| First Author | Hase K | Year | 2013 |
| Journal | Gastroenterology | Volume | 145 |
| Issue | 3 | Pages | 625-35 |
| PubMed ID | 23684748 | Mgi Jnum | J:226582 |
| Mgi Id | MGI:5697782 | Doi | 10.1053/j.gastro.2013.05.013 |
| Citation | Hase K, et al. (2013) AP-1B-mediated protein sorting regulates polarity and proliferation of intestinal epithelial cells in mice. Gastroenterology 145(3):625-35 |
| abstractText | BACKGROUND & AIMS: In epithelial cells, protein sorting mechanisms regulate localization of plasma membrane proteins that generate and maintain cell polarity. The clathrin-adaptor protein (AP) complex AP-1B is expressed specifically in polarized epithelial cells, where it regulates basolateral sorting of membrane proteins. However, little is known about its physiological significance. METHODS: We analyzed the intestinal epithelia of mice deficient in Ap1m2 (Ap1m2(-/-) mice), which encodes the AP-1B mu1B subunit, and compared it with 129/B6/CD1 littermates (controls). Notch signaling was inhibited by intraperitoneal injection of dibenzazepine, and beta-catenin signaling was inhibited by injection of IWR1. Intestinal tissue samples were collected and analyzed by immunofluorescence analysis. RESULTS: Ap1m2(-/-) mice developed intestinal epithelial cell hyperplasia. The polarity of intestinal epithelial cells was disrupted, as indicated by the appearance of ectopic microvilli-like structures on the lateral plasma membrane and mislocalization of basolateral membrane proteins, including the low-density lipoprotein receptor and E-cadherin. The E-cadherin-beta-catenin complex therefore was disrupted at the adherens junction, resulting in nuclear translocation of beta-catenin. This resulted in up-regulation of genes regulated by beta-catenin/transcription factor 4 (Tcf4) complex, and increased the proliferation of intestinal epithelial cells. CONCLUSIONS: AP-1B is required for protein sorting and polarization of intestinal cells in mice. Loss of AP-1B in the intestinal epithelia results in mislocalization of E-cadherin, activation of beta-catenin/Tcf4 complex, proliferation, and hyperplasia. |
