Article

Seeling, J. M. et al. Regulation of -catenin signaling by the B56 subunit of protein phosphatase 2A. Science 283, 2089-2091

Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84132, USA.
Science (Impact Factor: 33.61). 04/1999; 283(5410):2089-91. DOI: 10.1126/science.283.5410.2089
Source: PubMed

ABSTRACT

Dysregulation of Wnt–β-catenin signaling disrupts axis formation in vertebrate embryos and underlies multiple human malignancies.
The adenomatous polyposis coli (APC) protein, axin, and glycogen synthase kinase 3β form a Wnt-regulated signaling complex
that mediates the phosphorylation-dependent degradation of β-catenin. A protein phosphatase 2A (PP2A) regulatory subunit,
B56, interacted with APC in the yeast two-hybrid system. Expression of B56 reduced the abundance of β-catenin and inhibited
transcription of β-catenin target genes in mammalian cells and Xenopusembryo explants. The B56-dependent decrease in β-catenin was blocked by oncogenic mutations in β-catenin or APC, and by proteasome
inhibitors. B56 may direct PP2A to dephosphorylate specific components of the APC-dependent signaling complex and thereby
inhibit Wnt signaling.

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    • "The ARM domain (armadillo repeat) in the N­terminal region of APC binds a variety of proteins, suggesting that APC may also be involved in the regulation of cell adhesion, polarization, and migration. ARM­binding partners include the B56 regulatory subunit of protein phosphatase 2A (PP2A)[19]. APC­stimulated guanine nucleotide exchan ge factor (Asef)[20], and kinesin superfamily­associated protein 3[21]. "
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    ABSTRACT: Familial adenomatous polyposis (FAP) is an autosomal dominant disease manifesting as colorectal cancer in middle-aged patients. Mutations of the adenomatous polyposis coli (APC) gene contribute to both FAP and sporadic or familial colorectal carcinogenesis. Here we describe the identification of the causative APC gene defects associated with FAP in a Chinese pedigree. All patients with FAP were diagnosed by their combination of clinical features, family history, colonoscopy, and pathology examinations. Blood samples were collected and genomic DNA was extracted. Mutation analysis of APC was conducted by targeted next-generation sequencing, long-range PCR and Sanger sequencing. A novel mutation in exon 14-15(c.1936-2148 del) and intron 14 of the APC gene was demonstrated in all FAP patients and was absent in unaffected family members. This novel deletion causing FAP in Chinese kindred expands the germline mutation spectrum of the APC gene in the Chinese population.
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    • "Support for an involvement of PP2A also derives from the finding that its Ba (PR55a) subunit is required to downregulate the levels of P-Ser552 and P-Ser675 C-terminal phosphoforms of b- CATENIN in colon cancer cells (Zhang et al, 2009). The role of PP2A and its multiple subunits is thus likely to be complex since it can also act positively on WNT signaling with its B56 subunit through the inhibition of N-terminal b-CATENIN phosphorylation and thus inhibition of b-CATENIN destruction (Seeling et al, 1999). Nevertheless, in cancer cells lacking APC destruction complex function (e.g. "
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    • "β-catenin is the first identified target of PP2A-B56α. Overexpression of B56α decreased β-catenin expression in mammalian cells and Xenopus embryo explants (33). PP2A-B56α is thought to have targets within Axin1-mediated degradation complex for β-catenin and it has been found to be able to inhibit the Wnt signaling pathway (34). "
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