Dysregulation of Wnt/β-Catenin Signaling in Gastrointestinal Cancers Bryan D. White, Andy J. Chien, David W. Dawson  Gastroenterology  Volume 142, Issue 2, Pages 219-232 (February 2012) DOI: 10.1053/j.gastro.2011.12.001 Copyright © 2012 AGA Institute Terms and Conditions

Figure 1 Schematic illustrating the Wnt/β-catenin pathway. (A) In the absence of a Wnt signal, β-catenin is bound to E-cadherin (E-CAD) at adherens junctions or is phosphorylated by a destruction complex comprised of the core proteins AXIN, APC, GSK3, and CK1. N-terminal phosphorylated β-catenin is targeted for ubiquitination and subsequent proteasomal degradation, maintaining low levels of cytosolic and nuclear β-catenin. Expression of Wnt/β-catenin target genes via activation of TCF/LEF transcription factors is inhibited by the transcriptional repressor Groucho. (B) Wnt ligand initiates signaling through FZD receptor and LRP coreceptor, activating and recruiting DVL (Disheveled) and Axin to the membrane, thereby disrupting the destruction complex. Higher cytosolic levels of β-catenin result in its translocation into the nucleus, where it binds TCF/LEF transcription factors and displaces Groucho to trans-activate Wnt/β-catenin target gene expression. Gastroenterology 2012 142, 219-232DOI: (10.1053/j.gastro.2011.12.001) Copyright © 2012 AGA Institute Terms and Conditions

Figure 2 Common mechanisms by which the Wnt/β-catenin pathway is dysregulated in cancer. (A) Loss-of-function mutations in APC lead to a breakdown of the destruction complex, accumulation of β-catenin in the cytoplasm, translocation of β-catenin into the nucleus, and constitutive expression of Wnt/β-catenin–dependent genes. (B) Gain-of-function mutations in β-catenin, often occurring in exon 3, prevent its N-terminal phosphorylation, thus averting its ubiquitination and degradation. (C) Overexpression of FZD receptors or WNT ligands can lead to increased activation of the pathway. (D) Underexpression of secreted inhibitors of the pathway (ie, secreted frizzled-related proteins [sFRPs]) can also lead to increased sensitivity to Wnt ligands and increased pathway activation. Gastroenterology 2012 142, 219-232DOI: (10.1053/j.gastro.2011.12.001) Copyright © 2012 AGA Institute Terms and Conditions

Figure 3 Additional mechanisms by which Wnt/β-catenin signaling can be modulated in cancer. (A) In hepatocytes, β-catenin can be released from an additional membrane-bound pool associated with the receptor C-MET. When engaged by HGF, C-MET releases β-catenin into the cytoplasm with its eventual translocation into the nucleus. (B) Membrane-bound NOTCH1 can bind activated β-catenin and cause its lysosomal destruction, thereby inhibiting Wnt/β-catenin signaling. A decrease in NOTCH1 expression may therefore potentiate Wnt/β-catenin signaling in certain types of cancer. (C) Interactions with numerous proteins can modulate Wnt/β-catenin signaling at various levels in the pathway. Sulfatase-1 (SULF-1) can increase the efficiency of Wnt ligands by modulating their interactions with heparin sulfate proteoglycans in the extracellular environment. ATDC protein can potentiate pathway activation through its interaction with DVL (Disheveled). SMO can increase Wnt/β-catenin signaling by an unknown mechanism. Undoubtedly, novel mechanisms will be uncovered to explain the complex context dependency of Wnt/β-catenin signaling. Gastroenterology 2012 142, 219-232DOI: (10.1053/j.gastro.2011.12.001) Copyright © 2012 AGA Institute Terms and Conditions

Figure 4 Schematic illustrating numerous small molecules and biological compounds identified in the literature that inhibit Wnt/β-catenin signaling at various points in the pathway. Gastroenterology 2012 142, 219-232DOI: (10.1053/j.gastro.2011.12.001) Copyright © 2012 AGA Institute Terms and Conditions