truncated APC mutants destabilize the destruction complex

Stable Identifier
R-HSA-4839744
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Pathway
Species
Homo sapiens
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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).

Literature References
PubMed ID Title Journal Year
9065402 Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC

Morin, PJ, Sparks, AB, Korinek, V, Barker, N, Clevers, HC, Vogelstein, B, Kinzler, KW

Science 1997
8111410 Mutations of the APC (adenomatous polyposis coli) gene

Nagase, H, Nakamura, Y

Hum. Mutat. 1993
22761442 Reversible modification of adenomatous polyposis coli (APC) with K63-linked polyubiquitin regulates the assembly and activity of the ?-catenin destruction complex

Tran, H, Polakis, P

J. Biol. Chem. 2012
15327768 Mechanism of phosphorylation-dependent binding of APC to beta-catenin and its role in beta-catenin degradation

Ha, NC, Tonozuka, T, Stamos, JL, Choi, HJ, Weis, WI

Mol Cell 2004
10921899 Wnt signaling and cancer

Polakis, P

Genes Dev. 2000
8756721 XTcf-3 transcription factor mediates beta-catenin-induced axis formation in Xenopus embryos

Molenaar, M, van De Wetering, M, Oosterwegel, M, Peterson-Maduro, J, Godsave, S, Korinek, V, Roose, J, Destrée, O, Clevers, HC

Cell 1996
23256519 The way Wnt works: Components and mechanism

Saito-Diaz, K, Chen, TW, Wang, X, Thorne, CA, Wallace, HA, Page-McCaw, A, Lee, E

Growth Factors 2013
9065401 Constitutive transcriptional activation by a beta-catenin-Tcf complex in APC-/- colon carcinoma

Korinek, V, Barker, N, Morin, PJ, van Wichen, D, de Weger, R, Kinzler, KW, Vogelstein, B, Clevers, HC

Science 1997
17143297 Colorectal cancer and genetic alterations in the Wnt pathway

Segditsas, S, Tomlinson, I

Oncogene 2006
1338904 Somatic mutations of the APC gene in colorectal tumors: mutation cluster region in the APC gene

Miyoshi, Y, Nagase, H, Ando, H, Horii, A, Ichii, S, Nakatsuru, S, Aoki, T, Miki, Y, Mori, T, Nakamura, Y

Hum. Mol. Genet. 1992
23169527 The ?-catenin destruction complex

Stamos, JL, Weis, WI

Cold Spring Harb Perspect Biol 2013
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Name Identifier Synonyms
cancer 162 malignant tumor, malignant neoplasm, primary cancer
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