Transmembrane and Soluble Isoforms of Heparin-Binding Epidermal Growth Factor–Like Growth Factor Regulate Distinct Processes in the Pancreas

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.

Abbreviations used in this paper: EGFR, epidermal growth factor receptor, HB-EGF, heparin-binding epidermal growth factor–like growth factor, proHB-EGF, full-length isoform of HB-EGF, PSC, pancreatic stellate cells, sHB-EGF, soluble isoform of HB-EGF, TGF, transforming growth factor, tmHB-EGF, transmembrane isoform of HB-EGF