Mathematical modelling suggests a differential impact of ?-transducin repeat-containing protein paralogues on Wnt/?-catenin signalling dynamics
07.02.2015
Benary U, Kofahl B, Hecht A, Wolf J.
FEBS J. 2015 Mar;282(6):1080-96
Degradation of ?-catenin is mediated by the paralogous E3-ubiquitin ligases HOS and FWD1 which are both regulated by Wnt/?-catenin signaling, albeit in opposite directions. Here, we investigated the influence of interlocked negative and positive feedback loops on Wnt/?-catenin signal transduction under wild-type and cancerous conditions using a detailed ordinary differential equation model. In healthy cells, signaling dynamics are predominantly affected by the HOS feedback due to comparatively higher levels of HOS. In contrast, FWD1 feedback acts as a compensation mechanism against aberrant pathway activation when HOS concentrations are reduced. However, it does not protect against aberrant activation in APC mutant cancer cells.
