Construction and Experimental Validation of a Petri Net Model of Wnt/beta-Catenin Signaling

A. Jacobsen, N. Heijmans, F. Verkaar, M.J. Smit, J. Heringa, R. van Amerongen, K.A. Feenstra

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

The Wnt/β-catenin signaling pathway is important for multiple developmental processes and tissue maintenance in adults. Consequently, deregulated signaling is involved in a range of human diseases including cancer and developmental defects. A better understanding of the intricate regulatory mechanism and effect of physiological (active) and pathophysiological (hyperactive) WNT signaling is important for predicting treatment response and developing novel therapies. The constitutively expressed CTNNB1 (commonly and hereafter referred to as β-catenin) is degraded by a destruction complex, composed of amongst others AXIN1 and GSK3. The destruction complex is inhibited during active WNT signaling, leading to β-catenin stabilization and induction of β-catenin/TCF target genes. In this study we investigated the mechanism and effect of β-catenin stabilization during active and hyperactive WNT signaling in a combined in silico and in vitro approach. We constructed a Petri net model of Wnt/β-catenin signaling including main players from the plasma membrane (WNT ligands and receptors), cytoplasmic effectors and the downstream negative feedback target gene AXIN2. We validated that our model can be used to simulate both active (WNT stimulation) and hyperactive (GSK3 inhibition) signaling by comparing our simulation and experimental data. We used this experimentally validated model to get further insights into the effect of the negative feedback regulator AXIN2 upon WNT stimulation and observed an attenuated β-catenin stabilization. We furthermore simulated the effect of APC inactivating mutations, yielding a stabilization of β-catenin levels comparable to the Wnt-pathway activities observed in colorectal and breast cancer. Our model can be used for further investigation and viable predictions of the role of Wnt/β-catenin signaling in oncogenesis and development.

Original languageEnglish
Article numbere0155743
JournalPLoS ONE
Volume11
Issue number5
DOIs
Publication statusPublished - 2016

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Catenins
beta Catenin
Petri nets
Stabilization
Wnt Signaling Pathway
colorectal neoplasms
human diseases
breast neoplasms
carcinogenesis
plasma membrane
genes
Genes
mutation
therapeutics
receptors
neoplasms
prediction
Feedback
Cell membranes
Cytoplasmic and Nuclear Receptors

Cite this

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title = "Construction and Experimental Validation of a Petri Net Model of Wnt/beta-Catenin Signaling",
abstract = "The Wnt/β-catenin signaling pathway is important for multiple developmental processes and tissue maintenance in adults. Consequently, deregulated signaling is involved in a range of human diseases including cancer and developmental defects. A better understanding of the intricate regulatory mechanism and effect of physiological (active) and pathophysiological (hyperactive) WNT signaling is important for predicting treatment response and developing novel therapies. The constitutively expressed CTNNB1 (commonly and hereafter referred to as β-catenin) is degraded by a destruction complex, composed of amongst others AXIN1 and GSK3. The destruction complex is inhibited during active WNT signaling, leading to β-catenin stabilization and induction of β-catenin/TCF target genes. In this study we investigated the mechanism and effect of β-catenin stabilization during active and hyperactive WNT signaling in a combined in silico and in vitro approach. We constructed a Petri net model of Wnt/β-catenin signaling including main players from the plasma membrane (WNT ligands and receptors), cytoplasmic effectors and the downstream negative feedback target gene AXIN2. We validated that our model can be used to simulate both active (WNT stimulation) and hyperactive (GSK3 inhibition) signaling by comparing our simulation and experimental data. We used this experimentally validated model to get further insights into the effect of the negative feedback regulator AXIN2 upon WNT stimulation and observed an attenuated β-catenin stabilization. We furthermore simulated the effect of APC inactivating mutations, yielding a stabilization of β-catenin levels comparable to the Wnt-pathway activities observed in colorectal and breast cancer. Our model can be used for further investigation and viable predictions of the role of Wnt/β-catenin signaling in oncogenesis and development.",
author = "A. Jacobsen and N. Heijmans and F. Verkaar and M.J. Smit and J. Heringa and {van Amerongen}, R. and K.A. Feenstra",
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Construction and Experimental Validation of a Petri Net Model of Wnt/beta-Catenin Signaling. / Jacobsen, A.; Heijmans, N.; Verkaar, F.; Smit, M.J.; Heringa, J.; van Amerongen, R.; Feenstra, K.A.

In: PLoS ONE, Vol. 11, No. 5, e0155743, 2016.

Research output: Contribution to JournalArticleAcademicpeer-review

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AU - Jacobsen, A.

AU - Heijmans, N.

AU - Verkaar, F.

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AU - Heringa, J.

AU - van Amerongen, R.

AU - Feenstra, K.A.

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