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Mathematical Modelling suggests Differential Impact of β-TrCP 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 the two β-transducin repeat-containing protein (β-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/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 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/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 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/β-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.

10.1111/febs.13204

Projects: A2.5: Integration of insulin and Wnt signalling in hepatocytes, B2.2: Importance of Wnt- and Hedgehog factors for hepatic stellate cells...

FEBS J
FEBS J : n/a
2015

Uwe Benary, Bente Kofahl, Andreas Hecht, Jana Wolf

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[Andreas Hecht]

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None

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Cell
Views: 1252
  • Created: 20th Jan 2015 at 07:51
  • Last updated: 20th Jan 2015 at 07:52

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