title: Mathematical modelling suggests a differential impact of β-transducin repeat-containing protein paralogues on Wnt/β-catenin signalling dynamics.
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.
authors.affiliation: Mathematical Modelling of Cellular Processes, Max Delbrück Center for Molecular Medicine Berlin-Buch, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Benary
authors.forename: Bente
authors.initials: B
authors.lastname: Kofahl
authors.forename: Andreas
authors.initials: A
authors.lastname: Hecht
authors.forename: Jana
authors.initials: J
authors.lastname: Wolf
mesh_terms: D000818:Animals; D025461:Feedback, Physiological; D017491:Genes, APC; D006801:Humans; D008962:Models, Theoretical; D009154:Mutation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D015398:Signal Transduction; D051820:TCF Transcription Factors / Q000378:metabolism; D015293:Transducin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*; D044844:beta-Transducin Repeat-Containing Proteins / Q000378:metabolism*
chemical_list: C471644:BTRC protein, human; C471645:FBXW11 protein, human; D051820:TCF Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin; D044844:beta-Transducin Repeat-Containing Proteins; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex; D015293:Transducin
keywords: APC mutation; FWD1; HOS; cancer; feedback