Caveolin Is Necessary for Wnt-3a-Dependent Internalization of LRP6 and Accumulation of β-Catenin

Yamamoto, Hideki; Komekado, Hideyuki; Kikuchi, Akira

doi:10.1016/j.devcel.2006.07.003

Cited by 275 publications

(363 citation statements)

References 47 publications

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“…4F). In line with the luciferase data, whereas the S isoform did not affect LRP6DN perinuclear localization (26,27), the L isoform expression almost abrogated LRP6DN labeling (Fig. 4G).…”

Section: Membrane-associated Tmem131l Triggers Degradation Of Phosphosupporting

confidence: 86%

Identification of TMEM131L as a Novel Regulator of Thymocyte Proliferation in Humans

Maharzi

Parietti

Nelson

et al. 2013

The Journal of Immunology

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In this study, we identify transmembrane protein 131–like (TMEM131L) as a novel regulator of thymocyte proliferation and demonstrate that it corresponds to a not as yet reported inhibitor of Wnt signaling. Short hairpin RNA–mediated silencing of TMEM131L in human CD34+ hematopoietic progenitors, which were then grafted in NOD-SCID/IL-2rγnull mice, resulted in both thymocyte hyperproliferation and multiple pre– and post–β-selection intrathymic developmental defects. Consistent with deregulated Wnt signaling, TMEM131L-deficient thymocytes expressed Wnt target genes at abnormally high levels, and they displayed both constitutive phosphorylation of Wnt coreceptor LRP6 and β-catenin intranuclear accumulation. Using T cell factor reporter assays, we found that membrane-associated TMEM131L inhibited canonical Wnt/β-catenin signaling at the LRP6 coreceptor level. Whereas membrane-associated TMEM131L did not affect LRP6 expression under basal conditions, it triggered lysosome-dependent degradation of its active phosphorylated form following Wnt activation. Genetic mapping showed that phosphorylated LRP6 degradation did not depend on TMEM131L cytoplasmic part but rather on a conserved extracellular domain proximal to the membrane. Collectively, these data indicate that, during thymopoiesis, stage-specific surface translocation of TMEM131L may regulate immature single-positive thymocyte proliferation arrest by acting through mixed Wnt-dependent and -independent mechanisms.

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“…4F). In line with the luciferase data, whereas the S isoform did not affect LRP6DN perinuclear localization (26,27), the L isoform expression almost abrogated LRP6DN labeling (Fig. 4G).…”

Section: Membrane-associated Tmem131l Triggers Degradation Of Phosphosupporting

confidence: 86%

Identification of TMEM131L as a Novel Regulator of Thymocyte Proliferation in Humans

Maharzi

Parietti

Nelson

et al. 2013

The Journal of Immunology

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“…Thus, endocytic vesicles are postulated to provide a platform for assembly and transport of the Axin complex to the plasma membrane for inactivation by Wnt receptors (Cliffe et al, 2003). Consistent with this model, several recent reports have demonstrated that endocytosis and endosomal transport have been shown to facilitate and maximize Wnt signaling in Drosophila (Chen et al, 2003;Yamamoto et al, 2006).…”

Section: Dab2 and Wnt Signaling Y Jiang Et Almentioning

confidence: 79%

The inhibitory effects of Disabled-2 (Dab2) on Wnt signaling are mediated through Axin

2007

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b-Catenin-mediated Wnt signaling is essential in embryonic development and in adult tissues. Recent studies have demonstrated that Axin not only plays an important inhibitory role in coordinating b-catenin degradation, but is itself degraded by the low-density-lipoprotein receptorrelated protein (LRP)5/6 Wnt co-receptor. Here, we demonstrate that the endocytic adaptor molecule Disabled-2 (Dab2), which we have previously demonstrated to act as an inhibitor of b-catenin signaling, interacts with Axin and prevents its interaction with and degradation by the LRP5 co-receptor, thereby increasing its half-life and stabilization. Dab2 levels induced during retinoic acidinduced differentiation of F9, or during transforming growth factor-b-induced epithelial-mesenchymal transdifferentiation of mouse mammary epithelial cells result in the stabilization of Axin and concomitant inhibition of b-catenin signaling. Ectopic expression of Dab2 in F9 cells as well as in transformed cell lines results in increased Axin expression and attenuation of Wnt-mediated signaling. We conclude that Dab2 may play an important role in the maintenance of the differentiated state and restrain Wnt-mediated proliferation through its association with and modulation of Axin.

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“…Unexpectedly, Axin is also required for Wnt-induced LRP6 PPPSP phosphorylation, and Axin overexpression enhances PPPSP phosphorylation Yamamoto et al 2006), but only if Axin is not impaired in GSK3 binding . These findings led to a model that DVL binding to and recruitment of Axin into the FZD -LRP6 complex initiates GSK3 phosphorylation of LRP6 on PPPSP motifs .…”

Section: Lrp6 Phosphorylation: Kinases and Regulationmentioning

confidence: 99%

“…Another model, in which phosphorylated/ activated LRP6 signals in an endosomal platform, posits that LRP6 and phosphorylation in lipid rafts (a cholesterol-rich microdomain in the plasma membrane) and its subsequent endocytosis through caveolin are both required for signaling (Yamamoto et al 2006(Yamamoto et al , 2008. Caveolin binds to LRP6 upon Wnt stimulation and is required for phosphorylated LRP6 to recruit Axin (Yamamoto et al 2006).…”

Section: Lrp6 Signal Initiation-amplification Signalosomes and Endomentioning

confidence: 99%

“…Caveolin binds to LRP6 upon Wnt stimulation and is required for phosphorylated LRP6 to recruit Axin (Yamamoto et al 2006). One may notice significant similarities between lipid raft/endosomal LRP6 versus signalosomes, because methods (gradient fractionation and immunostaining) used to define them are similar, and signalosomes indeed contain caveolin (Yamamoto et al 2006;Bilic et al 2007), suggesting that these two models overlap despite different emphases. PIP2 is suggested to promote LRP6 signalosome formation and thus phosphorylation (Pan et al 2008), but its key roles in receptor endocytosis should be noted (Di Paolo and De Camilli 2006).…”

Section: Lrp6 Signal Initiation-amplification Signalosomes and Endomentioning

confidence: 99%

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

MacDonald

2012

Cold Spring Harbor Perspectives in Biology

494

403

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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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Caveolin Is Necessary for Wnt-3a-Dependent Internalization of LRP6 and Accumulation of β-Catenin

Cited by 275 publications

References 47 publications

Identification of TMEM131L as a Novel Regulator of Thymocyte Proliferation in Humans

Identification of TMEM131L as a Novel Regulator of Thymocyte Proliferation in Humans

The inhibitory effects of Disabled-2 (Dab2) on Wnt signaling are mediated through Axin

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

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