Self-association of the APC tumor suppressor is required for the assembly, stability, and activity of the Wnt signaling destruction complex.
Bottom Line: The destruction complex forms macromolecular particles we termed the destructosome.Here we show that a novel N-terminal coil, the APC self-association domain (ASAD), found in vertebrate and invertebrate APCs, directly mediates self-association of Drosophila APC2 and plays an essential role in the assembly and stability of the destructosome that regulates β-cat degradation in Drosophila and human cells.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: To rule out the possibility that this is a cell type–specific effect, we examined the role of APC2 in destructosome assembly in SW480 human colon cancer cells. Similar to Drosophila S2 cells, expression of Axin-GFP in SW480 cells led to the formation of discrete cytoplasmic puncta (Figure 4A1; Fiedler et al., 2011). In the presence of Drosophila APC2-FL, Axin-GFP puncta decreased in number and increased in size (Figure 4A, 1 and 2, and B), suggesting that the role of APC proteins in destructosome assembly is conserved in human cells. Consistent with this hypothesis, expression of APC2-∆ASAD resulted in fragmented, dispersed Axin-GFP puncta (Figure 4A3), suggesting that APC2 self-association is also required for destructosome assembly in human cells.
Affiliation: Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA 15213.