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

Kevin C. Ray, Stacy A. Blaine, M. Kay Washington, Ada H. Braun, Amar B. Singh, Raymond C. Harris, Paul A. Harding, Robert J. Coffey, Anna L. Means

Research output: Contribution to journalArticle

10 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1785-1794
Number of pages10
JournalGastroenterology
Volume137
Issue number5
DOIs
StatePublished - Nov 2009

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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    Ray, K. C., Blaine, S. A., Washington, M. K., Braun, A. H., Singh, A. B., Harris, R. C., Harding, P. A., Coffey, R. J., & Means, A. L. (2009). Transmembrane and Soluble Isoforms of Heparin-Binding Epidermal Growth Factor-Like Growth Factor Regulate Distinct Processes in the Pancreas. Gastroenterology, 137(5), 1785-1794. https://doi.org/10.1053/j.gastro.2009.07.067