Bridging of β-catenin and glycogen synthase kinase-3β by Axin and inhibition of β-catenin-mediated transcription

Sakanaka, Chie; Weiss, John H.; Williams, Lewis T.

doi:10.1073/pnas.95.6.3020

Cited by 284 publications

(204 citation statements)

References 23 publications

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“…We and others have demonstrated that Wnt-1 or Dvl1, when expressed in NIH3T3 cells, can activate the transcription regulator 16,28,29). This activation depends on β-catenin and is suppressed by GSK-3β and axin.…”

Section: Dep Domain Interacts With Upstream Regulators Of Dvlmentioning

confidence: 79%

Untitled

et al. 2000

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The DEP domain of Dishevelled (Dvl) proteins transduces signals to effector proteins downstream of Dvl in the Wnt pathway. Here we report that DEP-containing mutants inhibit Wnt-induced, but not Dvl-induced, activation of the transcription factor Lef-1. This inhibitory effect is weakened by a K434M mutation. Nuclear magnetic resonance spectroscopy revealed that the DEP domain of mouse Dvl1 comprises a three-helix bundle, a β-hairpin 'arm' and two short β-strands at the Cterminal region. Lys 434 is located at the tip of the β-hairpin 'arm'. Based on our findings, we conclude that DEP interacts with regulators upstream of Dvl via a strong electric dipole on the molecule's surface created by Lys 434, Asp 445 and Asp 448; the electric dipole and the putative membrane binding site are at two different locations.The Wnt signaling pathway is a key regulatory pathway for cellular development and growth. Wnt signaling has been extensively studied in Drosophila, Caenorhabditis elegans, Xenopus, and mammalian systems [1][2][3][4][5] . Through genetic studies, a working model of the Wnt signaling pathway has been established. Secreted Wnt proteins bind to Frizzled transmembrane receptors. The receptor-ligand complex activates the Dishevelled (Dsh and Dvl) proteins, which suppress the activity of glycogen synthase kinase-3β (GSK-3β). If its activity is not suppressed, GSK-3β binds to adenomatous polyposis coli (APC) protein and axin and then phosphorylates specific Ser and Thr residues at the N-terminus of β-catenin. In turn, the ubiquitin-proteasome pathway rapidly degrades hyperphosphorylated β-catenin. Wnt activation prevents this process by promoting the cytosolic accumulation and subsequent translocation of β-catenin into the nucleus. Once in the nucleus, β-catenin binds to the transcription factors T-cell factor (Tcf) or lymphoid enhancer factor (Lef) and acts as a transcriptional coactivator 5 . The result is increased expression of Tcf or Lef regulated target genes, such as Myc 6 and the gene encoding cyclin D 7 .© 2000 Nature America Inc. Correspondence should be addressed to: J.Z. Jie.Zheng@stjude.org. HHS Public Access DEP domain interacts with upstream regulators of DvlWe and others have demonstrated that Wnt-1 or Dvl1, when expressed in NIH3T3 cells, can activate the transcription regulator 16,28,29). This activation depends on β-catenin and is suppressed by GSK-3β and axin. To characterize the role of the mDvl1 DEP domain in Wnt signaling, we examined the effect of the Dvl1 N-terminal truncation mutant, DvlC1, on Wnt-induced activation of the transcription factor Lef-1. In Lef dependent reporter gene assays, DvlC1 inhibited Wnt-1 induced Lef-1 activation but not Dvl1 induced Lef-1 activation (Fig. 2). To further characterize the specific sequences that inhibit the Wnt-induced activation, we generated two additional mutants of mDvl1: DvlDEP, which contains only the DEP domain; and DvlC2, which encompasses the sequence downstream of the DEP domain. When expressed in NIH3T3 cells, DvlDEP, like DvlC1, bloc...

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Section: Dep Domain Interacts With Upstream Regulators Of Dvlmentioning

confidence: 79%

Untitled

et al. 2000

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“…A study of hepatocellular carcinomas showed that Axin mutations lead to inappropriate b-catenin-mediated transcription (Satoh et al 2000). Overexpression of Axin in colon cancer cells can rescue the accumulation of b-catenin that results from APC mutation (Behrens et al 1998;Hart et al 1998;Kishida et al 1998;Sakanaka et al 1998).…”

Section: Axin the Central Phosphorylation Scaffoldmentioning

confidence: 99%

The -Catenin Destruction Complex

Stamos

Weis

2012

Cold Spring Harbor Perspectives in Biology

875

783

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The Wnt/b-catenin pathway is highly regulated to insure the correct temporal and spatial activation of its target genes. In the absence of a Wnt stimulus, the transcriptional coactivator b-catenin is degraded by a multiprotein "destruction complex" that includes the tumor suppressors Axin and adenomatous polyposis coli (APC), the Ser/Thr kinases GSK-3 and CK1, protein phosphatase 2A (PP2A), and the E3-ubiquitin ligase b-TrCP. The complex generates a b-TrCP recognition site by phosphorylation of a conserved Ser/Thr-rich sequence near the b-catenin amino terminus, a process that requires scaffolding of the kinases and bcatenin by Axin. Ubiquitinated b-catenin is degraded by the proteasome. The molecular mechanisms that underlie several aspects of destruction complex function are poorly understood, particularly the role of APC. Here we review the molecular mechanisms of destruction complex function and discuss several potential roles of APC in b-catenin destruction.

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“…Overexpressed Axin destabilizes β-catenin (Behrens et al, 1998;Hart et al, 1998;Ikeda et al,1998;Kishida et al, 1998;Nakamura et al, 1998;Sakanaka et al, 1998;Yamamoto et al, 1998). Loss of Axin results in nuclear accumulation of β-catenin followed by formation of the β-catenin-TCF transcriptional complex involving transcriptional activation of its target genes (Sakanaka et al, 1998). Mutations of Axin have been reported in hepatocellular carcinoma (Clevers, 2000;Satoh et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

“…Axin is a multi-domain scaffold protein that associates directly with β-catenin, GSK3β, and phosphatase PP2A (Hsu et al, 1999). Axin is implicated in down-regulation of Wnt/β-catenin signaling Itoh et al, 1998;Sakanaka et al, 1998;Kikuchi et al, 2006). There are two vertebrate Axins (Axin 1 and Axin 2).…”

Section: Introductionmentioning

confidence: 99%

“…Axin1 is constitutively expressed, but Axin 2 is induced by active Wnt signaling and acts therefore in a negative feedback loop (Yan et al, 2001;Jho et al, 2002;Lustig et al, 2002). Overexpressed Axin destabilizes β-catenin (Behrens et al, 1998;Hart et al, 1998;Ikeda et al,1998;Kishida et al, 1998;Nakamura et al, 1998;Sakanaka et al, 1998;Yamamoto et al, 1998). Loss of Axin results in nuclear accumulation of β-catenin followed by formation of the β-catenin-TCF transcriptional complex involving transcriptional activation of its target genes (Sakanaka et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

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Akt is involved in the inhibition of cell proliferation by EGF

Jeon

Jeong²,

Cho³

et al. 2007

Exp Mol Med

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Axin is a negative regulator of the Wnt/β-catenin pathway and is involved in the regulation of axis formation and proliferation. Involvement of Axin in the regulation of other signaling pathways is poorly understood. In this study, we investigated the involvement of Akt in growth regulation by Axin in L929 fibroblasts stimulated by EGF. Akt activity was increased by EGF treatment and Ras activation, respectively. Both the EGFand Ras-induced Akt activations were abolished by Axin induction, as revealed by both Western blot and immunocytochemical analyses. The proliferation and Akt activation induced by EGF were decreased by Axin induction, and the effects of EGF were abolished by treatment of an Akt-specific inhibitor. Therefore, Axin inhibits EGF-induced proliferation of L929 fibroblasts by blocking Akt activation.

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Bridging of β-catenin and glycogen synthase kinase-3β by Axin and inhibition of β-catenin-mediated transcription

Cited by 284 publications

References 23 publications

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Untitled

The -Catenin Destruction Complex

Akt is involved in the inhibition of cell proliferation by EGF

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