Transmembrane and soluble isoforms of heparin-binding epidermal growth factor-like growth factor regulate distinct processes in the pancreas.
Gastroenterology
; 137(5): 1785-94, 2009 Nov.
Article
en En
| MEDLINE
| ID: mdl-19689925
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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Enfermedades Pancreáticas
/
Islotes Pancreáticos
/
Intolerancia a la Glucosa
/
Péptidos y Proteínas de Señalización Intercelular
/
Proteínas de la Membrana
Límite:
Animals
Idioma:
En
Revista:
Gastroenterology
Año:
2009
Tipo del documento:
Article
País de afiliación:
Estados Unidos