Beta-catenin Cleavage Enhances Transcriptional Activation

Sci Rep. 2018 Jan 12;8(1):671. doi: 10.1038/s41598-017-18421-8.

Abstract

Nuclear activation of Wnt/β-catenin signaling is required for cell proliferation in inflammation and cancer. Studies from our group indicate that β-catenin activation in colitis and colorectal cancer (CRC) correlates with increased nuclear levels of β-catenin phosphorylated at serine 552 (pβ-Cat552). Biochemical analysis of nuclear extracts from cancer biopsies revealed the existence of low molecular weight (LMW) pβ-Cat552, increased to the exclusion of full size (FS) forms of β-catenin. LMW β-catenin lacks both termini, leaving residues in the armadillo repeat intact. Further experiments showed that TCF4 predominantly binds LMW pβ-Cat552 in the nucleus of inflamed and cancerous cells. Nuclear chromatin bound localization of LMW pβ-Cat552 was blocked in cells by inhibition of proteasomal chymotrypsin-like activity but not by other protease inhibitors. K48 polyubiquitinated FS and LMW β-catenin were increased by treatment with bortezomib. Overexpressed in vitro double truncated β-catenin increased transcriptional activity, cell proliferation and growth of tumor xenografts compared to FS β-catenin. Serine 552-> alanin substitution abrogated K48 polyubiquitination, β-catenin nuclear translocation and tumor xenograft growth. These data suggest that a novel proteasome-dependent posttranslational modification of β-catenin enhances transcriptional activation. Discovery of this pathway may be helpful in the development of diagnostic and therapeutic tools in colitis and cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Caco-2 Cells
  • Cell Line, Tumor
  • Cell Nucleus / metabolism
  • Cell Proliferation
  • Colitis / genetics
  • Colitis / metabolism*
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / metabolism*
  • HCT116 Cells
  • HT29 Cells
  • Humans
  • Mice
  • Molecular Weight
  • Mutation
  • Neoplasm Transplantation
  • Proteasome Endopeptidase Complex / metabolism
  • Transcription Factor 4 / metabolism
  • Transcriptional Activation*
  • beta Catenin / genetics*
  • beta Catenin / metabolism*

Substances

  • CTNNB1 protein, human
  • TCF4 protein, human
  • Transcription Factor 4
  • beta Catenin
  • Proteasome Endopeptidase Complex