Regulation of Bone Morphogenetic Protein Activity by Pro Domains and Proprotein Convertases

doi:10.1083/jcb.144.1.139

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© The Rockefeller University Press, 0021-9525/1999//139 $5.00
The Journal of Cell Biology, Volume 144, Number 1, , 1999 139-149

Articles

Regulation of Bone Morphogenetic Protein Activity by Pro Domains and Proprotein Convertases

Daniel B. Constam and Elizabeth J. Robertson

Harvard University, Department of Molecular and Cellular Biology, Cambridge, Massachusetts 02138

Bone morphogenetic proteins (BMPs) are derived from inactiveprecursor proteins by endoproteolytic cleavage. Here we showthat processing of Nodal and Myc-tagged BMP4 is significantlyenhanced by SPC1/Furin or SPC4/PACE4, providing direct evidencethat regulation of BMP signaling is likely to be controlledby subtilisin-like proprotein convertase (SPC) activities.Nodal processing is dramatically enhanced if two residues adjacentto the precursor cleavage site are substituted with amino acidsfound at the equivalent positions of Activin, demonstratingthat structural constraints at the precursor cleavage site limit the processing efficiency. However, in transfection assays, mature Nodal is undetectable either in culture supernatantsor in cell lysates, despite efficient cleavage of the precursorprotein, suggesting that mature Nodal is highly unstable. Domainswap experiments support this conclusion since mature BMP4or Dorsalin are also destabilized when expressed in conjunctionwith the Nodal pro domain. By contrast, mature Nodal is stabilizedby the Dorsalin pro domain, which mediates the formation ofstable complexes. Collectively, these data show that the half-lifeof mature BMPs is greatly influenced by the identity of theirpro regions.

Key Words: transforming growth factor-β • Dorsalin • Nodal processing • pro domain • complex formation

Abbreviations used in this paper: BMP, bone morphogenetic protein; MIS, Muellerian inhibitory substance; SPC, subtilisin-like proprotein convertase.

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