The activity and signaling range of mature BMP-4 is regulated by sequential cleavage at two sites within the prodomain of the precursor

Yanzhen Cui; Renee Hackenmiller; Linnea Berg; François Jean; Takuya Nakayama; Gary Thomas; Jan L. Christian

doi:10.1101/gad.940001

The activity and signaling range of mature BMP-4 is regulated by sequential cleavage at two sites within the prodomain of the precursor

¹Department of Cell and Developmental Biology and ²Vollum Institute, Oregon Health Sciences University, Portland, Oregon 97201, USA

Abstract

Proteolytic maturation of proBMP-4 is required to generate an active signaling molecule. We show that proBMP-4 is cleaved by furin in a sequential manner. Cleavage at a consensus furin site adjacent to the mature ligand domain allows for subsequent cleavage at an upstream nonconsensus furin site within the prodomain. BMP-4 synthesized from precursor in which the upstream site is noncleavable is less active, signals at a shorter range, and accumulates at lower levels than does BMP-4 cleaved from native precursor. Conversely, BMP-4 cleaved from precursor in which both sites are rapidly cleaved is more active and signals over a greater range. Differential use of the upstream cleavage site could provide for tissue-specific regulation of BMP-4 activity and signaling range.

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Footnotes

Present addresses: ³Deptartment of Molecular and Cellular Biology, University of California, Berkeley, CA 94720, USA; ⁴Department of Microbiology and Immunology, University of British Columbia, Vancouver, B.C. V6T 1Z3, Canada; ⁵Department of Biology, University of Virginia, Charlottesville, VA 22903, USA.
↵6 These authors contributed equally to this work.
↵7 Corresponding author.
E-MAIL christia{at}ohsu.edu; FAX (503) 494-4253.
Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/gad.940001.
- Received August 22, 2001.
- Accepted September 5, 2001.
Cold Spring Harbor Laboratory Press