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BMP-4 is proteolytically activated by furin and/or PC6 during vertebrate embryonic development
1Department of Cell and Developmental Biology, Oregon Health Sciences University, School of Medicine, 3181 SW Sam Jackson Park Road, Portland, Oregon 97201-3098, USA.
The EMBO Journal
|August 26, 1998
Summary
The study reveals that furin and PC6 proteases activate Bone Morphogenetic Protein-4 (BMP-4) during vertebrate development. Inhibiting these proteases with alpha1-antitrypsin Portland (alpha1-PDX) blocks BMP-4 activity, impacting embryonic development.
Area of Science:
- Developmental Biology
- Molecular Biology
- Biochemistry
Background:
- Bone morphogenetic protein-4 (BMP-4) is crucial for embryonic development but its processing is poorly understood.
- Proprotein convertases (PCs) are serine proteases that activate precursor proteins, including those with cleavage sites like BMP-4's Arg-Ser-Lys-Arg motif.
Purpose of the Study:
- To investigate the role of proprotein convertases (PCs) in the proteolytic activation and secretion of BMP-4 during embryonic development.
- To determine if specific PCs, like furin, are involved in activating BMP-4 in vivo.
Main Methods:
- Misexpression of alpha1-antitrypsin Portland (alpha1-PDX), a furin inhibitor, in early Xenopus embryos.
- Oocyte translation and in vitro digestion assays to assess BMP-4 cleavage by PCs.
- Analysis of embryonic phenotypes, including mesoderm dorsalization and neural induction.
Main Results:
- Ectopic expression of alpha1-PDX mimicked the effects of blocked BMP activity, causing dorsalization and neural induction.
- alpha1-PDX prevented BMP-4 cleavage in oocytes, indicating inhibition upstream of receptor binding.
- In vitro assays showed furin and PC6B cleave BMP-4 and are sensitive to alpha1-PDX.
Conclusions:
- These findings provide the first in vivo evidence that furin and/or PC6 proteolytically activate BMP-4 in vertebrate embryogenesis.
- PCs play a critical role in regulating BMP-4 activity during early development.