Functions of EpCAM in physiological processes and diseases (Review)

Abstract

EpCAM (epithelial cell adhesion molecule) is a type I transmembrane glycoprotein, which was originally identified as a tumor‑associated antigen due to its high expression level in rapidly growing epithelial tumors. Germ line mutations of the human EpCAM gene have been indicated as the cause of congenital tufting enteropathy. Previous studies based on cell models have revealed that EpCAM contributes to various biological processes including cell adhesion, signaling, migration and proliferation. Due to the previous lack of genetic animal models, the in vivo functions of EpCAM remain largely unknown. However, EpCAM genetic animal models have recently been generated, and are useful for understanding the functions of EpCAM. The authors here briefly review the functions and mechanisms of EpCAM in physiological processes and different diseases.

Figure 1

In situ hybridization analysis of EpCAM mRNA in the small intestines of adult mice and E18.5 mouse embryos. (A) The EpCAM mRNA level in crypts was higher compared with in the villi of the small intestine. (B) At E18.5, the expression level of EpCAM in the intervillus domains was higher compared with in villi. EpCAM, epithelial cell adhesion molecule.

Figure 2

Schematic representation of the function of EpCAM in cell-cell adhesive structures. (A) In the normal intestinal epithelium, EpCAM and claudin-7 complex, together with E-cadherin, is essential to keep the balance between AJs and cortical tension. The strength of the total pulling force from E-Cadherin, EpCAM, claudin-7, other claudins, occludin and other junction connections is equal with the cortical tension between two epithelial cells; but the direction of the total pulling force is opposite to that of cortical tension. With this balance, AJs support TJs to keep the normal structure and functions of TJs. (B) In EpCAM knockout intestinal epithelium, the EpCAM and claudin-7 complex is completely lost; as is the balance between AJs and cortical tension. Therefore, the support of AJs to TJs becomes weak. TJs will therefore disperse and scatter with the EpCAM mutation and functions of TJs are also affected. EpCAM, epithelial cell adhesion molecule; AJs, adherens junctions; TJs, tight junctions.

Figure 3

Schematic representation of the function of EpCAM in the recruitment of EVs in the intestine. (A) EVs with TGF-β1 produced by the IECs bind to IECs through EpCAM molecules which are localized in the membranes of EVs and IECs respectively. Therefore, these EVs can be recruited to the intestine. (B) EVs are unable to localize in the intestine when EpCAM gene is deleted in the IECs. EVs, extracellular vesicles; TGF-β1, transforming growth factor-β1; IECs, intestinal epithelial cells; EpCAM, epithelial cell adhesion molecule.

Figure 4

Overview of the role of EpCAM in cell signaling. From the available data, EpCAM has emerged as a crucial signaling molecule, controlling four independent pathways. i) The nPKC-dependent pathway: The EpCAM cytoplasmic tail inhibits the nPKC activity and ERK pathway to protect cadherin-mediated adhesion. ii) Wnt signal pathway: EpCAM extracellular domain directly binds to Kremen1 and disrupts the Kremen1-Dkk2 interaction, which prevents Kremen1-Dkk2-mediated removal of Lrp6 from the cell surface. EpCAM derepresses Lrp6 and cooperates with Wnt ligand to activate the Wnt signaling through stabilizing membrane Lrp6 and allowing Lrp6 to cluster into active signalosomes. iii) ERas/AKT pathway: EpCAM fosters the activating phosphory-lation of AKT at serine473 by interacting with hyperactive Ras GTPase ERas, which induces the activation of AKT. iv) In tumor cells or ES cells, EpICD forms a transcription activator complex with FHL2, β-Catenin and LEF-1 to increase transcription of EpCAM target genes, such as c-Myc and Cyclins A/E. Dkk2, Dickkopf2; Lrp6, Lipoprotein-receptor-related protein 6; EpCAM, epithelial cell adhesion molecule; PKC, protein kinase C; ERK, extracellular signal regulated kinase; ERas, embryonic Ras; AKT, RAC-α serine/threonine-protein kinase; EpICD, intracellular domain of EpCAM; FHL, four and a half LIM domains; LEF-1, lymphoid enhancer binding factor 1.