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

Biochim Biophys Acta. 2016 Sep;1863(9):2345-57. doi: 10.1016/j.bbamcr.2016.06.010. Epub 2016 Jun 29.

Abstract

β-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, β-catenin acts as a crucial effector component of cadherin/catenin complex to physically interact with actin cytoskeleton along with α-catenin and E-cadherin for regulating cell-cell adhesion. Here, we have generated a library of β-catenin point and deletion mutants to delineate regions within β-catenin that are important for α-catenin-β-catenin interaction, nuclear localization, and transcriptional activity of β-catenin. We observed a unique mechanism for nuclear localization of β-catenin and its mutants and show that N-terminal exon-3 region and C-terminal domain of β-catenin are critical for this activity of β-catenin. Furthermore, we show HepG2 cells have high β-catenin mediated transcriptional activity due to the presence of an interstitial deletion at the N-terminal region of β-catenin. Due to this deletion mutant (hereupon called TM), GSK3β and HDAC inhibitors failed to show any impact whereas curcumin significantly inhibited β-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 α-catenin, localizes predominantly in the nucleus, and has nearly two-fold higher transcriptional activity than the wildtype β-catenin.

Keywords: Beta-catenin signaling; Cancer; Cell proliferation and differentiation; Cellular signaling; HepG2 cells; Transcription factors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Adhesion / drug effects
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Computer Simulation
  • Curcumin / pharmacology
  • Green Fluorescent Proteins / metabolism
  • HEK293 Cells
  • Hep G2 Cells
  • Humans
  • Models, Biological
  • Protein Binding / drug effects
  • Protein Transport / drug effects
  • Proteolysis / drug effects
  • Sequence Deletion
  • Structure-Activity Relationship
  • Subcellular Fractions / metabolism
  • Transcription, Genetic* / drug effects
  • Transcriptional Activation / drug effects
  • Transcriptional Activation / genetics
  • alpha Catenin / metabolism
  • beta Catenin / chemistry*
  • beta Catenin / metabolism*

Substances

  • alpha Catenin
  • beta Catenin
  • Green Fluorescent Proteins
  • Curcumin