Association of the APC Gene Product with β-Catenin

Abstract

Mutations in the human APC gene are linked to familial adenomatous polyposis and to the progression of sporadic colorectal and gastric tumors. To gain insight into APC function, APC-associated proteins were identified by immunoprecipitation experiments. Antibodies to APC precipitated a 95-kilodalton protein that was purified and identified by sequencing as beta-catenin, a protein that binds to the cell adhesion molecule E-cadherin. An antibody specific to beta-catenin also recognized the 95-kilodalton protein in the immunoprecipitates. These results suggest that APC is involved in cell adhesion.

GSK-3β-dependent phosphorylation of adenomatous polyposis coli gene product can be modulated by β-catenin and protein phosphatase 2A complexed with Axin

“…Taken together, GSK-3b and its substrates, b-catenin and APC, are simultaneously present in the Axin complex and their phosphorylation occurs e ciently in the complex. It has been shown that the phosphorylation of APC enhances its binding to b-catenin and that mutations in possible phosphorylation site of APC for GSK-3b impair the function of APC to downregulate b-catenin (Rubinfeld et al, , 1997. These results suggest that the phosphorylation of APC is important for its activity to degrade b-catenin.…”

“…The N-terminus contains an oligomerization domain followed by seven repeats of an Armadillo motif. The middle portion of APC contains three successive 15-amino acid (aa) repeats followed by seven related but distinct 20-aa repeats, both of which are able to bind independently to b-catenin (Su et al, 1993;Rubinfeld et al, 1993Rubinfeld et al, , 1995. Following the 20-aa repeats is a basic region, while the C-terminus has a S/ TXV motif that interacts with the PDZ domaincontaining human homolog Dlg (Matsumine et al, 1996).…”

“…Indeed, APC downregulates the level of cytoplasmic b-catenin when introduced into colorectal cancer cell line, SW480 cells . This APC activity was localized to the central region of the protein and at least three 20-aa repeats are necessary for the degradation of b-catenin (Polakis, 1997;Rubinfeld et al, 1997). However, the role of APC in the downregulation of b-catenin is not clear.…”

The Angiogenic Switch Molecule, Secreted FGF-Binding Protein, an Indicator of Early Stages of Pancreatic and Colorectal Adenocarcinoma

“…Carboxy-terminal truncations of the APC protein result in impairment of the ability of APC to interact with and downregulate betacatenin, a transcriptional activator regulated by the Wnt signaling pathway (7)(8)(9)(10)(11)(12)(13). The resulting constitutive overexpression of beta-catenin is likely responsible for the activation of growthpromoting oncogenes, such as cyclin D1 or c-myc (14)(15)(16).…”

The human F box protein β-Trcp associates with the Cul1/Skp1 complex and regulates the stability of β-catenin

“…Importantly, one of these genes was found to be proto-oncogene c-myc (He et al, 1998;Pennisi, 1998). b-catenin also binds the product of the tumor suppressor gene, adenomatous polyposis coli (Apc) (Rubinfeld et al, 1993;Su et al, 1993). Genetic mutations or altered protein expression of E-cadherin, b-catenin, and Apc have been implicated in human cancers, and all result in increased b-catenin levels which in turn leads to increased Lef-1/Tcf-1 transcriptional activity and deregulated proliferation (reviewed in Pennisi, 1998).…”