Computational Modeling of the Interplay between Cadherin-Mediated Cell Adhesion and Wnt Signaling Pathway

Abstract

Wnt signaling and cadherin-mediated adhesion have been implicated in both processes of embryonic development and the progression of carcinomas. Recent experimental studies revealed that Wnt signaling and cadherin-mediated cell adhesion have close crosstalk with each other. A comprehensive model that investigates the dynamic balance of β-catenins in Wnt signaling and cell adhesion will improve our understanding to embryonic development and carcinomas. We constructed a network model to evaluate the dynamic interplay between adhesion and Wnt signaling. The network is decomposed into three interdependent modules: the cell adhesion, the degradation circle and the transcriptional regulation. In the cell adhesion module, we consider the effect of cadherin’s lateral clustering. We found adhesion negatively contributes to Wnt signaling through competition for cytoplasmic β-catenins. In the network of degradation circle, we incorporated features from various existing models. Our simulations reproduced the most recent experimental phenomena with semi-quantitative accuracy. Finally, in the transcriptional regulation module, we developed a function selection strategy to analyze the outcomes of genetic feedback loops in modulating the gene expression of Wnt targets. The specific cellular phenomena such as cadherin switch and Axin oscillation were archived and their biological insights were discussed. Our model provides the theoretical basis of how spatial organization regulates the dynamics of cellular signaling pathways. We suggest that cell adhesion affects Wnt signaling in both negative and positive ways. Cadherins can inhibit Wnt signaling not only in a way as a stoichiometric binding partner of β-catenins that sequesters them from signaling, but also in a way through their clustering to impacts the rate at which β-catenins are involved in the destruction loop. Additionally, cadherin clustering increases the phosphorylation rate of β-catenins and promotes its signaling in nucleus.

Newly Constructed Network Models of Different WNT Signaling Cascades Applied to Breast Cancer Expression Data

“…Our model does not contain any kinetic or mechanistic information. Alternative modeling approaches such as kinetic WNT models [ 45 , 46 ] based on ordinary differential equations were not considered. The databases utilizing the BioPAX format differ in their level of encoded detail.…”

A Theoretical Model of the Wnt Signaling Pathway in the Epithelial Mesenchymal Transition

“…Experimental work suggests that it may not be necessary for the complex to release β-catenin for degradation to occur. Rather, it may be possible for the degradation complex to undergo a structural change that exposes the β-catenin and allows it to be degraded [ 11 ]. Regardless of the exact mechanisms of the process, it is through this constant degradation that the cytosolic β-catenin is maintained at a low concentration in the absence of Wnt [ 23 ].…”

“…In mature multicellular organisms, as well as during development, the Wnt pathway helps regulate proliferation, differentiation, migration, and polarity [ 9 , 10 ]. However, mutations and dysregulation of the pathway can ultimately lead to the occurrence of tumors and the activation of EMT leading to metastasis [ 9 , 11 ].…”

“…However, where Ramis-Conde et al considered the key component of cellular adhesion to be the binding of β-catenin and E-cadherin, which they modeled using ordinary differential equations (ODEs), Basan et al examined the relationship between β-catenin and E-cadherin and the involvement of α-catenin in the adhesion complex by using reaction-diffusion equations [ 14 ]. The dynamics that exist between the adhesion complex and the Wnt pathway were explored further by Chen et al [ 11 ]. In particular, the authors sought to understand the role spatial dynamics play in intracellular signaling.…”

Boolean model of anchorage dependence and contact inhibition points to coordinated inhibition but semi-independent induction of proliferation and migration

“…Adherens junctions and Pak1 activation are both known regulators of EMT transcriptional drivers such as Snai1, Snai2 and Zeb1 . Weak adherens junctions allow β-catenin to translocate to the nucleus where it helps induce Snai2 and Zeb1 [135] , [135] , while Pak1 phosphorylates and activates Snai1 [136] .…”