β-Catenin destruction complex: insights and questions from a structural perspective

Kimelman, David; Xu, Wenqing

doi:10.1038/sj.onc.1210055

Cited by 566 publications

(504 citation statements)

References 71 publications

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“…In addition, aberrant Wnt signaling in adult tissues leads to a variety of human diseases including cancer (Bienz and Clevers, 2000;Polakis, 2000). In the absence of Wnt activation, cytoplasmic b-catenin is assembled in a multimeric protein complex comprising Axin, adenomatous polyposis coli, casein kinase 1 (CK1) and glycogen synthase kinase 3b (GSK3b; Kimelman and Xu, 2006), after which it is sequentially phosphorylated at its Ser and Thr residues by CK1 and GSK3b, respectively (Liu et al, 2002), and degraded via the b-TrCP-mediated ubiquitin-proteasome pathway (Latres et al, 1999;Winston et al, 1999). Upon Wnt stimulation, the Wnt ligand binds to the frizzled receptor and LRP5/6 co-receptors, forming a multimeric membrane receptor complex (Cong et al, 2004;Zeng et al, 2008) in which the cytoplasmic domain of LRP5/6 is highly phophorylated by GSK3b and CK1 at multiple PPPSPxS sites.…”

Section: Introductionmentioning

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, 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: Introductionmentioning

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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“…This model suggests that displacement from or inhibition of GSK3 in the Axin complex causes Axin hypophosphorylation, which further results in reduced b-catenin binding to Axin and thus bcatenin phosphorylation (Kimelman and Xu 2006). Some of these earlier studies included a role for FRAT/GBP (Frequently Rearranged in Advanced T-cell lymphoma/GSK3-Binding Protein), which is a family of GSK3-binding proteins that displace GSK3 from Axin and thus inhibit GSK3 (Yost et al 1998;Ferkey and Kimelman 2002;Dajani et al 2003).…”

Section: Wnt Receptors and Signaling Mechanismsmentioning

confidence: 99%

“…An earlier model (Fig. 5A), prior to knowledge of LRP6 phosphorylation, suggests that Wnt signaling via DVL leads to disruption of the Axin complex (Kimelman and Xu 2006;MacDonald et al 2009). Indeed, upon Wnt stimulation, reduced association of Axin with b-catenin and GSK3 is observed (Kishida et al 1999a; Li et al…”

Section: Inhibition Of B-catenin Phosphorylation Post Receptor Activamentioning

confidence: 99%

Frizzled and LRP5/6 Receptors for Wnt/ -Catenin Signaling

MacDonald

2012

Cold Spring Harbor Perspectives in Biology

531

411

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Frizzled and LRP5/6 are Wnt receptors that upon activation lead to stabilization of cytoplasmic b-catenin. In this study, we review the current knowledge of these two families of receptors, including their structures and interactions with Wnt proteins, and signaling mechanisms from receptor activation to the engagement of intracellular partners Dishevelled and Axin, and finally to the inhibition of b-catenin phosphorylation and ensuing b-catenin stabilization.T he Wnt/b-catenin pathway, or canonical Wnt pathway as it is often referred to, is an ancient and conserved signaling cascade involving b-catenin acting as a transcriptional coactivator (Logan and Nusse 2004). The pathway is best understood when considered in a two-state model of OFF (without Wnt) and ON (with Wnt). In the OFF state, cytoplasmic b-catenin is constitutively targeted for degradation by two multidomain scaffolding proteins, Axin and Adenomatous polyposis coli (APC), which facilitate the amino-terminal phosphorylation of b-catenin via the kinases GSK3 and CKIa. Phosphorylated b-catenin is recognized by the E3 ubiquitin ligase b-Trcp and is thus ubiquitinated and degraded by the proteasome, thereby maintaining low levels of free b-catenin in the cytoplasm and nucleus (MacDonald et al. 2009). In the ON state, a Wnt ligand binds to the seven-pass transmembrane receptor Frizzled (FZD) and the single-pass low-density lipoprotein receptor-related protein 5 or 6 (LRP5/6) ). The Wnt-FZD -LRP5/6 trimeric complex recruits Dishevelled (DVL) and Axin through the intracellular domains of FZD and LRP5/6, resulting in inhibition of b-catenin phosphorylation and thus ensuing b-catenin stabilization. The rise of cytoplasmic and nuclear levels of b-catenin levels promotes b-catenin partnering with the TCF/ LEF transcription factors for activation of Wntresponsive gene expression.Wnt/b-catenin signaling controls cell proliferation and differentiation and is a key regulatory mechanism for stem cells. As such, mutations in the Wnt pathway cause many diseases including cancer (Clevers 2006). All of the above "core" Wnt/b-catenin signaling components are present in vertebrates and the well-studied fruit fly Drosophila and are also encoded in sequenced genomes of radial symmetric Cnidarians Hydra magnipapillata and Nematostella vectensis (Guder et al. 2006) and of the primitive metazoan sponge Amphimedon queenslandica

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“…npg rylation through the interaction with CK1/GSK-3β and β-catenin [24]. To further investigate the mechanism of activation of the Wnt/β-catenin pathway by SKL2001, we first tested the effect of SKL2001 on the level of Axin.…”

Section: Skl2001 Disrupts the Axin/β-catenin Interactionmentioning

confidence: 99%

Small molecule-based disruption of the Axin/β-catenin protein complex regulates mesenchymal stem cell differentiation

Gwak

Hwang

Park³

et al. 2011

Cell Res

113

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The Wnt/β-catenin pathway plays important roles in the differentiation of multiple cell types, including mesenchymal stem cells. Using a cell-based chemical screening assay with a synthetic chemical library of 270 000 compounds, we identified the compound SKL2001 as a novel agonist of the Wnt/β-catenin pathway and uncovered its molecular mechanism of action. SKL2001 upregulated β-catenin responsive transcription by increasing the intracellular β-catenin protein level and inhibited the phosphorylation of β-catenin at residues Ser33/37/Thr41 and Ser45, which would mark it for proteasomal degradation, without affecting CK1 and GSK-3β enzyme activities. Biochemical analysis revealed that SKL2001 disrupted the Axin/β-catenin interaction, which is a critical step for CK1-and GSK-3β-mediated phosphorylation of β-catenin at Ser33/37/Thr41 and Ser45. The treatment of mesenchymal stem cells with SKL2001 promoted osteoblastogenesis and suppressed adipocyte differentiation, both of which were accompanied by the activation of Wnt/β-catenin pathway. Our findings provide a new strategy to regulate mesenchymal stem cell differentiation by modulation of the Wnt/β-catenin pathway.

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β-Catenin destruction complex: insights and questions from a structural perspective

Cited by 566 publications

References 71 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

Frizzled and LRP5/6 Receptors for Wnt/ -Catenin Signaling

Small molecule-based disruption of the Axin/β-catenin protein complex regulates mesenchymal stem cell differentiation

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