<i>Drosophila</i>Twins regulates Armadillo levels in response to Wg/Wnt signal

Bajpai, Ruchi; Makhijani, Kalpana; Rao, Prashanth R; Shashidhara, L. S.

doi:10.1242/dev.00980

Cited by 35 publications

(31 citation statements)

References 72 publications

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“…It could be possible that Arm dephosphorylation by PP2A was not sufficient to activate Arm, or, PP2A has additional role(s) in regulating Arm signaling activity. Our finding that PP2A plays a positive role in Wnt signaling is consistent with a previous study (11). However, PP2A also plays negative roles in other studies probably by regulating different substrates.…”

Section: Discussionsupporting

confidence: 93%

“…Our mechanistic studies of ␤-catenin dephosphorylation by PP2A/PR55␣ are fully consistent with the genetic results of the PR55␣ mutant in Drosophila (11). The Drosophila PR55␣ homolog is encoded by twins (tws).…”

Section: Pr55␣ Directly Interacts With ␤-Catenin and Axin-pr55␣supporting

confidence: 84%

“…The Drosophila PR55␣ homolog is encoded by twins (tws). In the tws Ϫ wing disc, both Arm and its target genes were down-regulated, suggesting that Twins is required for Arm stabilization (11). We also found that overexpression of Twins increased Arm in the wing disc.…”

Section: Pr55␣ Directly Interacts With ␤-Catenin and Axin-pr55␣supporting

confidence: 57%

“…PP2C and PP1 may regulate dephosphorylation of Axin and play positive roles in Wnt signaling (6, 7). PP2A is a multisubunit enzyme (8 -10); it has been reported to play either positive or negative roles in Wnt signaling likely by targeting different components (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21). Toward the goal of understanding the mechanism of ␤-catenin phosphorylation, we carried out siRNA screening targeting several major phosphatases, in which we found that PP2A dephosphorylates ␤-catenin.…”

mentioning

confidence: 99%

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

Zhang

Yang

Liu

et al. 2009

Journal of Biological Chemistry

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A central question in Wnt signaling is the regulation of ␤-catenin phosphorylation and degradation. Multiple kinases, including CKI␣ and GSK3, are involved in ␤-catenin phosphorylation. Protein phosphatases such as PP2A and PP1 have been implicated in the regulation of ␤-catenin. However, which phosphatase dephosphorylates ␤-catenin in vivo and how the specificity of ␤-catenin dephosphorylation is regulated are not clear. In this study, we show that PP2A regulates ␤-catenin phosphorylation and degradation in vivo. We demonstrate that PP2A is required for Wnt/␤-catenin signaling in Drosophila. Moreover, we have identified PR55␣ as the regulatory subunit of PP2A that controls ␤-catenin phosphorylation and degradation. PR55␣, but not the catalytic subunit, PP2Ac, directly interacts with ␤-catenin. RNA interference knockdown of PR55␣ elevates ␤-catenin phosphorylation and decreases Wnt signaling, whereas overexpressing PR55␣ enhances Wnt signaling. Taken together, our results suggest that PR55␣ specifically regulates PP2A-mediated ␤-catenin dephosphorylation and plays an essential role in Wnt signaling.Wnt/␤-catenin signaling plays essential roles in development and tumorigenesis (1-3). Our previous work found that ␤-catenin is sequentially phosphorylated by CKI␣ 4 and GSK3 (4), which creates a binding site for ␤-Trcp (5), leading to degradation via the ubiquitination/proteasome machinery (3). Mutations in ␤-catenin or APC genes that prevent ␤-catenin phosphorylation or ubiquitination/degradation lead ultimately to cancer (1, 2).In addition to the involvement of kinases, protein phosphatases, such as PP1, PP2A, and PP2C, are also implicated in Wnt/ ␤-catenin regulation. PP2C and PP1 may regulate dephosphorylation of Axin and play positive roles in Wnt signaling (6, 7). PP2A is a multisubunit enzyme (8 -10); it has been reported to play either positive or negative roles in Wnt signaling likely by targeting different components (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21). Toward the goal of understanding the mechanism of ␤-catenin phosphorylation, we carried out siRNA screening targeting several major phosphatases, in which we found that PP2A dephosphorylates ␤-catenin. This is consistent with a recent study where PP2A is shown to dephosphorylate ␤-catenin in a cell-free system (18).PP2A consists of a catalytic subunit (PP2Ac), a structure subunit (PR65/A), and variable regulatory B subunits (PR/B, PR/BЈ, PR/BЉ, or PR/Bٞ). The substrate specificity of PP2A is thought to be determined by its B subunit (9). By siRNA screening, we further identified that PR55␣, a regulatory subunit of PP2A, specifically regulates ␤-catenin phosphorylation and degradation. Mechanistically, we found that PR55␣ directly interacts with ␤-catenin and regulates PP2A-mediated ␤-catenin dephosphorylation in Wnt signaling. EXPERIMENTAL PROCEDURESPlasmids-Myc-tagged PR55␣ was cloned into CS2ϩMT vector. FLAG-tagged PP2Ac was cloned into pRK5 vector. ␤-Catenin and Axin constructs have been described previously (4). PR55␣ shRNA constructs were purch...

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Section: Discussionsupporting

confidence: 93%

Section: Pr55␣ Directly Interacts With ␤-Catenin and Axin-pr55␣supporting

confidence: 84%

Section: Pr55␣ Directly Interacts With ␤-Catenin and Axin-pr55␣supporting

confidence: 57%

mentioning

confidence: 99%

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

Zhang

Yang

Liu

et al. 2009

Journal of Biological Chemistry

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“…Others have previously shown that other PP2A B-subunits are also involved in modulation of the Wnt-signaling pathway (28)(29)(30)(31). These results and ours illustrate the dynamic interaction of the PP2A holoenzyme with the Wnt-signaling cascade at different levels and underscore the importance of investigating separate holoenzyme complexes rather than general PP2A activity.…”

Section: Discussionsupporting

confidence: 79%

PR130 is a modulator of the Wnt-signaling cascade that counters repression of the antagonist Naked cuticle

Creyghton

Roël

Eichhorn

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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The Wnt-signaling cascade is required for several crucial steps during early embryogenesis, and its activity is modulated by various agonists and antagonists to provide spatiotemporalspecific signaling. Naked cuticle is a Wnt antagonist that itself is induced by Wnt signaling to keep Wnt signaling in check. Little is known about the regulation of this antagonist. We have recently shown that the protein phosphatase 2A regulatory subunit PR72 is required for the inhibitory effect of Naked cuticle on Wnt signaling. In the present study, we show that PR130, which has an N terminus that differs from that of PR72 but shares the same C terminus, also interacts with Naked cuticle but instead functions as an activator of the Wnt-signaling pathway, both in cell culture and during development. We find that PR130 modulates Wnt signal transduction by restricting the ability of Naked cuticle to function as a Wnt inhibitor. Our data establish PR130 as a modulator of the Wntsignaling pathway and suggest a mechanism of Wnt signal regulation in which the inhibitory activity of Naked cuticle is determined by the relative level of expression of two transcripts of the same protein phosphatase 2A regulatory subunit.development ͉ protein phosphatase 2A ͉ Xenopus

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Understanding the Pathogenicity of Noncoding RNA Expansion-Associated Neurodegenerative Disorders

Das

Chakraborty

Mukherjee

et al. 2019

Insights Into Human Neurodegeneration: Lessons Learnt From Drosophila

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DrosophilaTwins regulates Armadillo levels in response to Wg/Wnt signal

Cited by 35 publications

References 72 publications

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

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

PR130 is a modulator of the Wnt-signaling cascade that counters repression of the antagonist Naked cuticle

Understanding the Pathogenicity of Noncoding RNA Expansion-Associated Neurodegenerative Disorders

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