Terminal regions of beta-catenin are critical for regulating its adhesion and transcription functions

摘要

beta-Catenin, the central molecule of canonical Wnt signaling pathway, has multiple binding partners and performs many roles in the cell. Apart from being a transcriptional activator, beta-catenin acts as a crucial effector component of cadherin/catenin complex to physically interact with actin cytoskeleton along with a-catenin and E-cadherin for regulating cell-cell adhesion. Here, we have generated a library of S-catenin point and deletion mutants to delineate regions within p-catenin that are important for a-catenin-S-catenin interaction, nuclear localization, and transcriptional activity of D-catenin. We observed a unique mechanism for nuclear localization of beta-catenin and its mutants and show that N-terminal exon-3 region and C-terminal domain of beta-catenin are critical for this activity of beta-catenin. Furthermore, we show HepG2 cells have high S-catenin mediated transcriptional activity due to the presence of an interstitial deletion at the N-terminal region of beta-catenin. Due to this deletion mutant (hereupon called TM), GSK3 beta and HDAC inhibitors failed to show any impact whereas curcumin significantly inhibited p-catenin mediated transcriptional activity reiterating that TM is primarily responsible for the high transcriptional activity of HepG2 cells. Moreover, we show the recombinant TM does not physically interact with a-catenin, localizes predominantly in the nucleus, and has nearly two-fold higher transcriptional activity than the wildtype S-catenin. (C) 2016 Elsevier B.V. All rights reserved.