Self-association of the APC tumor suppressor is required for the assembly, stability, and activity of the Wnt signaling destruction complex.
Bottom Line: The tumor suppressor adenomatous polyposis coli (APC) is an essential negative regulator of Wnt signaling through its activity in the destruction complex with Axin, GSK3β, and CK1 that targets β-catenin/Armadillo (β-cat/Arm) for proteosomal degradation.The destruction complex forms macromolecular particles we termed the destructosome.These results suggest that APC proteins are required not only for the activity of the destructosome, but also for the assembly and stability of this macromolecular machine.
Affiliation: Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA 15213.Show MeSH
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Mentions: In addition, APC self-association may contribute to both destruction complex function and dysfunction (Kunttas-Tatli et al., 2012). Vertebrate APC (vAPC) can self-associate via multiple mechanisms and domains. However, the precise role of APC self-association in normal destruction complex function and the affects this has on cancer initiation and progression are unclear. Two self-association domains C-terminal to the Armadillo (Arm) repeats in vAPC have been clearly implicated in APC's normal cytoskeletal functions. The dimerization coil ANS2 (Figure 1A) within the basic domain is required for APC's actin nucleation function (Okada et al., 2010), whereas a second oligomerization domain (OD-2; Figure 1A) can modulate the clustering of APC at microtubule plus ends at the tips of membrane protrusions (Li et al., 2008). N-terminal to the Arm repeats, vAPC can form coiled-coil–based dimers through an N-terminal coil (OD-1; Figure 1A), but the precise role of OD-1 in normal APC function is not well understood. The presence of multiple self-association sites within vAPC suggests that the protein may have the ability to form large oligomers in addition to dimers, although it is not clear whether this occurs in vivo.
Affiliation: Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA 15213.