title: Construction and Experimental Validation of a Petri Net Model of Wnt/β-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.
authors.affiliation: Centre for Integrative Bioinformatics (IBIVU), VU University Amsterdam, Amsterdam, The Netherlands.|Department of Computer Science, VU University Amsterdam, Amsterdam, The Netherlands.|Amsterdam Institute for Molecules, Medicines and Systems, VU University Amsterdam, Amsterdam, The Netherlands.
authors.forename: Annika
authors.identifier: 0000-0003-4818-2360
authors.initials: A
authors.lastname: Jacobsen
authors.affiliation: Section of Molecular Cytology and Van Leeuwenhoek Centre for Advanced Microscopy, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Nika
authors.initials: N
authors.lastname: Heijmans
authors.affiliation: Amsterdam Institute for Molecules, Medicines and Systems, VU University Amsterdam, Amsterdam, The Netherlands.|Division of Medicinal Chemistry, VU University Amsterdam, Amsterdam, The Netherlands.
authors.forename: Folkert
authors.initials: F
authors.lastname: Verkaar
authors.affiliation: Amsterdam Institute for Molecules, Medicines and Systems, VU University Amsterdam, Amsterdam, The Netherlands.|Division of Medicinal Chemistry, VU University Amsterdam, Amsterdam, The Netherlands.
authors.forename: Martine J
authors.initials: MJ
authors.lastname: Smit
authors.affiliation: Centre for Integrative Bioinformatics (IBIVU), VU University Amsterdam, Amsterdam, The Netherlands.|Department of Computer Science, VU University Amsterdam, Amsterdam, The Netherlands.|Amsterdam Institute for Molecules, Medicines and Systems, VU University Amsterdam, Amsterdam, The Netherlands.
authors.forename: Jaap
authors.initials: J
authors.lastname: Heringa
authors.affiliation: Section of Molecular Cytology and Van Leeuwenhoek Centre for Advanced Microscopy, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Renée
authors.identifier: 0000-0002-8808-2092
authors.initials: R
authors.lastname: van Amerongen
authors.affiliation: Centre for Integrative Bioinformatics (IBIVU), VU University Amsterdam, Amsterdam, The Netherlands.|Department of Computer Science, VU University Amsterdam, Amsterdam, The Netherlands.|Amsterdam Institute for Molecules, Medicines and Systems, VU University Amsterdam, Amsterdam, The Netherlands.
authors.forename: K Anton
authors.identifier: 0000-0001-6755-9667
authors.initials: KA
authors.lastname: Feenstra
mesh_terms: D003198:Computer Simulation; D057809:HEK293 Cells; D006801:Humans; D008954:Models, Biological; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism
chemical_list: C495270:CTNNB1 protein, human; D051176:beta Catenin