Document Detail

Furin is the major processing enzyme of the cardiac-specific growth factor bone morphogenetic protein 10.
MedLine Citation:
PMID:  21550985     Owner:  NLM     Status:  MEDLINE    
Bone morphogenetic protein 10 (BMP10) is a member of the TGF-β superfamily and plays a critical role in heart development. In the postnatal heart, BMP10 is restricted to the right atrium. The inactive pro-BMP10 (∼60 kDa) is processed into active BMP10 (∼14 kDa) by an unknown protease. Proteolytic cleavage occurs at the RIRR(316)↓ site (human), suggesting the involvement of proprotein convertase(s) (PCs). In vitro digestion of a 12-mer peptide encompassing the predicted cleavage site with furin, PACE4, PC5/6, and PC7, showed that furin cleaves the best, whereas PC7 is inactive on this peptide. Ex vivo studies in COS-1 cells, a cell line lacking PC5/6, revealed efficient processing of pro-BMP10 by endogenous PCs other than PC5/6. The lack of processing of overexpressed pro-BMP10 in the furin- and PACE4-deficient cell line, CHO-FD11, and in furin-deficient LoVo cells, was restored by stable (CHO-FD11/Fur cells) or transient (LoVo cells) expression of furin. Use of cell-permeable and cell surface inhibitors suggested that endogenous PCs process pro-BMP10 mostly intracellularly, but also at the cell surface. Ex vivo experiments in mouse primary hepatocytes (wild type, PC5/6 knock-out, and furin knock-out) corroborated the above findings that pro-BMP10 is a substrate for endogenous furin. Western blot analyses of heart right atria extracts from wild type and PACE4 knock-out adult mice showed no significant difference in the processing of pro-BMP10, implying no in vivo role of PACE4. Overall, our in vitro, ex vivo, and in vivo data suggest that furin is the major convertase responsible for the generation of BMP10.
Delia Susan-Resiga; Rachid Essalmani; Josée Hamelin; Marie-Claude Asselin; Suzanne Benjannet; Ann Chamberland; Robert Day; Dorota Szumska; Daniel Constam; Shoumo Bhattacharya; Annik Prat; Nabil G Seidah
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2011-05-05
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  286     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2011 Jul 
Date Detail:
Created Date:  2011-06-27     Completed Date:  2011-09-09     Revised Date:  2014-02-24    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  22785-94     Citation Subset:  IM    
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MeSH Terms
Bone Morphogenetic Proteins / genetics,  metabolism*
COS Cells
Cercopithecus aethiops
Furin / antagonists & inhibitors,  genetics,  metabolism*
Gene Knockdown Techniques
Heart Ventricles / enzymology*
Mice, Knockout
Myocardium / enzymology*
Organ Specificity
Serine Proteinase Inhibitors / pharmacology
Grant Support
075491/Z/04//Wellcome Trust; 090532//Wellcome Trust; CH/09/003//British Heart Foundation; MOP-44363//Canadian Institutes of Health Research
Reg. No./Substance:
0/BMP10 protein, human; 0/Bmp10 protein, mouse; 0/Bone Morphogenetic Proteins; 0/Serine Proteinase Inhibitors; EC

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