Figure 16. Regulation of the balance between proliferative and terminally differentiating epithelial cells, based on descriptions by [105], [107]–[109]}[106].

The interaction system involving ST14/matriptase, PRSS8/prostasin, and SPINT1/Hai1 (detailed in Figure 15) is shown here in abbreviated form. The genes that were expressed selectively in the NEC cell lines are denoted in red. The diagram shows terminal differentiation of epithelial cells requiring IRF6, NOTCH1, ST14/matriptase, and PRSS8/prostasin. The actions of the latter two are inhibited by SPINT1/hai1. The continued proliferation or cell division on the path to terminal differentiation requires MYC and MYB. IRF6 and MYB transcriptionally activate OVOL1, which down-regulates the transcription of OVOL2, MYB, and MYC, and tends to inhibit terminal differentiation. OVOL2 inhibits the transcription of MYC and NOTCH1. TP63 enhances the transcription of IRF6, but is down-regulated by IRF6. Also shown is the regulation of OVOL1 by the TGF beta and beta-catenin pathways.