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

By Ethan Lee, A. Salic, R. Krüger, Reinhart Heinrich, Marc Kirschner. PLoS Biology, 2003

736 citations recorded by the source corpus.

Wnt signaling plays an important role in both oncogenesis and development. Activation of the Wnt pathway results in stabilization of the transcriptional coactivator β-catenin. Recent studies have demonstrated that axin, which coordinates β-catenin degradation, is itself degraded. Although the key molecules required for transducing a Wnt signal have been identified, a quantitative understanding of this pathway has been lacking. We have developed a mathematical model for the canonical Wnt pathway that describes the interactions among the core components: Wnt, Frizzled, Dishevelled, GSK3β, APC, axin, β-catenin, and TCF. Using a system of differential equations, the model incorporates the kinetics of protein–protein interactions, protein synthesis/degradation, and phosphorylation/dephosphorylation. We initially defined a reference state of kinetic, thermodynamic, and flux data from experiments using Xenopus extracts. Predictions based on the analysis of the reference state were used iteratively to develop a more refined model from which we analyzed the effects of prolonged and transient Wnt stimulation on β-catenin and axin turnover. We predict several unusual features of the Wnt pathway, some of which we tested experimentally. An insight from our model, which we confirmed experimentally, is that the two scaffold proteins axin and APC promote the formation of degradation complexes in very different ways. We can also explain the importance of axin degradation in amplifying and sharpening the Wnt signal, and we show that the dependence of axin degradation on APC is an essential part of an unappreciated regulatory loop that prevents the accumulation of β-catenin at decreased APC concentrations. By applying control analysis to our mathematical model, we demonstrate the modular design, sensitivity, and robustness of the Wnt pathway and derive an explicit expression for tumor suppression and oncogenicity.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/298fd24b3d6e2a1e1d39eca4f22e20db25536740

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In Molecular Biology

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Citations in the corpus

• Wnt signaling in development and tissue homeostasis (2018, background): “Given that Axin proteins are thought to be limiting components of the β -catenin destruction complex (Lee et al., 2003), the rise in Axin levels in response to Wnt signaling leads to increased destruction complex formation and β -catenin degradation, thereby providing a mechanism for negative…”
• Introduction to systems biology. (2007, methodology): “, [7–12, 51, 52]).”
• Deep Proteomics of the Xenopus laevis Egg using an mRNA-derived Reference Database (2014, neutral): “The detected proteins with published concentrations range over four orders of magnitude from 30 μM for Nucleoplasmin [26] to 3 nM for the MAPKKK Mos; [27] from our panel, we only failed to detect the 20 pM Axin [28].”
• LDL receptor-related proteins 5 and 6 in Wnt/β-catenin signaling: Arrows point the way (2004, background): “…possible and may complement its role as a scaffolding protein for β-catenin phosphorylation, one caveat is that the Axin protein level may be significantly lower than that of cytosolic β-catenin (Lee et al., 2003), implying that Axin may only be sufficient to anchor a small fraction of β-catenin.”
• Proximal events in Wnt signal transduction (2009, background): “It is possible that the stability of Axin, as with β-catenin, is regulated by Wnt signallin”
• Mutations in AXIN2 cause familial tooth agenesis and predispose to colorectal cancer. (2004, background): “Recent data based on a mathematical model for Wnt pathway and its experimental confirmation indicate that Axin and APC promote the formation of b-catenin degradation complexes in very different ways (Lee et al. 2003).”
• Wnt/beta-catenin signaling in development and disease. (2006, positive): “Quantitatively, Axin indeed appears to be the limiting factor (Lee et al., 2003) and may be the key scaffolding molecule that promotes the rapid assembly and disassembly of the destruction complex.”
• β-Catenin destruction complex: insights and questions from a structural perspective (2006, background): “GSK3 appears to bind quite tightly to Axin, with a KD of 10 nM (Lee et al., 2003).”