Ray Kevin C, Blaine Stacy A, Washington M Kay, Braun Ada H, Singh Amar B, Harris Raymond C, Harding Paul A, Coffey Robert J, Means Anna L
Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Gastroenterology. 2009 Nov;137(5):1785-94. doi: 10.1053/j.gastro.2009.07.067. Epub 2009 Aug 16.
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.
To understand the function of each isoform of HB-EGF, we made transgenes expressing either a constitutively transmembrane or a constitutively secreted protein.
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.
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.
肝素结合表皮生长因子样生长因子（HB-EGF）最初作为一种I型单次跨膜蛋白产生，可被切割以释放一种可扩散的肽。HB-EGF通常在受损或患病的上皮细胞中过度表达，在胰岛中正常表达，但其功能尚不清楚。
为了解HB-EGF各同工型的功能，我们构建了表达组成型跨膜蛋白或组成型分泌蛋白的转基因。
跨膜同工型不是一种无活性的前体蛋白，而是一种功能性分子，可下调胰岛的葡萄糖感知装置。相反，分泌形式的HB-EGF改善了胰岛功能，但对周围组织有严重的纤维化和肿瘤形成作用。即使全长蛋白被有效切割从而产生两种同工型，每种同工型的表型都比全长HB-EGF更严重，这表明分离同工型会导致一定程度的调控丧失。
这项研究表明，胰岛功能取决于切割型与未切割型HB-EGF的比例，并且跨膜中间体虽然对胰岛功能有害，但对于限制可溶性HB-EGF对周围组织的作用是必要的。
