Toward a quantitative understanding of the Wnt/<i>β</i>‐catenin pathway through simulation and experiment

Lloyd-Lewis, Bethan; Fletcher, Alexander G.; Dale, Trevor; Byrne, Helen M.

doi:10.1002/wsbm.1221

Cited by 35 publications

(37 citation statements)

References 122 publications

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“…the removal of spatial dependencies. In general, more recent models of the Wnt signaling pathway have been based on the Lee model [21-24], as discussed in recent reviews [25,26]. However, to understand the Wnt signaling pathway for human cells, it is logical to want to progress the existing Xenopus Wnt signaling model to one which is parameterized for a mammalian cell system [27].…”

Section: Introductionmentioning

confidence: 99%

“…Recent Wnt signaling models have progressed towards spatial multi-compartmental models [25,28-31] taking into account spatial complexity of cellular signaling [32]. Schmitz et al [29,30] developed ODE models, based on a two compartment (nucleus and cytoplasm) model, to study the influence of nucleo-cytoplasmic shuttling of APC and β-catenin on Wnt signaling [29].…”

Section: Introductionmentioning

confidence: 99%

“…What was clear from these studies was the need for more quantitative spatial data. The current limitation to multi-scale and multi-compartment modelling is the lack of quantitative spatial and temporal data on the key signaling proteins and complexes (this was also the case for van Leeuwen et al) [25]. Clearly we need more quantitative data on the Wnt Pathway in mammalian cell systems [27], particularly quantitative spatial temporal data.…”

Section: Introductionmentioning

confidence: 99%

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Analysis of Wnt signaling β-catenin spatial dynamics in HEK293T cells

et al. 2014

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BackgroundWnt/β-catenin signaling is involved in different stages of mammalian development and implicated in various cancers (e.g. colorectal cancer). Recent experimental and computational studies have revealed characteristics of the pathway, however a cell-specific spatial perspective is lacking. In this study, a novel 3D confocal quantitation protocol is developed to acquire spatial (two cellular compartments: nucleus and cytosol-membrane) and temporal quantitative data on target protein (e.g. β-catenin) concentrations in Human Epithelial Kidney cells (HEK293T) during perturbation (with either cycloheximide or Wnt3A). Computational models of the Wnt pathway are constructed and interrogated based on this data.ResultsA single compartment Wnt pathway model is compared with a simple β-catenin two compartment model to investigate Wnt3A signaling in HEK293T cells. When protein synthesis is inhibited, β-catenin decreases at the same rate in both cellular compartments, suggesting diffusional transport is fast compared to β-catenin degradation in the cytosol. With Wnt3A stimulation, the total amount of β-catenin rises throughout the cell, however the increase is initially (~first hour) faster in the nuclear compartment. While both models were able to reproduce the whole cell changes in β-catenin, only the compartment model reproduced the Wnt3A induced changes in β-catenin distribution and it was also the best fit for the data obtained when active transport was included alongside passive diffusion transport.ConclusionsThis integrated 3D quantitation imaging protocol and computational modeling approach allowed cell-specific compartment models of the signaling pathways to be constructed and analyzed. The Wnt models constructed in this study are the first for HEK293T and have suggested potential roles of inter-compartment transport to the dynamics of signaling.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Analysis of Wnt signaling β-catenin spatial dynamics in HEK293T cells

et al. 2014

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“…They allow one to test conditions that may currently be difficult to attain or even unapproachable in the laboratory. During the past decade, a variety of mathematical or computational models have been applied to study the Wnt signaling pathway at different levels [27]. The first quantitative model of the canonical Wnt pathway was proposed by Lee et al by a system of coupled ODEs to describe how the key proteins in the pathway change over time in response to the Wnt stimulation [28].…”

Section: Introductionmentioning

confidence: 99%

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

Chen

Xie

2014

PLoS ONE

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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.

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“…However, critical cell-level, tissue-level and disease-relevant quantitative data (spatial and dynamic responses of signalling proteins to bioactive stimuli) essential for producing robust models capable of predicting reliably crypt development, the effects of perturbation of tumour suppressor genes, the activation of proto-oncogenes or crypt responses to anti-cancer therapeutics1415 are lacking.…”

mentioning

confidence: 99%

Analysis of Wnt signalling dynamics during colon crypt development in 3D culture

Tan

Hirokawa

Burgess

2015

Sci Rep

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Many systems biology studies lack context-relevant data and as a consequence the predictive capabilities can be limited in developing targeted cancer therapeutics. Production of colon crypt in vitro is ideal for studying colon systems biology. This report presents the first production of, to our knowledge, physiologically-shaped, functional colon crypts in vitro (i.e. single crypts with cells expressing Mucin 2 and Chromogranin A). Time-lapsed monitoring of crypt formation revealed an increased frequency of single-crypt formation in the absence of noggin. Using quantitative 3D immunofluorescence of β-catenin and E-cadherin, spatial-temporal dynamics of these proteins in normal colon crypt cells stimulated with Wnt3A or inhibited by cycloheximide has been measured. Colon adenoma cultures established from APCmin/+ mouse have developmental differences and β-catenin spatial localization compared to normal crypts. Quantitative data describing the effects of signalling pathways and proteins dynamics for both normal and adenomatous colon crypts is now within reach to inform a systems approach to colon crypt biology.

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Toward a quantitative understanding of the Wnt/β‐catenin pathway through simulation and experiment

Cited by 35 publications

References 122 publications

Analysis of Wnt signaling β-catenin spatial dynamics in HEK293T cells

Analysis of Wnt signaling β-catenin spatial dynamics in HEK293T cells

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

Analysis of Wnt signalling dynamics during colon crypt development in 3D culture

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