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J. Cell Biol.,
Volume 144, Number 1, January 11, 1999 139-149
Harvard University, Department of Molecular and Cellular Biology, Cambridge, Massachusetts 02138
Bone morphogenetic proteins (BMPs) are
derived from inactive precursor proteins by endoproteolytic cleavage. Here we show that processing of
Nodal and Myc-tagged BMP4 is significantly enhanced
by SPC1/Furin or SPC4/PACE4, providing direct evidence that regulation of BMP signaling is likely to be
controlled by subtilisin-like proprotein convertase
(SPC) activities. Nodal processing is dramatically enhanced if two residues adjacent to the precursor cleavage site are substituted with amino acids found at the
equivalent positions of Activin, demonstrating that
structural constraints at the precursor cleavage site
limit the processing efficiency. However, in transfection
assays, mature Nodal is undetectable either in culture
supernatants or in cell lysates, despite efficient cleavage
of the precursor protein, suggesting that mature Nodal is highly unstable. Domain swap experiments support
this conclusion since mature BMP4 or Dorsalin are also
destabilized when expressed in conjunction with the
Nodal pro domain. By contrast, mature Nodal is stabilized by the Dorsalin pro domain, which mediates the
formation of stable complexes. Collectively, these data
show that the half-life of mature BMPs is greatly influenced by the identity of their pro regions.
;
Dorsalin;
Nodal processing;
pro domain;
complex formation
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