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.
Highlights
The Wnt signaling pathway has crucial roles in the normal processes of embryonic development [1,2]
One of the most remarkable hallmarks of epithelialmesenchymal transition (EMT) is the repression of cadherin-mediated cell adhesion [10,11]
A comprehensive model that investigates the interplay between these two processes will provide useful information to understand EMT and cancer metastasis
Summary
The Wnt signaling pathway has crucial roles in the normal processes of embryonic development [1,2]. Can b-catenins switch the Wnt signaling pathway between ‘‘on’’ and ‘‘off’’ states, but they can bind to the cytoplasmic domain of classic cadherins as part of the cell adhesive complex [20,21]. Cadherin mediated adhesion can: (1) compete for ABCs with their degradation; (2) affect the kinetics of destruction cycle through membrane spatial organization; and (3) modulate phosphorylation rate of ABCs and their binding with Bcl9.
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