title: Analysing the impact of nucleo-cytoplasmic shuttling of β-catenin and its antagonists APC, Axin and GSK3 on Wnt/β-catenin signalling.
abstract: The canonical Wnt signalling pathway plays a critical role in development and disease. The key player of the pathway is β-catenin. Its activity is mainly regulated by the destruction complex consisting of APC, Axin and GSK3. In the nucleus, the complex formation of β-catenin and TCF initiates target gene expression. Our study provides a comprehensive analysis of the role of nucleo-cytoplasmic shuttling of APC, Axin, and GSK3 and the inactivation of β-catenin by the destruction complex in Wnt/β-catenin signalling. We address the following questions: Can nucleo-cytoplasmic shuttling of APC, Axin and GSK3 increase the [β-catenin/TCF] concentration? And, how is the [β-catenin/TCF] concentration influenced by phosphorylation and subsequent degradation of nuclear β-catenin? Based on experimental findings, we develop a compartmental model and conduct several simulation experiments. Our analysis reveals the following key findings: 1) nucleo-cytoplasmic shuttling of β-catenin and its antagonists can yield a spatial separation between the said proteins, which results in a breakdown of β-catenin degradation, followed by an accumulation of β-catenin and hence leads to an increase of the [β-catenin/TCF] concentration. Our results strongly suggest that Wnt signalling can benefit from nucleo-cytoplasmic shuttling of APC, Axin and GSK3, although they are in general β-catenin antagonising proteins. 2) The total robustness of the [β-catenin/TCF] output is closely linked to its absolute concentration levels. We demonstrate that the compartmental separation of β-catenin and the destruction complex does not only lead to a maximization, but additionally to an increased robustness of [β-catenin/TCF] signalling against perturbations in the cellular environment. 3) A nuclear accumulation of the destruction complex renders the pathway robust against fluctuations in Wnt signalling and against changes in the compartmental distribution of β-catenin. 4) Elucidating the impact of destruction complex inhibition, we show that the [β-catenin/TCF] concentration is more effectively enhanced by inhibition of the kinase GSK3 rather than the binding of β-catenin to the destruction complex.
authors.affiliation: Dept. of Systems Biology and Bioinformatics, University of Rostock, 18051 Rostock, Germany. schmitz@informatik.uni-rostock.de
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Schmitz
authors.forename: Katja
authors.initials: K
authors.lastname: Rateitschak
authors.forename: Olaf
authors.initials: O
authors.lastname: Wolkenhauer
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D060466:Axin Protein / Q000235:genetics / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D005786:Gene Expression Regulation; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D007700:Kinetics; D008322:Mammals / Q000235:genetics / Q000378:metabolism; D015233:Models, Statistical; D009865:Oocytes / Q000166:cytology / Q000378:metabolism; D051820:TCF Transcription Factors / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway; D029867:Xenopus Proteins / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D060466:Axin Protein; C495266:CTNNB1 protein, Xenopus; D003598:Cytoskeletal Proteins; D051820:TCF Transcription Factors; D029867:Xenopus Proteins; C555454:axin1 protein, Xenopus; D051176:beta Catenin; C581760:GSK3B protein, Xenopus; D038362:Glycogen Synthase Kinase 3
keywords: Destruction complex; Intracellular transport; Mathematical model; Sensitivity analysis; Wnt pathway; β-catenin degradation