The Roles of APC and Axin Derived from Experimental and Theoretical Analysis of the Wnt Pathway

The simulation model by Lee et al. (2003) was the first validated simulation model of the canonical Wnt signaling pathway.

“which was the first validated simulation model of the canonical Wnt signaling pathway”

The quantitative requirement that "Axin stimulates the phosphorylation of β-catenin by GSK3β at least 24,000-fold" actually refers to the wet-lab data WD1 obtained in another study by Dajani et al. (2003).

“The quantitative requirement that “Axin stimulates the phosphorylation of β-catenin by GSK3β at least 24,000-fold” [28] actually refers to the wet-lab data WD1 obtained in another study by Dajani et al. (2003) [65].”

Lee et al. (2003) executed in vitro wet-lab experiments with an egg extract of Xenopus and showed in WD1 that the turnover of GSK3β, Dsh, and TCF is relatively slow.

“In the provenance example, Lee et al. (2003) have executed in vitro wet-lab experiments with an egg extract of Xenopus and have shown in WD1 that the “turnover of GSK3β, Dsh, and TCF is relatively slow” [28].”

Assumption A1 reads "Dsh, TCF, and GSK3β are degraded very slowly, we assume that their concentrations remain constant throughout the timecourse of a Wnt signaling event" and was matched to ID 362 (Concentration conservation law) of SBO.

“A1, for instance, reads “Dsh, TCF, and GSK3β are degraded very slowly, we assume that their concentrations remain constant throughout the timecourse of a Wnt signaling event” [28] and was matched to ID 362 (Concentration conservation law) of SBO.”

BSM1 uses wet-lab data, the research question, the qualitative model, a requirement and assumptions to develop a "provisional reference state model", which forms the not yet calibrated simulation model in the study.

“BSM1 is using wet-lab data, the research question, the qualitative model, a requirement and assumptions to develop a “provisional reference state model” [28], which forms the not yet calibrated simulation model in the study.”

Lee et al. (2003) questioned in RQ1 the necessity of the two scaffold proteins APC and Axin for Wnt signaling and whether their roles differ.

“As for the provenance example shown in Fig 3, Lee et al. (2003) questioned in RQ1 the necessity of “the two scaffold proteins, APC and Axin” (for Wnt signaling) and whether “their roles differ” [28].”

Six out of 19 publications recorded their own wet-lab data [28, 31, 32, 45, 51, 57].

“When looking at Wet-lab Data, six out of 19 publications recorded their own wet-lab data [28, 31, 32, 45, 51, 57].”

Requirements could only be identified in the publications of Lee et al. (2003) [28], Wang et al. (2013) [48], Chen et al. (2014) [49], and Haack et al. (2020) [56].

“We could only identify Requirements in the publications of Lee et al. (2003) [28], Wang et al. (2013) [48], Chen et al. (2014) [49], and Haack et al. (2020) [56].”

Only a few simulation models were both calibrated and validated based on wet-lab data, namely those of Lee et al. (2003) [28], Kogan et al. (2012) [45], and Haack et al. (2015) [51].

“When looking at the CSM and VSM activities, we detect that only a few simulation models were both calibrated and validated based on wet-lab data, namely those of Lee et al. (2003) [28], Kogan et al. (2012) [45], and Haack et al. (2015) [51].”

Some studies develop a story line where a simulation model has been successively refined, extended, or composed ([28, 33, 34, 36, 41, 46, 48, 49, 51, 56]).

“Some studies develop a story line where a simulation model has been successively refined, extended, or composed ([28, 33, 34, 36, 41, 46, 48, 49, 51, 56]).”

In Mazemondet et al. (2012) [46], the core model of the Wnt/β-catenin signaling pathway has been calibrated with wet-lab data from Lee et al. (2003) [28], but this calibrated simulation model was not used and instead, a new calibration with wet-lab data from another study took place.

“For example, in Mazemondet et al. (2012) [46], the core model of the Wnt/β-catenin signaling pathway has been calibrated with wet-lab data from Lee et al. (2003) [28], but this calibrated simulation model was not used and instead, a new calibration with wet-lab data from another study took place.”

The two simulation models not linked to Lee et al. (2003) are those by Sick et al. (2006) and by Rodríguez-González et al. (2007).

“The two exceptions not linked to Lee et al. (2003) [28] are the simulation models by Sick et al. (2006) [31] and by Rodríguez-González et al. (2007) [33].”

The central cluster includes the Wnt model by Lee et al. (2003) as well as the studies [30, 34, 35, 41].

“The central cluster includes the Wnt model by Lee et al. (2003) [28] as well as the studies [30, 34, 35, 41].”

All but two of the simulation models considered in the survey are (indirectly) connected to the model proposed by Lee et al. (2003).

“All but two simulation models are (indirectly) connected to the model proposed by Lee et al. (2003) [28], which was the first validated simulation model of the canonical Wnt signaling pathway.”

The Wnt simulation model by Lee et al. (2003) has an outstanding role as the origin for most other models in the survey.

“Our results show the outstanding role of the Wnt simulation model by Lee et al. (2003) [28] as the origin for most other models in our survey.”