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 μ1B subunit, and compared it with 129/B6/CD1 littermates (controls). Notch signaling was inhibited by intraperitoneal injection of dibenzazepine, and β-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-β-catenin complex therefore was disrupted at the adherens junction, resulting in nuclear translocation of β-catenin. This resulted in up-regulation of genes regulated by β-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 β-catenin/Tcf4 complex, proliferation, and hyperplasia.
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 μ1B subunit, and compared it with 129/B6/CD1 littermates (controls). Notch signaling was inhibited by intraperitoneal injection of dibenzazepine, and β-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-β-catenin complex therefore was disrupted at the adherens junction, resulting in nuclear translocation of β-catenin. This resulted in up-regulation of genes regulated by β-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 β-catenin/Tcf4 complex, proliferation, and hyperplasia.
Authors: Lynn M Boyden; Lihi Atzmony; Claire Hamilton; Jing Zhou; Young H Lim; Ronghua Hu; John Pappas; Rachel Rabin; Joseph Ekstien; Yoel Hirsch; Julie Prendiville; Richard P Lifton; Shawn Ferguson; Keith A Choate Journal: Am J Hum Genet Date: 2019-10-17 Impact factor: 11.025
Authors: Xiaoli Guo; Rafael Mattera; Xuefeng Ren; Yu Chen; Claudio Retamal; Alfonso González; Juan S Bonifacino Journal: Dev Cell Date: 2013-11-11 Impact factor: 12.270
Authors: Muhammad A Usmani; Zubair M Ahmed; Pamela Magini; Victor Murcia Pienkowski; Kristen J Rasmussen; Rebecca Hernan; Faiza Rasheed; Mureed Hussain; Mohsin Shahzad; Brendan C Lanpher; Zhiyv Niu; Foong-Yen Lim; Tommaso Pippucci; Rafal Ploski; Verena Kraus; Karolina Matuszewska; Flavia Palombo; Jessica Kianmahd; Julian A Martinez-Agosto; Hane Lee; Emma Colao; M Mahdi Motazacker; Karlla W Brigatti; Erik G Puffenberger; S Amer Riazuddin; Claudia Gonzaga-Jauregui; Wendy K Chung; Matias Wagner; Matthew J Schultz; Marco Seri; Anneke J A Kievit; Nicola Perrotti; J S Klein Wassink-Ruiter; Hans van Bokhoven; Sheikh Riazuddin; Saima Riazuddin Journal: Am J Hum Genet Date: 2021-06-07 Impact factor: 11.025