Domains of Axin Involved in Protein–Protein Interactions, Wnt Pathway Inhibition, and Intracellular Localization

Fagotto, François; Jho, Eek‐hoon; Zeng, Li; Kurth, Thomas; Joos, Thomas; Kaufmann, Christine; Costantini, Frank

doi:10.1083/jcb.145.4.741

Cited by 248 publications

(276 citation statements)

References 47 publications

(92 reference statements)

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“…Several reports have shown that the phosphorylation of Axin by GSK3b enhances protein stability by preventing degradation by poly-ubiquitination (Fagotto et al, 1999;Willert et al, 1999;Yamamoto et al, 1999;Kim et al, 2008). Consistent with these reports, mutant Axin (R378A) that interacts weakly with GSK3b was more highly ubiquitinated and unstable than wild type (Figure 5f and g), and knockdown of PRMT1 clearly reduced the endogenous level of Axin ( Figure 4d).…”

Section: Discussionsupporting

confidence: 84%

“…pGEX-PRMT3, pGEX-PRMT6 and pGEX-GAR were kindly provided by Dr Herschman (UCLA, Los Angeles, CA, USA) and Dr Bedford (The University of Texas, Smithville, TX, USA). pCS2-Myc-tagged Axin, HA-tagged Axin and pGEX-GST-tagged Axin constructs were generated in the same way as described previously (Fagotto et al, 1999). These three Axin constructs were used for site-directed mutagenesis to obtain Axin R89A, R163A, R358A and R368A.…”

Section: Plasmidsmentioning

confidence: 99%

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Methylation by protein arginine methyltransferase 1 increases stability of Axin, a negative regulator of Wnt signaling

Cha

Kim

et al. 2011

Oncogene

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Axin, a negative regulator of Wnt signaling, is a key scaffold protein for the b-catenin destruction complex. It has been previously shown that multiple post-translational modification enzymes regulate the level of Axin. Here, we provide evidence that protein arginine methyltransferase 1 (PRMT1) directly interacts with and methylates the 378th arginine residue of Axin both in vitro and in vivo. We found that the transient expression of PRMT1 led to an increased level of Axin and that knockdown of endogenous PRMT1 by short hairpin RNA reduced the level of Axin. These results suggest that methylation by PRMT1 enhanced the stability of Axin. Methylation of Axin by PRMT1 also seemingly enhanced the interaction between Axin and glycogen synthase kinase 3b, leading to decreased ubiquitination of Axin. Consistent with the role of PRMT1 in the regulation of Axin, knockdown of PRMT1 enhanced the level of cytoplasmic b-catenin as well as b-catenin-dependent transcription activity. In summary, we show that the methylation of Axin occurred in vivo and controlled the stability of Axin. Therefore, methylation of Axin by PRMT1 may serve as a finely tuned regulation mechanism for Wnt/b-catenin signaling.

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Section: Discussionsupporting

confidence: 84%

Section: Plasmidsmentioning

confidence: 99%

Methylation by protein arginine methyltransferase 1 increases stability of Axin, a negative regulator of Wnt signaling

Cha

Kim

et al. 2011

Oncogene

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“…Axin and Dvl are colocalized in punctate intracellular 'dots' thought to represent intracellular vesicles (Fagotto et al, 1999;Cliffe et al, 2003). Wnt also induces co-clustering of LRP5/6 and Dvl into plasma membrane-associated aggregates that contain Wnt-pathway components (Bilic et al, 2007).…”

Section: Dab2 and Wnt Signaling Y Jiang Et Almentioning

confidence: 99%

The inhibitory effects of Disabled-2 (Dab2) on Wnt signaling are mediated through Axin

2007

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b-Catenin-mediated Wnt signaling is essential in embryonic development and in adult tissues. Recent studies have demonstrated that Axin not only plays an important inhibitory role in coordinating b-catenin degradation, but is itself degraded by the low-density-lipoprotein receptorrelated protein (LRP)5/6 Wnt co-receptor. Here, we demonstrate that the endocytic adaptor molecule Disabled-2 (Dab2), which we have previously demonstrated to act as an inhibitor of b-catenin signaling, interacts with Axin and prevents its interaction with and degradation by the LRP5 co-receptor, thereby increasing its half-life and stabilization. Dab2 levels induced during retinoic acidinduced differentiation of F9, or during transforming growth factor-b-induced epithelial-mesenchymal transdifferentiation of mouse mammary epithelial cells result in the stabilization of Axin and concomitant inhibition of b-catenin signaling. Ectopic expression of Dab2 in F9 cells as well as in transformed cell lines results in increased Axin expression and attenuation of Wnt-mediated signaling. We conclude that Dab2 may play an important role in the maintenance of the differentiated state and restrain Wnt-mediated proliferation through its association with and modulation of Axin.

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“…A proportion of Axin Fu transcripts retain a part of the IAP element, introducing a stop codon. This fusion RNA encodes the RGS signaling domain of Axin but lacks the DIX regulatory domain 18,19 . Axin Fu produces dominant tail kinks with somewhat variable penetrance on several genetic backgrounds we examined.…”

Section: Mvb1 Is Selective For Class Of Retrovirus and Mutagenic Mechmentioning

confidence: 99%

A natural allele of Nxf1 suppresses retrovirus insertional mutations

et al. 2003

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Endogenous retroviruses have shaped the evolution of mammalian genomes. Host genes that control the effects of retrovirus insertions are therefore of great interest. The Modifier-of-vibrator-1 locus controls level of correctly processed mRNA from genes mutated by endogenous retrovirus insertions into introns, including the pitpn vb tremor mutation and the Eya1 BOR model of human branchiootorenal syndrome. Positional complementation cloning identifies Mvb1 as the nuclear export factor Nxf1, providing an unexpected link between mRNA export receptor and pre-mRNA processing. Population structure of the suppressing allele in wild M. m. castaneus suggests selective advantage. A congenic Mvb1 CAST allele is a useful tool for modifying gene expression from existing mutations and could be used to manipulate engineered mutations containing retroviral elements.Mus musculus is a complex species group with subpopulations that have diverged and hybridized since becoming commensal with humans some 10,000 years ago. Allopatric divergence and re-hybridization of mouse lineages are thought to contribute to the diversity and activity of retroviral elements in the current mouse genomes 1,2 . Host genes that can NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript influence the expression of newly introduced (or newly mobilized) viral elements might be selected for variants that blunt these effects. Our results suggest that Mvb1 is such a locus.Mvb1 was originally identified as a strain-derived locus that modifies the neurological mutant, vibrator 3. The vibrator (vb) mutation is a hypomorphic allele of the phosphatidylinositol transfer protein α (PITPα) gene (pitpn) caused by the insertion of an endogenous retrovirus (intracisternal A particle, or IAP) into the fourth intron of the gene, resulting in 5 to 10-fold loss of PITPα expression. Homozygous vibrator mice show severe action tremor, progressive degeneration of interneurons in the brain stem and spinal cord, and uniform juvenile lethality. However, vibrator mice carrying Mvb1 alleles from the wild-derived CAST/Ei inbred strain show reduced tremor severity and survive to adulthood. In principle, this could be due to a change in physiological requirement for PITPα function or to a change in the steady-state expression level of PITPα derived from the mutant allele. RESULTS Mvb1 is a dosage-sensitive modifier of vibrator RNA accumulationMvb1 modifies the severity of vibrator tremor and the associated juvenile lethality 3 . To examine this effect in more detail, we monitored the longevity of vb mutant mice congenic on a C57BL/6J (B6) strain background with zero, one or two CAST/Ei alleles of Mvb1 ( Figure 1a). Consistent with our behavioral observations, the longevity data indicate a semi-dominant mode of action and high penetrance.To extend these observations to the cellular level, we examined histology of vibrator animals homozygous for either the B6 or CAST allele of Mvb1 (Figure 1b To ask whether Mvb1 acts by altering RNA levels from the mutant...

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Domains of Axin Involved in Protein–Protein Interactions, Wnt Pathway Inhibition, and Intracellular Localization

Cited by 248 publications

References 47 publications

Methylation by protein arginine methyltransferase 1 increases stability of Axin, a negative regulator of Wnt signaling

Methylation by protein arginine methyltransferase 1 increases stability of Axin, a negative regulator of Wnt signaling

The inhibitory effects of Disabled-2 (Dab2) on Wnt signaling are mediated through Axin

A natural allele of Nxf1 suppresses retrovirus insertional mutations

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