Mathematical modelling suggests a differential impact of β-transducin repeat-containing protein paralogues on...

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.