BMP-4 is proteolytically activated by furin and/or PC6 during vertebrate embryonic development

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Abstract
Bone morphogenetic protein‐4 (BMP‐4) is a multifunctional developmental regulator. BMP‐4 is synthesized as an inactive precursor that is proteolytically activated by cleavage following the amino acid motif ‐Arg‐Ser‐Lys‐Arg‐. Very little is known about processing and secretion of BMPs. The proprotein convertases (PCs) are a family of seven structurally related serine endoproteases, at least one of which, furin, cleaves after the amino acid motif ‐Arg‐X‐Arg/Lys‐Arg‐. To examine potential roles of PCs during embryonic development we have misexpressed a potent protein inhibitor of furin, α1‐antitrypsin Portland (α1‐PDX) in early Xenopus embryos. Ectopic expression of α1‐PDX phenocopies the effect of blocking endogenous BMP activity, leading to dorsalization of mesoderm and direct neural induction. α1‐PDX‐mediated neural induction can be reversed by co‐expression of downstream components of the BMP‐4 signaling pathway. Thus, α1‐PDX can block BMP activity upstream of receptor binding, suggesting that it inhibits an endogenous BMP‐4 convertase(s). Consistent with this hypothesis, α1‐PDX prevents cleavage of BMP‐4 in an oocyte translation assay. Using an in vitro digestion assay, we demonstrate that four members of the PC family have the ability to cleave BMP‐4, but of these, only furin and PC6B are sensitive to α1‐PDX. These studies provide the first in vivo evidence that furin and/or PC6 proteolytically activate BMP‐4 during vertebrate embryogenesis.