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. 2019 Dec 16;9:1359. doi: 10.3389/fonc.2019.01359

Figure 7.

Figure 7

EpCAM, claudin7 and their cooperation in PaCa. (A) In tight junctions, cldn7 is associated with additional cldns, occludin, JAM, and ZO1, 2, and 3, the latter being associated with pMIC2 and the cytoskeleton. Upon stimulation by several cytokine receptors, PI3K, ERK, RhoA/Rock, and MLCK promote MLC2 dephosphorylation, which promotes reorganization of the cytoskeleton with consequences on the cldn associated transporter activity. A stress response provokes internalization of the TJ complex. It is suggested that the internalized complex may be partly digested, recycle and become integrated into Exo. (B) EpCAM form tetramers, which with low affinity bind to EpCAM tetramers on neighboring cells and concomitantly prevent PRKD1 activation that leads to ERK1/2 and myosin activation, which inhibits Ca++-dependent Cadherin adhesion. Alternatively, EpCAM becomes cleaved by TACE and subsequently by PSN2. The cotranscription factor EpICD becomes supported by LEF and ß-catenin that might derive from Kremen1-DKK2-LRP6 promoted Wnt-Frizzled activation. This transcription factor complex mostly supports EpCAM and Wnt target gene expression. (C) Palmitoylated cld7 associates with monomeric EpCAM. As cldn7 is associated with PSN2, EpICD generation is augmented. Palmitoylated cldn7 may also contribute to NICD generation that acts as cotranscription factor. In association with CD44v6 and Tspan8, cldn7palm associates with ERM and contributes to ERM activation and actin binding. In association with uPAR and integrins it promotes both uPAR and integrin activation. Finally, a cldn7Palm-integrin-HSP complex assists talin-FAK-src-RhoA activation and by activation of the Grb2-SOS-RAS pathway ILK and the MAPK-JNK pathway. EpICD, NICD, and ILK contribute to c-myc, cyclinD1 and EMT gene transcription; NICD via HES and c-jun interfere with Pten transcription. Full name of proteins are listed in Table S1. Thus, TJ cldn7 is important particularly in lipid transport and cytoskeleton organization, EpCAM by promoting oncogenes and EMT genes, which also accounts for cldn7Palm-associated EpCAM. Cldn7Palm additionally contributes to Pten silencing.