-Catenin degradation mediated by the CID domain of APC provides a model for the selection of APC mutations in colorectal, desmoid and duodenal tumours

Abstract

Biallelic mutation of the ADENOMATOUS POLYPOSIS COLI (APC) gene is a hallmark of sporadic colorectal cancer and colorectal, duodenal and desmoid tumours that develop in familial adenomatous polyposis (FAP) patients. The mutations affecting both APC alleles are interdependent, the position of the first APC mutation determining where the second hit will occur. This results in a complex pattern of mutation distribution in the APC sequence that translates into the stabilization of beta-catenin that in turn feeds the affected cells with a permanent mitogenic signal. We describe here a new APC domain, the beta-catenin inhibitory domain (CID) of APC located between the second and third 20 amino acid repeats and therefore present in many truncated APC products found in human tumours. In truncated APC, the CID is absolutely necessary to down-regulate the transcriptional activity and the level of beta-catenin, even when an axin/conductin binding site is present. The activity of the CID is dramatically reduced in several colon cancer cell lines and can be inhibited by shorter truncated APC lacking the CID. The CID is a direct target of the selective pressure acting on APC during tumourigenesis. It explains the interdependence of both APC mutations, not only in colorectal but also in duodenal and desmoid tumours.

Desmoid Tumors in Familial Adenomatous Polyposis

“…conversely, germline mutations between codons 1429 and 1564, promoting the maintenance of ciD domain, very often induced loss of the second allele, suggesting that in this case ciD retention is tolerated and not counter-selected. The authors explained these different mechanisms of selective pressure assuming two alternative methods of partial regulation of the β-catenin level, based on the retention of repetition 20R3, which showed a strong affinity for β-catenin (41). our data on DTs are also consistent with these findings, confirming that if the first germline mutation affects the domains involved in the regulation of β-catenin level, the second somatic mutation occurs in a downstream region of the APC gene (9,42).…”

Destruction Complex Function in the Wnt Signaling Pathway ofDrosophilaRequires Multiple Interactions Between Adenomatous Polyposis Coli 2 and Armadillo

“…Consistent with this idea, Roberts et al (2011) recently demonstrated that deletion of 20R2 alone produces a protein that is unable to promote bcat degradation in either SW480 cells or the Drosophila embryo. Together with their other observations, the authors suggest that 20R2 and the adjacent region B [also known as CID (Kohler et al 2009)] together form the binding site for an unknown destruction complex protein. …”

“…APC also binds Axin directly through the SAMP repeats, of which there are three in vertebrate APC (Figure 1) (Behrens et al 1998;Hart et al 1998). Conserved sequence B or CID (sequence B), that lies between 20R1 and 20R2 in both vertebrate and Drosophila APCs has recently been shown to play a significant role in bcat degradation, although the mechanism is unknown (Kohler et al 2009;Roberts et al 2011). In cancer, most APC mutations are found in what is termed the mutational cluster region (MCR) that results in the production of truncated APC proteins that are missing five or more of the 20Rs and the SAMP repeats, retaining the N-terminal domains, the 15Rs, approximately two of the 20Rs, and centers over conserved sequence B (Figure 1).…”

Wnt Signaling from Development to Disease: Insights from Model Systems

“…Behrens' laboratory explored possible roles of another conserved sequence they term the CID (Kohler et al 2009), using a cultured cell assay pioneered by Polakis (Munemitsu et al 1995;Rubinfeld et al 1997). To their surprise, truncated APC lacking all SAMP repeats substantially rescued bcat regulation, in contrast to what is seen in mice (Smits et al 1999).…”