Author response: A novel GSK3-regulated APC:Axin interaction regulates Wnt signaling by driving a catalytic cycle of efficient βcatenin destruction
Year: 2015
Type: peer-review
Abstract: An embryo starts off as a small ball of stem cells, each of which has the potential to become any type of cell in the body. Adult organs and tissues also contain small numbers of stem cells that can replace old or damaged cells. In both of these processes, stem cells need to ‘decide’ when they should start to change into a more specialized cell type, and which cell fate to choose (e.g., liver cell vs kidney cell). A signaling pathway involving Wnt proteins helps to direct many of these decisions. But if the ‘Wnt signaling pathway’ becomes activated at the wrong time, it can lead to cancer. For example, the first step in development of colon cancer is the inappropriate activation of Wnt signaling, and is most often caused by mutations in the gene that encodes a protein called APC. The APC protein is a tumor suppressor and normally inhibits Wnt signaling. However, even after over 20 years of effort, it remains largely mysterious how APC does this. APC is known to work with another protein called Axin as part of a large protein machine. This protein complex performs one of the first steps in a process that ultimately marks a key component of the Wnt signaling pathway for destruction. Pronobis et al. have now used a range of techniques to define APC's role in this so-called ‘destruction complex’. This analysis revealed the internal structure of a complex made from APC and Axin, and showed that cable- and sheet-like assemblies of Axin were intertwined with APC cables. Further experiments then revealed how APC and Axin proteins are added into or leave these complexes, and showed that this is critical for this protein machine to work. Pronobis et al.'s data also suggest that APC plays two roles, which make the destruction complex more efficient. Firstly, it can interact with Axin via two separate interaction sites that help to assemble the destruction complex. Secondly, specific features in APC allow it to interact with a third protein (called GSK3), which can then regulate how APC interacts with Axin. One of the next challenges will be to uncover how APC helps to transfer the components of Wnt signaling to the next step of their destruction, and to clear up the role played by GSK3.
Authors: Mira I Pronobis, Nasser M Rusan, Mark Peifer
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
OpenAlex ID: W2986814899