title: Bone morphogenetic protein-1 processes insulin-like growth factor-binding protein 3.
abstract: The bone morphogenetic protein-1 (BMP1)-like metalloproteinases play key roles in extracellular matrix formation, by converting precursors into mature functional proteins involved in forming the extracellular matrix. The BMP1-like proteinases also play roles in activating growth factors, such as BMP2/4, myostatin, growth differentiation factor 11, and transforming growth factor β1, by cleaving extracellular antagonists. The extracellular insulin-like growth factor-binding proteins (IGFBPs) are involved in regulating the effects of insulin-like growth factors (IGFs) on growth, development, and metabolism. Of the six IGFBPs, IGFBP3 has the greatest interaction with the large pool of circulating IGFs. It is also produced locally in tissues and is itself regulated by proteolytic processing. Here, we show that BMP1 cleaves human and mouse IGFBP3 at a single conserved site, resulting in markedly reduced ability of cleaved IGFBP3 to bind IGF-I or to block IGF-I-induced cell signaling. In contrast, such cleavage is shown to result in enhanced IGF-I-independent ability of cleaved IGFBP3 to block FGF-induced proliferation and to induce Smad phosphorylation. Consistent with in vivo roles for such cleavage, it is shown that, whereas wild type mouse embryo fibroblasts (MEFs) produce cleaved IGFBP3, MEFs doubly null for the Bmp1 gene and for the Tll1 gene, which encodes the related metalloproteinase mammalian Tolloid-like 1 (mTLL1), produce only unprocessed IGFBP3, thus demonstrating endogenous BMP1-related proteinases to be responsible for IGFBP3-processing activity in MEFs. Similarly, in zebrafish embryos, overexpression of Bmp1a is shown to reverse an Igfbp3-induced phenotype, consistent with the ability of BMP1-like proteinases to cleave IGFBP3 in vivo.
authors.affiliation: Department of Cell and Regenerative Biology, and the Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, Wisconsin 53706 and.
authors.forename: Byoungjae
authors.initials: B
authors.lastname: Kim
authors.affiliation: Department of Cell and Regenerative Biology, and the Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, Wisconsin 53706 and.
authors.forename: Guorui
authors.initials: G
authors.lastname: Huang
authors.affiliation: FibroGen, Inc., San Francisco, California 94158.
authors.forename: Wen-Bin
authors.initials: WB
authors.lastname: Ho
authors.affiliation: Department of Cell and Regenerative Biology, and the Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, Wisconsin 53706 and. Electronic address: dsgreens@wisc.edu.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Greenspan
mesh_terms: D000818:Animals; D055395:Bone Morphogenetic Protein 1 / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3; D018969:Insulin-Like Growth Factor Binding Proteins / Q000235:genetics / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D015398:Signal Transduction / Q000502:physiology; D051785:Smad Proteins; D055394:Tolloid-Like Metalloproteinases / Q000235:genetics / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology / Q000235:genetics / Q000378:metabolism
chemical_list: C515497:IGFBP3 protein, human; D018972:Insulin-Like Growth Factor Binding Protein 3; D018969:Insulin-Like Growth Factor Binding Proteins; D051785:Smad Proteins; D007334:Insulin-Like Growth Factor I; D055394:Tolloid-Like Metalloproteinases; C484478:TLL1 protein, human; C484477:Tll1 protein, mouse; C525705:BMP1 protein, human; C525707:Bmp1 protein, mouse; D055395:Bone Morphogenetic Protein 1