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Mathematical modelling suggests differential impact of β-TrCP paralogues on Wnt/β-catenin signalling dynamics

Authors

  • U. Benary
  • B. Kofahl
  • A. Hecht
  • J. Wolf

Journal

  • FEBS Journal

Citation

  • FEBS J 282 (6): 1080-1096

Abstract

  • The Wnt/{beta}-catenin signalling pathway is involved in the regulation of a multitude of cellular processes by controlling the concentration of the transcriptional regulator {beta}-catenin. Proteasomal degradation of {beta}-catenin is mediated by the two {beta}-transducin repeat-containing protein ({beta}-TrCP) paralogues HOS and FWD1, which are functionally interchangeable and thereby considered to function redundantly in the pathway. HOS and FWD1 are both regulated by Wnt/{beta}-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/{beta}-catenin signalling in conjunction with their redundant activities in proteasomal degradation of {beta}-catenin is an unresolved issue. Using a detailed ordinary differential equation (ODE) model, we investigated the specific influence of each individual feedback mechanism and their combination on Wnt/{beta}-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 due to 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/{beta}-catenin signalling allows employing the FWD1 feedback as a compensation mechanism against aberrant pathway activation due to reduced HOS concentration. In contrast, the FWD1 feedback provides no protection against aberrant activation in APC mutant cancer cells.


DOI

doi:10.1111/febs.13204