FIGURE 4: Reduced schematic of EpCAM regulation in the context of EMT. Stimulation of tyrosine kinase receptors via TGF-β1 or EGF is leading to ERK2 activation and suppresses EPCAM mRNA expression indirectly through activation of EMT-associated transcription factors (TF) like SNAI1, SNAI2, TWIST1 and ZEB1. The EpCAM protein on the other hand could also contribute to the regulation of EMT by suppressing ERK2 activity. The soluble EpEX-fragment is acting as an EGF competitor for EGFR, counteracted EMT via inhibiting of the EMTTF (Snail, ZEB1, and Slug) which leads to activation of EPCAM expression. For detailed review, see references [42, 91, 92].

42. Pan M, Schinke H, Luxenburger E, Kranz G, Shakhtour J, Libl D, Huang Y, Gaber A, Pavsic M, Lenarcic B, Kitz J, Jakob M, Schwenk- Zieger S, Canis M, Hess J, Unger K, Baumeister P, Gires O (2018). EpCAM ectodomain EpEX is a ligand of EGFR that counteracts EGF- mediated epithelial-mesenchymal transition through modulation of phospho-ERK1/2 in head and neck cancers. PLoS Biol 16(9): e2006624. doi: 10.1371/journal.pbio.2006624

91. Sankpal NV, Fleming TP, Sharma PK, Wiedner HJ, Gillanders WE (2017). A double-negative feedback loop between EpCAM and ERK contributes to the regulation of epithelial-mesenchymal transition in cancer. Oncogene 36(26): 3706-3717. doi: 10.1038/onc.2016.504

92. Driemel C, Kremling H, Schumacher S, Will D, Wolters J, Lindenlauf N, Mack B, Baldus SA, Hoya V, Pietsch JM, Panagiotidou P, Raba K, Vay C, Vallbohmer D, Harreus U, Knoefel WT, Stoecklein NH, Gires O (2014). Context-dependent adaption of EpCAM expression in early systemic esophageal cancer. Oncogene 33(41): 4904-4915. doi: 10.1038/onc.2013.441