Transmembrane and soluble isoforms of heparin-binding epidermal growth factor-like growth factor regulate distinct processes in the pancreas.
OBJECTIVE
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.
Ray
Kevin C
KC
Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Blaine
Stacy A
SA
Washington
M Kay
MK
Braun
Ada H
AH
Singh
Amar B
AB
Harris
Raymond C
RC
Harding
Paul A
PA
Coffey
Robert J
RJ
Means
Anna L
AL
D000818:Animals; D018929:Cell Culture Techniques; D002460:Cell Line; D018149:Glucose Intolerance / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D007515:Islets of Langerhans / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D010182:Pancreatic Diseases / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D020033:Protein Isoforms / Q000502:physiology; D011498:Protein Precursors / Q000502:physiology
C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D020033:Protein Isoforms; D011498:Protein Precursors
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