Mathematical modelling suggests a differential impact of β-transducin repeat-containing protein paralogues on Wnt/β-catenin signalling dynamics

FEBS J. 2015 Mar;282(6):1080-96. doi: 10.1111/febs.13204. Epub 2015 Feb 7.

Abstract

The Wnt/β-catenin signalling pathway is involved in the regulation of a multitude of cellular processes by controlling the concentration of the transcriptional regulator β-catenin. Proteasomal degradation of β-catenin is mediated by two β-transducin repeat-containing protein paralogues, homologous to Slimb protein (HOS) and F-box/WD repeat-containing protein 1A (FWD1), which are functionally interchangeable and thereby considered to function redundantly in the pathway. HOS and FWD1 are both regulated by Wnt/β-catenin signalling, albeit in opposite directions, thus establishing interlocked negative and positive feedback loops. The functional relevance of the opposite regulation of HOS and FWD1 by Wnt/β-catenin signalling in conjunction with their redundant activities in proteasomal degradation of β-catenin remains unresolved. Using a detailed ordinary differential equation model, we investigated the specific influence of each individual feedback mechanism and their combination on Wnt/β-catenin signal transduction under wild-type and cancerous conditions. We found that, under wild-type conditions, the signalling dynamics are predominantly affected by the HOS feedback as a result of a higher concentration of HOS than FWD1. Transcriptional up-regulation of FWD1 by other signalling pathways reduced the impact of the HOS feedback. The opposite regulation of HOS and FWD1 expression by Wnt/β-catenin signalling allows the FWD1 feedback to be employed as a compensation mechanism against aberrant pathway activation as a result of a reduced HOS concentration. By contrast, the FWD1 feedback provides no protection against aberrant activation in adenomatous polyposis coli protein mutant cancer cells.

Keywords: APC mutation; FWD1; HOS; cancer; feedback.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Feedback, Physiological
  • Genes, APC
  • Humans
  • Models, Theoretical
  • Mutation
  • Proteasome Endopeptidase Complex / metabolism
  • Signal Transduction
  • TCF Transcription Factors / metabolism
  • Transducin / metabolism*
  • Ubiquitin-Protein Ligases / metabolism
  • Wnt Proteins / metabolism*
  • beta Catenin / metabolism*
  • beta-Transducin Repeat-Containing Proteins / metabolism*

Substances

  • BTRC protein, human
  • FBXW11 protein, human
  • TCF Transcription Factors
  • Wnt Proteins
  • beta Catenin
  • beta-Transducin Repeat-Containing Proteins
  • Ubiquitin-Protein Ligases
  • Proteasome Endopeptidase Complex
  • Transducin