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Modeling the Effect of APC Truncation on Destruction Complex Function in Colorectal Cancer Cells

Figure 1

Overview of the signaling proteins and interactions considered in the model.

Panel A is a simplified version of Fig. 2, which follows and goes beyond the diagram shown here by illustrating the functional components of proteins responsible for interactions. Selected protein complexes considered in the model are illustrated in Panels B–D. (A) Proteins are represented by boxes. In the model, five proteins, , APC, Axin, , and , are considered explicitly, whereas , PP2A (not shown), and other proteins are considered implicitly. , which mediates phosphorylation of APC, and PP2A, which mediates dephosphorylation of APC, are assumed to be constitutively associated with Axin. In the model, their activities are engaged when Axin is in complex with APC. Interactions included in the model are represented by arrows; numbering of arrows is the same as in Fig. 2. The arrows labeled 1–6 represent reversible direct binding interactions. The arrows labeled 7–10 represent catalytic (phosphorylation) interactions (and enzyme-substrate relationships). All phosphorylation events are taken to be reversed by phosphatases. The interaction represented by Arrow 1 is constitutive. The interaction represented by Arrow 2 depends on sequential phosphorylation of APC by and (Arrows 9 and 10). The interactions represented by Arrows 2 and 3 are mutually exclusive, because they involve the same binding site in , i.e., Axin and APC compete for binding to this site. The interaction between APC and Axin represented by Arrow 4 is missing for typical truncated forms of APC (i.e., forms of APC, such as APC1338, missing SAMP repeats). Arrows 5 and 6 represent recruitment of and to Axin. Arrows 7–10 represent phosphorylation reactions mediated by Axin-associated kinases. (B) A binary complex of APC and connected through two distinct protein-protein interfaces. The interactions represented by Arrows 1 and 2 are allowed to occur simultaneously. (C) A complex wherein is directly bound to Axin via the interaction represented by Arrow 3. Recall that this interaction cannot occur if is bound to APC via the interaction represented by Arrow 2. (D) A complex containing a linear (vs. cyclic) ternary complex of APC, Axin, and . This linear complex is allowed to close and form a cyclic complex via the interaction represented by Arrow 3. Note that the complex depicted here cannot form when APC is truncated such that the interaction represented by Arrow 4 is missing. The model is further described in Fig. 2 and Text S1.

doi: https://doi.org/10.1371/journal.pcbi.1003217.g001