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
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.
Available from: impactjournals.com
- "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). APCstimulated guanine nucleotide exchan ge factor (Asef), and kinesin superfamilyassociated protein 3. "
[Show abstract] [Hide abstract]
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.
Available from: onlinelibrary.wiley.com
- "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. "
[Show abstract] [Hide abstract]
ABSTRACT: Constitutive activation of canonical WNT-TCF signaling is implicated in multiple diseases, including intestine and lung cancers, but there are no WNT-TCF antagonists in clinical use. We have performed a repositioning screen for WNT-TCF response blockers aiming to recapitulate the genetic blockade afforded by dominant-negative TCF. We report that Ivermectin inhibits the expression of WNT-TCF targets, mimicking dnTCF, and that its low concentration effects are rescued by direct activation by TCFVP16. Ivermectin inhibits the proliferation and increases apoptosis of various human cancer types. It represses the levels of C-terminal β-CATENIN phosphoforms and of CYCLIN D1 in an okadaic acid-sensitive manner, indicating its action involves protein phosphatases. In vivo, Ivermectin selectively inhibits TCF-dependent, but not TCF-independent, xenograft growth without obvious side effects. Analysis of single semi-synthetic derivatives highlights Selamectin, urging its clinical testing and the exploration of the macrocyclic lactone chemical space. Given that Ivermectin is a safe anti-parasitic agent used by > 200 million people against river blindness, our results suggest its additional use as a therapeutic WNT-TCF pathway response blocker to treat WNT-TCF-dependent diseases including multiple cancers.
- "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). "
[Show abstract] [Hide abstract]
ABSTRACT: Cantharidin is an active constituent of mylabris, a traditional Chinese medicine, and presents strong anticancer activity in various cell lines. Cantharidin is a potent and selective inhibitor of serine/threonine protein phosphatase 2A (PP2A). Our previous studies revealed the prospect of application of cantharidin, as well as other PP2A inhibitors, in the treatment of pancreatic cancer. However, the mechanisms involved in the anticancer effect of PP2A inhibitors have not been fully explored. The Wnt/β‑catenin pathway is involved in cell migration and proliferation and participates in the progression of pancreatic cancer. If β‑catenin is phosphorylated and degraded, the Wnt/β‑catenin pathway is blocked. PP2A dephosphorylates β‑catenin and keeps the Wnt/β‑catenin pathway active. In the present study, we found that PP2A inhibitor treatment induced phosphorylation and degradation of β‑catenin. The suppression on the migration and growth of PANC‑1 pancreatic cancer cells could be attenuated by pretreatment with FH535, a β‑catenin pathway inhibitor. Microarray showed that PP2A inhibitor treatment induced expression changes in 13 of 138 genes downstream of the β‑catenin pathway. Real‑time PCR further confirmed that FH535 attenuated the expression changes induced by PP2A inhibitors in 6 of these 13 candidate genes. These 6 genes, VEGFB, Dkk3, KRT8, NRP1, Cacnalg and WISP2, have been confirmed to participate in the migration and/or growth regulation in previous studies. Thus, the phosphorylation- and degradation-mediated suppression on β‑catenin participates in the cytotoxicity of PP2A inhibitors. Our findings may provide insight into the treatment of pancreatic cancer using a targeting PP2A strategy.
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.