protein. We also show that cleavage at the S2, but not the S1 site is enhanced at reduced pH, consistent with the possibility that the two cleavages occur in distinct subcellular compartments. Based on these results, we propose a model for how cleavage at the upstream site regulates the activity and signaling range of mature BMP-4 after it has been released from the prodomain.

{ddagger}Present address: Department of Microbiology and Immunology, University of British Columbia, #300 - 6174 University Boulevard, Vancouver, British Columbia, Canada V6T 1Z3.

||Corresponding author. E-mail: christia{at}ohsu.edu






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