2008
DOI: 10.1073/pnas.0803025105
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LRP6 transduces a canonical Wnt signal independently of Axin degradation by inhibiting GSK3's phosphorylation of β-catenin

Abstract: Wnt/␤-catenin signaling controls various cell fates in metazoan development and is misregulated in several cancers and developmental disorders. Binding of a Wnt ligand to its transmembrane coreceptors inhibits phosphorylation and degradation of the transcriptional coactivator ␤-catenin, which then translocates to the nucleus to regulate target gene expression. To understand how Wnt signaling prevents ␤-catenin degradation, we focused on the Wnt coreceptor low-density lipoprotein receptor-related protein 6 (LRP… Show more

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Cited by 187 publications
(200 citation statements)
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“…Wnt stimulation or LRP overexpression decrease Axin protein levels in several systems (Kofron et al 2007;Mao et al 2001;Tolwinski et al 2003), which should compromise the destruction complex. LRP-mediated Axin down-regulation and inhibition of bcat degradation can be recapitulated in vitro, but LRP still stabilizes bcat when endogenous Axin is replaced with a nondegradable version (Cselenyi et al 2008). LRP's phosphorylated tail can directly inhibit GSK3 activity (Cselenyi et al 2008;Piao et al 2008), which may contribute to destruction complex inhibition.…”
Section: Pip5kmentioning
confidence: 99%
See 1 more Smart Citation
“…Wnt stimulation or LRP overexpression decrease Axin protein levels in several systems (Kofron et al 2007;Mao et al 2001;Tolwinski et al 2003), which should compromise the destruction complex. LRP-mediated Axin down-regulation and inhibition of bcat degradation can be recapitulated in vitro, but LRP still stabilizes bcat when endogenous Axin is replaced with a nondegradable version (Cselenyi et al 2008). LRP's phosphorylated tail can directly inhibit GSK3 activity (Cselenyi et al 2008;Piao et al 2008), which may contribute to destruction complex inhibition.…”
Section: Pip5kmentioning
confidence: 99%
“…LRP-mediated Axin down-regulation and inhibition of bcat degradation can be recapitulated in vitro, but LRP still stabilizes bcat when endogenous Axin is replaced with a nondegradable version (Cselenyi et al 2008). LRP's phosphorylated tail can directly inhibit GSK3 activity (Cselenyi et al 2008;Piao et al 2008), which may contribute to destruction complex inhibition. Consistent with this, dephosphorylated bcat and APC are recruited to the plasma membrane on Wnt signaling (Hendriksen et al 2008).…”
Section: Pip5kmentioning
confidence: 99%
“…CK1-mediated phosphorylation acts as primer, which triggers GSK3-mediated phosphorylation. CK1 and GSK3 phosphorylate PP(S/T)PX(S/T) repeats in the cytoplasmic C-domain of LRP5/6, a step that is crucial for rescuing -catenin from degradation [53,217,219,231]. Upon binding to LRP5/6, the kinases GSK3 and CK1 switch from phosphorylating -catenin to phosphorylating LRP5/6 [217,232].…”
Section: The Wnt Receptor Complexmentioning
confidence: 99%
“…To integrate recent findings of LRP6 phosphorylation and DVL acting primarily through LRP6 phosphorylation, a newer model has emerged in which phosphorylated PPPSPxS motifs directly inhibit GSK3 (Cselenyi et al 2008;Piao et al 2008;Wu et al 2009). This model is based on findings that LRP6 binds to GSK3 (Zeng et al 2005;Mi et al 2006) and that phosphorylated recombinant LRP6 cytoplasmic domain and, in fact, phosphorylated PPPSPxS peptides bind to and inhibit b-catenin phosphorylation by GSK3 in vitro and activate b-catenin signaling in vivo (Cselenyi et al 2008;Piao et al 2008;Wu et al 2009).…”
Section: Wnt Receptors and Signaling Mechanismsmentioning
confidence: 99%
“…This model is based on findings that LRP6 binds to GSK3 (Zeng et al 2005;Mi et al 2006) and that phosphorylated recombinant LRP6 cytoplasmic domain and, in fact, phosphorylated PPPSPxS peptides bind to and inhibit b-catenin phosphorylation by GSK3 in vitro and activate b-catenin signaling in vivo (Cselenyi et al 2008;Piao et al 2008;Wu et al 2009). This inhibition mechanism bears apparent similarity to GSK3 inhibition during insulin signaling by its own amino-terminal region, whose phosphorylation (at S21 in GSK3a or S9 in GSK3b by the AKT kinase) creates an inhibitory and binding pseudosubstrate for GSK3 inhibition (Dajani et al 2001;Frame et al 2001).…”
Section: Wnt Receptors and Signaling Mechanismsmentioning
confidence: 99%