Stability elements in the LRP6 cytoplasmic tail confer efficient signalling upon DIX-dependent polymerization

Metcalfe, Ciara; Mendoza-Topaz, Carolina; Mieszczanek, Juliusz; Bienz, Mariann

doi:10.1242/jcs.067546

Cited by 98 publications

(105 citation statements)

References 43 publications

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“…4), a notion that is supported by Dvl depletion experiments . The recent observation in Drosophila that Dsh acts upstream of Arrow further corroborates this biochemical relationship (Metcalfe et al 2010).…”

Section: Lrp6 Phosphorylation: Kinases and Regulationmentioning

confidence: 63%

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

MacDonald

2012

Cold Spring Harbor Perspectives in Biology

506

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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Section: Lrp6 Phosphorylation: Kinases and Regulationmentioning

confidence: 63%

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

MacDonald

2012

Cold Spring Harbor Perspectives in Biology

506

411

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“…The stability of Wnt signalosomes is essential for their signalling activity, and appears to depend on the interaction of additional proteins with the cytoplasmic tail of LRP6 (Metcalfe et al, 2010). Such 'stability' factors might include phosphatidylinositol (4,5)-bisphosphate, production of which is stimulated by Dishevelled acting on phosphatidylinositol kinases (Pan et al, 2008); in mammalian cells, this phospholipid is recognised by the signalosome-promoting protein AMER1 (also known as Amer1/WTX) (Tanneberger et al, 2011).…”

Section: Signalosome Assemblymentioning

confidence: 99%

Inhibition of GSK3 by Wnt signalling – two contrasting models

Metcalfe

Bienz

2011

Journal of Cell Science

Self Cite

165

136

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SummaryThe key read-out of Wnt signalling is a change in the transcriptional profile of the cell, which is driven by b-catenin. b-catenin levels are normally kept low by a phosphorylation event that is mediated by glycogen synthase kinase 3 (GSK3, -and b-isoforms), which targets b-catenin for ubiquitylation and proteasomal degradation. Wnt blocks this phosphorylation event, thereby allowing b-catenin to accumulate and to co-activate transcription in the nucleus. Exactly how Wnt inhibits GSK3 activity towards b-catenin is unclear and has been the focus of intensive research. Recent studies on the role of conserved PPPSPxS motifs in the cytoplasmic tail of lowdensity lipoprotein receptor-related protein (LRP, isoforms 5 and 6) culminated in a biochemical model: Wnt induces the phosphorylation of LRP6 PPPSPxS motifs, which consequently access the catalytic pocket of GSK3 as pseudo-substrates, thus directly blocking its activity against b-catenin. A distinct cell-biological model was proposed more recently: Wnt proteins induce the uptake of GSK3 into multivesicular bodies (MVBs), an event that sequesters the enzyme away from newly synthesised b-catenin substrate in the cytoplasm, thus blocking its phosphorylation. This new model is based on intriguing observations but also challenges a body of existing evidence, so will require further experimental consolidation. We shall consider whether the two models apply to different modes of Wnt signaling: acute versus chronic.

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“…Our observation that APC2-⌬C30 provides a slightly enhanced rescue compared with that of APC2-FL (Table 1) suggests that blocking cortical localization might increase the amount of available APC2 for a cytoplasmic destruction complex function. Furthermore, Wnt-dependent relocalization of Axin to the cortex is one proposed mechanism for deactivation of the destruction complex (Cliffe et al, 2003;Metcalfe et al, 2010) and cortical localization of APC2 is not Wnt dependent (McCartney et al, 1999).…”

Section: The Role Of Cortical Localization In the Regulation Of Wnt Smentioning

confidence: 99%

Cortical localization of APC2 plays a role in actin organization but not in Wnt signaling inDrosophila

Zhou

Kunttas-Tatli

Zimmerman

et al. 2011

Journal of Cell Science

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SummaryThe tumor suppressor Adenomatous polyposis coli (APC) has roles in both Wnt signaling and in actin and microtubule organization. Within the cell, APC proteins have been reported to localize in the cytoplasm, at the cell cortex and in the nucleus. How these localizations relate to the functions of the protein is an aspect of APC biology that is poorly understood. Using Drosophila S2 cells, we have dissected the structural and functional requirements for the cortical localization of Drosophila APC2. Here, we show that both the Armadillo repeats and a novel C-terminal domain are necessary for the cortical localization of APC2 in S2 cells and in the embryo, and that neither domain alone is sufficient for this localization. Furthermore, we show that the Armadillo repeats mediate selfassociation of APC2 molecules. To test the function of the cortical localization of APC2, we asked whether an APC2 protein deleted for the C-terminal localization domain could rescue APC mutant defects in Wnt signaling and actin organization in the Drosophila embryo. We show that although cortical localization is required for the APC2 function in organizing actin, cortical localization is dispensable for its role in regulating Wnt signaling.

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Stability elements in the LRP6 cytoplasmic tail confer efficient signalling upon DIX-dependent polymerization

Cited by 98 publications

References 43 publications

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

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

Inhibition of GSK3 by Wnt signalling – two contrasting models

Cortical localization of APC2 plays a role in actin organization but not in Wnt signaling inDrosophila

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