PR55α, a Regulatory Subunit of PP2A, Specifically Regulates PP2A-mediated β-Catenin Dephosphorylation

Zhang, Wen; Yang, Jun; Liu, Yajuan; Chen, Xi; Yu, Ting; Jia, Jianhang; Liu, Chunming

doi:10.1074/jbc.m109.013698

Cited by 97 publications

(111 citation statements)

References 32 publications

(35 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The dephosphorylation of β-catenin and its resulting translocation to the nucleus are associated with tumor grade in various cancers, including AdCC. Previous reports revealed interactions between β-catenin and PP2A (15)(16)(17). Moreover, it was shown that a specific regulatory subunit of PP2A, PR55α, directly interacts with β-catenin (17).…”

Section: Discussionmentioning

confidence: 99%

“…Previous reports revealed interactions between β-catenin and PP2A (15)(16)(17). Moreover, it was shown that a specific regulatory subunit of PP2A, PR55α, directly interacts with β-catenin (17). Together with our current results on the involvement of PR55β in the Wnt/β-catenin signalling pathway, these data suggest that the regulation of β-catenin via the phosphatase activity of PP2A is driven by the inclusion of regulatory subunits of the B (PR55) class, such as PR55α and PR55β.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Regulation of β-Catenin Phosphorylation by PR55β in Adenoid Cystic Carcinoma

Ishibashi

Ishii

Sugiyama

et al. 2018

CGP

View full text Add to dashboard Cite

Abstract. Background Adenoid cystic carcinoma (AdCC) is a rare cancer that arises within the secretory glands, mainly the salivary gland. For head and neck AdCC, the age-adjusted incidence rate is 4.5 cases per 100,000 individuals and exhibits a slight female predominance (1). The risks for delayed recurrence and metastasis in other organs are higher in AdCC than in other oral cancers, such as squamous cell carcinoma (SCC), because of the propensity of AdCC to invade neighbouring tissues and migrate into blood vessels (2, 3). Despite the fact that hundreds of malignant AdCC tumors have been characterized at the molecular level, the underlying regulatory mechanisms of this cancer type remain unclear.To date, many clinical AdCC studies have reported that poor prognosis is associated with pathological features such as AdCC type and grade (4). Histological specimens can be divided into three groups: tubular, cribriform, or solid. Because patients with solid AdCC are especially likely to present with distant metastases, they are the strongest candidates for further surveillance and preventative treatment (5). The use of molecular approaches to elucidate the pathways involved in invasion and migration should significantly add to our understanding of AdCC pathogenesis. Using cell sublines derived from ACCS (an AdCC cell line) by in vivo selection in mice, Ishii et al. (6) demonstrated that interactions between β-catenin and E-cadherin are associated with cell adhesion and lead to tumor metastasis. Further analysis of the molecular mechanisms involved in AdCC should contribute to the identification of potential therapeutic targets.β-catenin is a key molecule in Wnt signalling and plays an important role in cell growth, development, and cancer. The phosphorylation of β-catenin is regulated by several kinases and phosphatases (7). In the absence of extracellular activation, phosphorylated β-catenin is degraded by proteasomes in the cytoplasm. Upon activation of the Wnt signalling pathway, these proteasomes are inhibited, and 53 This article is freely accessible online.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Regulation of β-Catenin Phosphorylation by PR55β in Adenoid Cystic Carcinoma

Ishibashi

Ishii

Sugiyama

et al. 2018

CGP

View full text Add to dashboard Cite

show abstract

“…Our previous work has demonstrated that CKI␣ regulates Drosophila embryonic development by regulating ␤-catenin phosphorylation and degradation (3). We have also demonstrated that PP2A (Twins) regulates Drosophila wing development by regulating ␤-catenin dephosphorylation (18). The Drosophila model provides a powerful tool to study Wnt/Wg signaling in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…Phosphatase 2A (PP2A) and its regulatory subunit, PR55␣, directly interact with and inhibit ␤-catenin phosphorylation (18). Whether ␤-catenin ubiquitination is also directly regulated by a deubiquitinase is not known.…”

mentioning

confidence: 99%

Deubiquitinase USP47/UBP64E Regulates β-Catenin Ubiquitination and Degradation and Plays a Positive Role in Wnt Signaling

Shi

Liu

et al. 2015

Molecular and Cellular Biology

Self Cite

View full text Add to dashboard Cite

Wnt signaling plays important roles in development and tumorigenesis. A central question about the Wnt pathway is the regulation of ␤-catenin. Phosphorylation of ␤-catenin by CK1␣ and GSK3 promotes ␤-catenin binding to ␤-TrCP, leading to ␤-catenin degradation through the proteasome. The phosphorylation and ubiquitination of ␤-catenin have been well characterized; however, it is unknown whether and how a deubiquitinase is involved. In this study, by screening RNA interference (RNAi) libraries, we identified USP47 as a deubiquitinase that prevents ␤-catenin ubiquitination. Inactivation of USP47 by RNAi increased ␤-catenin ubiquitination, attenuated Wnt signaling, and repressed cancer cell growth. Furthermore, USP47 deubiquitinates itself, whereas ␤-TrCP promotes USP47 ubiquitination through interaction with an atypical motif in USP47. Finally, in vivo studies in the Drosophila wing suggest that UBP64E, the USP47 counterpart in Drosophila, is required for Armadillo stabilization and plays a positive role in regulating Wnt target gene expression. Wnt/␤-catenin signaling plays an essential role in animal development and tumorigenesis (1, 2). In normal cells, ␤-catenin is sequentially phosphorylated by CKI␣ and GSK-3 in a protein complex containing the tumor suppressor proteins axin and APC (3). Phosphorylated ␤-catenin is recognized by the ubiquitin (Ub) ligase ␤-TrCP, an F-box and WD40 repeat protein (4). The WD40 repeat domain of ␤-TrCP binds ␤-catenin. ␤-TrCP also binds, via its F-box, to components of the ubiquitination machinery, including Skp1, cullin 1, ring box protein 1 (Rbx1), and ubiquitin-conjugating enzyme (E2). Ubiquitinated ␤-catenin is degraded via the 26S proteasome (4-7). Upon Wnt stimulation, the Wnt protein binds its receptor, Frizzled, and coreceptor, LRP5/6; disrupts the axin complex; blocks the phosphorylation required for ␤-TrCP-mediated ubiquitination; and thus stabilizes ␤-catenin (8-10). Wnt further promotes the accumulated ␤-catenin entry into the nucleus; binding of TCF/LEF; and recruitment of transcriptional coactivators, such as Bcl9/legless, Pygopus, and CBP/p300, to activate downstream target genes (2, 11).In human cancers, particularly in colorectal cancer, ␤-catenin is stabilized by mutations in APC or ␤-catenin (12, 13). ␤-Catenin mutations prevent CKI␣ or GSK-3 phosphorylation and ␤-TrCP recognition of ␤-catenin, resulting in abnormal ␤-catenin accumulation that ultimately leads to cancer (3, 4). APC truncations inhibit both phosphorylation and ubiquitination of ␤-catenin, also resulting in ␤-catenin accumulation (14-16). Understanding the molecular mechanisms of ␤-catenin ubiquitination/degradation is essential for developing therapeutic agents targeting this important pathway for cancer prevention and therapeutics (17).The kinases and ubiquitin protein ligase for ␤-catenin phosphorylation and ubiquitination have been well studied. Phosphatase 2A (PP2A) and its regulatory subunit, PR55␣, directly interact with and inhibit ␤-catenin phosphorylation (18). Whether ␤-catenin ubiquiti...

show abstract

“…Moreover, the same regulatory subunit might target a set of diverse substrates. For example, the B55␣ (55-kDa regulatory subunit, alpha isoform) subunit has been involved in dephosphorylation of CDK1/cyclin B1 substrates during the mitotic transition (14)(15)(16), dephosphorylation of AKT (Thr308) (17), Tau protein (18), FOXO1 (forkhead box O1) transcription factor (19), EDD (a negative regulator of p53) (20), betacatenin (21), and p107 (22). The latter was also reported to be a substrate of PP2A-PR59 holoenzyme (23).…”

mentioning

confidence: 99%

The B55α Regulatory Subunit of Protein Phosphatase 2A Mediates Fibroblast Growth Factor-Induced p107 Dephosphorylation and Growth Arrest in Chondrocytes

Kolupaeva

Daempfling

Basilico

2013

Molecular and Cellular Biology

View full text Add to dashboard Cite

Fibroblast growth factor (FGF)-induced growth arrest of chondrocytes is a unique cell type-specific response which contrasts with the proliferative response of most cell types and underlies several genetic skeletal disorders caused by activating FGF receptor (FGFR) mutations. We have shown that one of the earliest key events in FGF-induced growth arrest is dephosphorylation of the retinoblastoma protein (Rb) family member p107 by protein phosphatase 2A (PP2A), a ubiquitously expressed multisubunit phosphatase. In this report, we show that the PP2A-B55␣ holoenzyme (PP2A containing the B55␣ subunit) is responsible for this phenomenon. Only the B55␣ (55-kDa regulatory subunit, alpha isoform) regulatory subunit of PP2A was able to bind p107, and this interaction was induced by FGF in chondrocytes but not in other cell types. Small interfering RNA (siRNA)-mediated knockdown of B55␣ prevented p107 dephosphorylation and FGF-induced growth arrest of RCS (rat chondrosarcoma) chondrocytes. Importantly, the B55␣ subunit bound with higher affinity to dephosphorylated p107. Since the p107 region interacting with B55␣ is also the site of cyclin-dependent kinase (CDK) binding, B55␣ association may also prevent p107 phosphorylation by CDKs. FGF treatment induces dephosphorylation of the B55␣ subunit itself on several serine residues that drastically increases the affinity of B55␣ for the PP2A A/C dimer and p107. Together these observations suggest a novel mechanism of p107 dephosphorylation mediated by activation of PP2A through B55␣ dephosphorylation. This mechanism might be a general signal transduction pathway used by PP2A to initiate cell cycle arrest when required by external signals.T he response of cells to growth factor signaling is often cell type specific, so that different cells exposed to the same growth factor will show a totally different biological response ranging from stimulation of proliferation, differentiation, or growth inhibition. While in some cases this could be due to the utilization of distinct, although cognate receptors, in many other cases it can be shown that different biological outcomes result from activation of the same receptor in a different biological context.An example of such behavior is the response of chondrocytes to fibroblast growth factor (FGF) signaling. Chondrocyte proliferation and differentiation are required for the process of endochondral ossification that mediates the formation and growth of long bones and vertebrae. One of the major regulators of this process is FGF signaling. Excessive or unregulated FGF signaling caused by activating FGF receptor (FGFR) mutations strongly inhibits chondrocyte proliferation and affects their differentiation, resulting in several bone morphogenetic disorders (1), and it is now quite clear that the major biological response of chondrocytes to FGF is inhibition of cell proliferation.This response is cell type specific and contrasts with the proliferative FGF response in most other cells. We have sought to identify the determinants of the growth i...

show abstract

PR55α, a Regulatory Subunit of PP2A, Specifically Regulates PP2A-mediated β-Catenin Dephosphorylation

Cited by 97 publications

References 32 publications

Regulation of β-Catenin Phosphorylation by PR55β in Adenoid Cystic Carcinoma

Regulation of β-Catenin Phosphorylation by PR55β in Adenoid Cystic Carcinoma

Deubiquitinase USP47/UBP64E Regulates β-Catenin Ubiquitination and Degradation and Plays a Positive Role in Wnt Signaling

The B55α Regulatory Subunit of Protein Phosphatase 2A Mediates Fibroblast Growth Factor-Induced p107 Dephosphorylation and Growth Arrest in Chondrocytes

Contact Info

Product

Resources

About