APC is a large and central component of the destruction comp...

created [InstanceEdit:5251517] Rothfels, K, 2014-02-04
dbId 5251516
displayName APC is a large and central component of the destruction comp...
modified [InstanceEdit:5545625] Rothfels, Karen, 2014-05-22
schemaClass Summation
text APC is a large and central component of the destruction complex, which limits signaling in the absence of WNT ligand by promoting the ubiquitin-mediated degradation of beta-catenin. APC interacts with numerous components of the destruction complex, including AXINs (AXIN1 and AXIN2), GSK3s (GSK3alpha and GSK3beta), CK1, PP2A and beta-catenin, and these interactions are critical for the phosphorylation and degradation of beta-catenin (reviewed in Saito-Diaz et al, 2013). APC is itself the target of phosphorylation and K63 ubiquitination in the absence of WNT signaling and these modifications are required for its interactions with other components of the destruction complex (Tran and Polakis, 2012; Ha et al, 2004; reviewed in Stamos and Weis, 2013).

More than 85% of sporadic and hereditary colorectal tumors carry loss-of-function mutations in APC. Most of the mutations are frameshifts and result in truncated proteins that lack the SAMP motifs and the 15 and 20 aa repeats that are implicated in binding AXIN and regulating beta-catenin binding and degradation (Miyoshi et al, 1992; Nagase and Nakamura, 1993; reviewed in Segditas and Tomlinson, 2006). Cancers expressing truncated APC have high levels of cytoplasmic beta-catenin and deregulated expression of WNT target genes (Korinek et al, 1997). Approximately 15% of the colorectal tumors with wild-type APC harbor phosphodegron mutations of beta-catenin; interestingly, mutations in APC and beta-catenin are mutually exclusive events. Similar to APC-mutant tumors, beta-catenin is stabilized in these tumors and constitutive WNT target activation is detected (Morin et al, 1997; reviewed in Polakis, 2000).
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