Transmembrane and soluble isoforms of heparin-binding epidermal growth factor-like growth factor regulate distinct processes in the pancreas.

Ray KC, Blaine SA, Washington MK, Braun AH, Singh AB, Harris RC, Harding PA, Coffey RJ, Means AL
Gastroenterology. 2009 137 (5): 1785-94

PMID: 19689925 · PMCID: PMC2767440 · DOI:10.1053/j.gastro.2009.07.067

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.

MeSH Terms (13)

Animals Cell Culture Techniques Cell Line Glucose Intolerance Heparin-binding EGF-like Growth Factor Intercellular Signaling Peptides and Proteins Islets of Langerhans Membrane Proteins Mice Mice, Transgenic Pancreatic Diseases Protein Isoforms Protein Precursors

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