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Arginine methylation of G3BP1 in response to Wnt3a regulates β-catenin mRNA.

Bikkavilli RK, Malbon CC - J. Cell. Sci. (2011)

Bottom Line: Mass spectrometry of a prominent arginine-methylated, Dishevelled-associated protein identified the Ras GTPase activating protein-binding protein 1 G3BP1.Methylation of G3BP1 constitutes a molecular switch that regulates Ctnnb1 mRNA in response to Wnt3a.Thus, the protein arginine methylation that targets G3BP1 acts as a novel regulator of Ctnnb1 mRNA.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, School of Medicine, Health Sciences Center, State University of New York at Stony Brook, Stony Brook, NY 11794-8651, USA. kamesh@pharm.stonybrook.edu

ABSTRACT
Wnt/β-catenin signaling is essential for normal mammalian development. Wnt3a activates the Wnt/β-catenin pathway through stabilization of β-catenin; a process in which the phosphoprotein Dishevelled figures prominently. Protein arginine methylation in signaling complexes containing Dishevelled was investigated. Mass spectrometry of a prominent arginine-methylated, Dishevelled-associated protein identified the Ras GTPase activating protein-binding protein 1 G3BP1. Stimulation of totipotent mouse embryonic F9 cells with Wnt3a provoked increased methylation of G3BP1. We show that G3BP1 is a novel Ctnnb1 mRNA binding protein. Methylation of G3BP1 constitutes a molecular switch that regulates Ctnnb1 mRNA in response to Wnt3a. Thus, the protein arginine methylation that targets G3BP1 acts as a novel regulator of Ctnnb1 mRNA.

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Arginine methylation of G3BP1 regulates both Ctnnb1 mRNA and canonical Wnt/β-catenin signaling. In the absence of Wnt stimulation (–Wnt3a), the G3BP1of Dvl3-based supermolecular complex (signalsomes) binds and regulates Ctnnb1 mRNA (left). Stimulation of cells by Wnt3a activates PRMT1, which methylates G3BP1, provoking release of Ctnnb1 mRNA as well as release of G3BP1 from the signalsome. Increased Ctnnb1 mRNA provokes increased accumulation of β-catenin and activation of canonical Wnt pathway via Lef/Tcf-sensitive gene transcription.
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Figure 7: Arginine methylation of G3BP1 regulates both Ctnnb1 mRNA and canonical Wnt/β-catenin signaling. In the absence of Wnt stimulation (–Wnt3a), the G3BP1of Dvl3-based supermolecular complex (signalsomes) binds and regulates Ctnnb1 mRNA (left). Stimulation of cells by Wnt3a activates PRMT1, which methylates G3BP1, provoking release of Ctnnb1 mRNA as well as release of G3BP1 from the signalsome. Increased Ctnnb1 mRNA provokes increased accumulation of β-catenin and activation of canonical Wnt pathway via Lef/Tcf-sensitive gene transcription.

Mentions: We show herein a previously unidentified role for protein arginine methylation in canonical Wnt/β-catenin signaling, focusing upon Ctnnb1 mRNA. Ctnnb1 mRNA is regulated post-transcriptionally (Gherzi et al., 2006; Bikkavilli and Malbon, 2010). Now we show a post-translational modification-mediated regulation of Ctnnb1 mRNA. Under basal conditions, the Dvl3–G3BP1 complex actively mediates downregulation of Ctnnb1 mRNA. Wnt3a stimulation provokes methylation of G3BP1 by PRMT1, releasing Ctnnb1 mRNA from this regulatory degradation. We propose that protein arginine methylation is a Wnt3a-sensitive ‘molecular switch’ that fosters decreased binding of Ctnnb1 mRNA to G3BP1, which accompanies loss of G3BP1 from the Dvl3-based signalosome (Fig. 7). The molecular details of these altered interactions of G3BP1 and Ctnnb1 mRNA remain to be discerned; however, their functional role on canonical Wnt signaling is clearly important.


Arginine methylation of G3BP1 in response to Wnt3a regulates β-catenin mRNA.

Bikkavilli RK, Malbon CC - J. Cell. Sci. (2011)

Arginine methylation of G3BP1 regulates both Ctnnb1 mRNA and canonical Wnt/β-catenin signaling. In the absence of Wnt stimulation (–Wnt3a), the G3BP1of Dvl3-based supermolecular complex (signalsomes) binds and regulates Ctnnb1 mRNA (left). Stimulation of cells by Wnt3a activates PRMT1, which methylates G3BP1, provoking release of Ctnnb1 mRNA as well as release of G3BP1 from the signalsome. Increased Ctnnb1 mRNA provokes increased accumulation of β-catenin and activation of canonical Wnt pathway via Lef/Tcf-sensitive gene transcription.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3113675&req=5

Figure 7: Arginine methylation of G3BP1 regulates both Ctnnb1 mRNA and canonical Wnt/β-catenin signaling. In the absence of Wnt stimulation (–Wnt3a), the G3BP1of Dvl3-based supermolecular complex (signalsomes) binds and regulates Ctnnb1 mRNA (left). Stimulation of cells by Wnt3a activates PRMT1, which methylates G3BP1, provoking release of Ctnnb1 mRNA as well as release of G3BP1 from the signalsome. Increased Ctnnb1 mRNA provokes increased accumulation of β-catenin and activation of canonical Wnt pathway via Lef/Tcf-sensitive gene transcription.
Mentions: We show herein a previously unidentified role for protein arginine methylation in canonical Wnt/β-catenin signaling, focusing upon Ctnnb1 mRNA. Ctnnb1 mRNA is regulated post-transcriptionally (Gherzi et al., 2006; Bikkavilli and Malbon, 2010). Now we show a post-translational modification-mediated regulation of Ctnnb1 mRNA. Under basal conditions, the Dvl3–G3BP1 complex actively mediates downregulation of Ctnnb1 mRNA. Wnt3a stimulation provokes methylation of G3BP1 by PRMT1, releasing Ctnnb1 mRNA from this regulatory degradation. We propose that protein arginine methylation is a Wnt3a-sensitive ‘molecular switch’ that fosters decreased binding of Ctnnb1 mRNA to G3BP1, which accompanies loss of G3BP1 from the Dvl3-based signalosome (Fig. 7). The molecular details of these altered interactions of G3BP1 and Ctnnb1 mRNA remain to be discerned; however, their functional role on canonical Wnt signaling is clearly important.

Bottom Line: Mass spectrometry of a prominent arginine-methylated, Dishevelled-associated protein identified the Ras GTPase activating protein-binding protein 1 G3BP1.Methylation of G3BP1 constitutes a molecular switch that regulates Ctnnb1 mRNA in response to Wnt3a.Thus, the protein arginine methylation that targets G3BP1 acts as a novel regulator of Ctnnb1 mRNA.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, School of Medicine, Health Sciences Center, State University of New York at Stony Brook, Stony Brook, NY 11794-8651, USA. kamesh@pharm.stonybrook.edu

ABSTRACT
Wnt/β-catenin signaling is essential for normal mammalian development. Wnt3a activates the Wnt/β-catenin pathway through stabilization of β-catenin; a process in which the phosphoprotein Dishevelled figures prominently. Protein arginine methylation in signaling complexes containing Dishevelled was investigated. Mass spectrometry of a prominent arginine-methylated, Dishevelled-associated protein identified the Ras GTPase activating protein-binding protein 1 G3BP1. Stimulation of totipotent mouse embryonic F9 cells with Wnt3a provoked increased methylation of G3BP1. We show that G3BP1 is a novel Ctnnb1 mRNA binding protein. Methylation of G3BP1 constitutes a molecular switch that regulates Ctnnb1 mRNA in response to Wnt3a. Thus, the protein arginine methylation that targets G3BP1 acts as a novel regulator of Ctnnb1 mRNA.

Show MeSH
Related in: MedlinePlus