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Transmembrane and Soluble Isoforms of Heparin-Binding Epidermal Growth Factor–Like Growth Factor Regulate Distinct Processes in the Pancreas.
- Source :
- Gastroenterology (00165085); Nov2009, Vol. 137 Issue 5, p1785-1794, 10p
- Publication Year :
- 2009
-
Abstract
- Background & Aims: Heparin-binding epidermal growth factor–like growth factor (HB-EGF) is produced as a type-I, single-pass transmembrane protein that can be cleaved to release a diffusible peptide. HB-EGF, often overexpressed in damaged or diseased epithelium, is normally expressed in pancreatic islets, but its function is not understood. Methods: To understand the function of each isoform of HB-EGF, we made transgenes expressing either a constitutively transmembrane or a constitutively secreted protein. Results: The transmembrane isoform was not an inert precursor protein, but a functional molecule, downregulating the glucose-sensing apparatus of pancreatic islets. Conversely, the secreted form of HB-EGF improved islet function, but had severe fibrotic and neoplastic effects on surrounding tissues. Each isoform had a more severe phenotype than that of full-length HB-EGF, even though the full-length protein was efficiently cleaved, thus producing both isoforms, suggesting that a level of regulation was lost by separating the isoforms. Conclusions: This work demonstrates that islet function depends on the ratio of cleaved to uncleaved HB-EGF and that the transmembrane intermediate, while deleterious to islet function, is necessary to restrict action of soluble HB-EGF away from surrounding tissue. [Copyright &y& Elsevier]
Details
- Language :
- English
- ISSN :
- 00165085
- Volume :
- 137
- Issue :
- 5
- Database :
- Supplemental Index
- Journal :
- Gastroenterology (00165085)
- Publication Type :
- Academic Journal
- Accession number :
- 44841495
- Full Text :
- https://doi.org/10.1053/j.gastro.2009.07.067