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Isolation of Whole Cell Protein Lysates from Mouse Facial Processes and Cultured Palatal Mesenchyme Cells for Phosphoprotein Analysis

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Bone morphogenetic protein-1 processes insulin-like growth factor-binding protein 3.

Byoungjae Kim¹, Guorui Huang¹, Wen-Bin Ho²

¹Department of Cell and Regenerative Biology, and the Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, Wisconsin 53706 and.

The Journal of Biological Chemistry

|June 24, 2011

Summary

Bone morphogenetic protein-1 (BMP1) cleaves insulin-like growth factor-binding protein 3 (IGFBP3), altering its ability to bind IGF-I and affect cell signaling. This cleavage impacts growth factor activity and extracellular matrix regulation.

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Area of Science:

Biochemistry
Molecular Biology
Cell Biology

Background:

Bone morphogenetic protein-1 (BMP1)-like metalloproteinases are crucial for extracellular matrix formation and growth factor activation.
Insulin-like growth factor-binding proteins (IGFBPs), particularly IGFBP3, regulate insulin-like growth factor (IGF) effects on growth, development, and metabolism.
IGFBP3 undergoes proteolytic processing, influencing its biological activity.

Purpose of the Study:

To investigate the specific cleavage of IGFBP3 by BMP1.
To determine the functional consequences of BMP1-mediated IGFBP3 cleavage on IGF-I binding and cell signaling.
To demonstrate the in vivo relevance of BMP1-related proteinases in processing IGFBP3.

Main Methods:

In vitro cleavage assays using human and mouse IGFBP3 with BMP1.
Assessment of IGF-I binding and IGF-I-induced cell signaling in cleaved versus uncleaved IGFBP3.
Analysis of IGFBP3 processing in wild-type and Bmp1/Tll1 double knockout mouse embryo fibroblasts (MEFs).
In vivo studies in zebrafish embryos involving Bmp1a overexpression and Igfbp3 phenotypes.

Main Results:

BMP1 cleaves human and mouse IGFBP3 at a conserved site, significantly reducing its ability to bind IGF-I and inhibit IGF-I-induced signaling.
Cleaved IGFBP3 exhibits enhanced IGF-I-independent inhibition of FGF-induced proliferation and promotes Smad phosphorylation.
MEFs deficient in BMP1 and mammalian Tolloid-like 1 (mTLL1) show reduced IGFBP3 processing, confirming the role of endogenous BMP1-related proteinases.
Overexpression of Bmp1a in zebrafish embryos reverses Igfbp3-induced phenotypes, supporting in vivo cleavage of IGFBP3.

Conclusions:

BMP1-mediated cleavage of IGFBP3 alters its interaction with IGF-I and modulates downstream signaling pathways.
The proteolytic processing of IGFBP3 by BMP1-like proteinases is biologically relevant in vivo, affecting cellular processes.
This study elucidates a novel regulatory mechanism for IGFBP3 function by BMP1-like metalloproteinases.