July 2009

Document Type


Degree Name



Dept. of Molecular and Medical Genetics


Oregon Health & Science University


Bone morphogenetic protein 4 (BMP4) is a member of the transforming growth factor-β (TGFβ) family of signaling molecules. It has been highly conserved throughout evolution and is essential for many aspects of development and for tissue homeostasis in adults. BMP4 activity is tightly regulated at many levels, including via proteolytic activation of the precursor protein; cleavage of proBMP4 by members of the proprotein convertase (PC) family is required to generate an active ligand. ProBMP4 is initially cleaved at a site adjacent to the mature ligand domain (S1), and then at an upstream site (S2) within the prodomain. Interestingly, cleavage at the S2 site appears to regulate the activity and signaling range of mature BMP4 in a tissue-specific manner. Based upon this intriguing observation, I hypothesized that cleavage of the S2 site might depend on tissue-specific expression of an S2 site-specific enzyme. To test my hypothesis, we cloned and characterized the expression of PC orthologs in Xenopus and identified which PCs cleave each site of proBMP4 in vivo. Loss of function and protein-based inhibitor techniques revealed that furin and PC6 cleave both the S1 and S2 sites of proBMP4, and that a third S1-specific enzyme, likely PC7, functions redundantly to cleave the S1 site in embryos but not oocytes. These results suggest that PC7, or a convertase with similar substrate specificity, functions to selectively cleave the S1 site of proBMP4 in a developmentally regulated fashion. Constitutive cleavage of proBMP4 at S1 by PC7, which is ubiquitously expressed, combined with S1 + S2 cleavage of proBMP4 by Furin and/or PC6, which display tissue-restricted expression, may be a mechanism by which BMP4 activity could be regulated in a tissue-specific manner.




School of Medicine



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