PUBLICATION
Bone morphogenetic protein-1 processes insulin-like growth factor-binding protein 3
- Authors
- Kim, B., Huang, G., Ho, W.B., and Greenspan, D.S.
- ID
- ZDB-PUB-110629-25
- Date
- 2011
- Source
- The Journal of biological chemistry 286(33): 29014-25 (Journal)
- Registered Authors
- Greenspan, Daniel S.
- Keywords
- bone morphogenetic protein (BMP), fibronectin, insulin-like growth factor (IGF), metalloprotease, zebrafish, bone morphogenetic protein-1, insulin-like growth factor binding protein 3
- MeSH Terms
-
- Animals
- Bone Morphogenetic Protein 1/genetics
- Bone Morphogenetic Protein 1/metabolism*
- Cell Line, Tumor
- Cell Proliferation
- Humans
- Insulin-Like Growth Factor Binding Protein 3
- Insulin-Like Growth Factor Binding Proteins/genetics
- Insulin-Like Growth Factor Binding Proteins/metabolism*
- Insulin-Like Growth Factor I/genetics
- Insulin-Like Growth Factor I/metabolism
- Mice
- Mice, Mutant Strains
- Signal Transduction/physiology
- Smad Proteins
- Tolloid-Like Metalloproteinases/genetics
- Tolloid-Like Metalloproteinases/metabolism
- Zebrafish/embryology
- Zebrafish/genetics
- Zebrafish/metabolism
- PubMed
- 21697095 Full text @ J. Biol. Chem.
Citation
Kim, B., Huang, G., Ho, W.B., and Greenspan, D.S. (2011) Bone morphogenetic protein-1 processes insulin-like growth factor-binding protein 3. The Journal of biological chemistry. 286(33):29014-25.
Abstract
The bone morphogenetic protein-1 (BMP1)-like metalloproteinases play key roles in extracellular matrix (ECM) formation, by converting precursors into mature functional proteins involved in forming the ECM. 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 an 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping