Nucleo-cytoplasmic shuttling of APC can maximize β‐catenin/TCF concentration

Schmitz, Yvonne; Rateitschak, Katja

doi:10.1016/j.jtbi.2011.03.018

Cited by 15 publications

(10 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…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]. Subsequently they extended the model [30] to investigate the impact of nucleo-cytoplasmic shuttling of β-catenin with its component binding partners in the degradation complex.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2014

View full text Add to dashboard Cite

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.

show abstract

Section: Introductionmentioning

confidence: 99%

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

et al. 2014

View full text Add to dashboard Cite

show abstract

“…(g) The molecular mass diffuses in consideration of excluded volumes, (h) resulting in a distribution of molecular mass on all grid cells assigned to accessible space. 8 C. Kossow et al…”

Section: An Explicit Numerical Scheme To Approximate the Diffusion Eqmentioning

confidence: 99%

“…Case 1 represents an enclosed intracellular volume (molecular environment) where excluded volumes are represented by organelles, for example, the endoplasmic reticulum, that affect the diffusion of molecules [7]. A further example is the diffusion of signalling molecules and transcriptional co-factors, for example, β-catenin, across pore complexes (accessible space) of the nuclear envelope (excluded volume) into the nucleus where they, for instance, initiate gene expression [8,9], as shown in Figure 1(b)-(c). In case 2, Figure 1 is interpreted in a different way.…”

Section: Introductionmentioning

confidence: 99%

“…(b)-(c) An example for case 1 is the translocation of β-catenin from the cytoplasm into the nucleus in the Wnt signalling pathway. It has been shown that β-catenin (black) accumulates in the cytoplasm and then diffuses into the nucleus through pore complexes of the nuclear envelope (grey) [8]. The simulation in a three-dimensional (3D) space was realized in JAMES II based on Equation (4).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

An explicit numerical scheme to efficiently simulate molecular diffusion in environments with dynamically changing barriers

Kossow

Rybacki

Millat

et al. 2015

Mathematical and Computer Modelling of Dynamical Systems

Self Cite

View full text Add to dashboard Cite

Despite temporal changes in the quantities of molecules, the functioning of cells also depends on their distribution within cells and in their extracellular environment. The dynamics of molecules are often governed by diffusion in heterogeneous environments consisting of dynamically changing impenetrable barriers (excluded volumes). This provides a challenge for efficient simulations of cellular processes with large numbers of molecules. To model the diffusion of molecular mass in consideration of excluded volumes, we here present an explicit numerical scheme that approximates the diffusion equation by using cellular automata. Because this approach represents molecular diffusion at the macroscopic scale, it is more amenable for efficient simulations than comparable microscopic approaches that treat diffusing molecules individually. In contrast to implicit numerical schemes (macroscopic approach), our approach is capable of accounting for excluded volumes, even if those exhibit a dynamic of their own, without increasing computational costs. The presented approach can easily be integrated into certain types of spatio-temporal multiscale models, as demonstrated by an existing model investigating cancer progression. Thereby, it allows to take the spatial effects of a heterogeneous environment on diffusing molecules into account.

show abstract

“…Besides that, the importance of phosphorylation in regulation of cytoplasmic pool of β-catenins was not fully considered. Additionally, subcellular models were developed to study the intracellular localization of protein complex in the pathway, for instance, the nucleo-cytoplasmic shuttling of APC [37]. Efforts have also been made to link Wnt signaling to the changes of inter-cellular interactions.…”

Section: Introductionmentioning

confidence: 99%

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

Chen

Xie

2014

PLoS ONE

View full text Add to dashboard Cite

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.

show abstract

Nucleo-cytoplasmic shuttling of APC can maximize β‐catenin/TCF concentration

Cited by 15 publications

References 55 publications

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

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

An explicit numerical scheme to efficiently simulate molecular diffusion in environments with dynamically changing barriers

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

Contact Info

Product

Resources

About