Munz Markus, Fellinger Karin, Hofmann Tanja, Schmitt Barbel, Gires Olivier
Clinical Cooperation Group Molecular Oncology, GSF-Research Center for Environment and Health, and Head and Neck Research Dept. Munich, Germany.
Front Biosci. 2008 May 1;13:5195-201. doi: 10.2741/3075.
Epithelial cell adhesion molecule EpCAM is strongly over-expressed in a variety of carcinomas where it is involved in signalling events resulting in increased expression of target genes such as c-Myc, cyclins and others, eventually conferring cells an oncogenic phenotype. However, EpCAM is also expressed in a series of healthy epithelia, albeit generally to a far lesser extend. We have uncovered differential glycosylation of EpCAM as a means to discriminate normal from malignant tissues. EpCAM was hyperglycosylated in carcinoma tissue as compared with autologous normal epithelia. All three N-glycosylation consensus sequences within EpCAM's extracellular domain were used in human and murine cells. We show that glycosylation at asparagine198 is crucial for protein stability. Mutants of EpCAM that substitute asparagine198 for alanine showed a decreased overall expression and half-life of the molecule at the plasma membrane. This is of considerable importance with respect to EpCAM variants expressed in normal tissue, where it might reveal to be less stable and thus may have repercussions on functionality.
上皮细胞粘附分子EpCAM在多种癌组织中强烈过表达，它参与信号转导事件，导致c-Myc、细胞周期蛋白等靶基因表达增加，最终赋予细胞致癌表型。然而，EpCAM也在一系列健康上皮组织中表达，尽管表达水平通常要低得多。我们发现EpCAM的糖基化差异可作为区分正常组织和恶性组织的一种手段。与自体正常上皮组织相比，癌组织中的EpCAM发生了高糖基化。EpCAM胞外域的所有三个N-糖基化共有序列在人和小鼠细胞中均被利用。我们发现天冬酰胺198位点的糖基化对蛋白质稳定性至关重要。将天冬酰胺198替换为丙氨酸的EpCAM突变体在质膜上的整体表达和半衰期均降低。这对于正常组织中表达的EpCAM变体具有重要意义，因为它可能稳定性较低，从而可能对其功能产生影响。
