LRP6 transduces a canonical Wnt signal independently of Axin degradation by inhibiting GSK3's phosphorylation of β-catenin

Cselenyi, Christopher S.; Jernigan, Kristin K.; Tahinci, Emilios; Thorne, Curtis A.; Lee, Laura A.; Lee, Ethan

doi:10.1073/pnas.0803025105

Cited by 187 publications

(200 citation statements)

References 37 publications

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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%

“…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%

See 1 more Smart Citation

Wnt Signaling from Development to Disease: Insights from Model Systems

Cadigan¹,

Peifer²

2009

Cold Spring Harbor Perspectives in Biology

274

264

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One of the early surprises in the study of cell adhesion was the discovery that b-catenin plays dual roles, serving as an essential component of cadherin-based cell -cell adherens junctions and also serving as the key regulated effector of the Wnt signaling pathway. Here, we review our current model of Wnt signaling and discuss how recent work using model organisms has advanced our understanding of the roles Wnt signaling plays in both normal development and in disease. These data help flesh out the mechanisms of signaling from the membrane to the nucleus, revealing new protein players and providing novel information about known components of the pathway.

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Section: Pip5kmentioning

confidence: 99%

Section: Pip5kmentioning

confidence: 99%

Wnt Signaling from Development to Disease: Insights from Model Systems

Cadigan¹,

Peifer²

2009

Cold Spring Harbor Perspectives in Biology

274

264

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“…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%

Wnt/beta-Catenin Signaling and Small Molecule Inhibitors

Voronkov¹,

Krauß²

2012

CPD

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Wnt/ -catenin signaling is a branch of a functional network that dates back to the first metazoans and it is involved in a broad range of biological systems including stem cells, embryonic development and adult organs. Deregulation of components involved in Wnt/ -catenin signaling has been implicated in a wide spectrum of diseases including a number of cancers and degenerative diseases. The key mediator of Wnt signaling, -catenin, serves several cellular functions. It functions in a dynamic mode at multiple cellular locations, including the plasma membrane, where -catenin contributes to the stabilization of intercellular adhesive complexes, the cytoplasm where -catenin levels are regulated and the nucleus where -catenin is involved in transcriptional regulation and chromatin interactions. Central effectors of -catenin levels are a family of cysteine-rich secreted glycoproteins, known as Wnt morphogens. Through the LRP5/6-Frizzled receptor complex, Wnts regulate the location and activity of the destruction complex and consequently intracellularcatenin levels. However, -catenin levels and their effects on transcriptional programs are also influenced by multiple other factors including hypoxia, inflammation, hepatocyte growth factor-mediated signaling, and the cell adhesion molecule E-cadherin. The broad implications of Wnt/ -catenin signaling in development, in the adult body and in disease render the pathway a prime target for pharmacological research and development. The intricate regulation of -catenin at its various locations provides alternative points for therapeutic interventions.

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“…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%

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

MacDonald

2012

Cold Spring Harbor Perspectives in Biology

508

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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LRP6 transduces a canonical Wnt signal independently of Axin degradation by inhibiting GSK3's phosphorylation of β-catenin

Cited by 187 publications

References 37 publications

Wnt Signaling from Development to Disease: Insights from Model Systems

Wnt Signaling from Development to Disease: Insights from Model Systems

Wnt/beta-Catenin Signaling and Small Molecule Inhibitors

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

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