Endocytosis: A Positive or a Negative Influence on Wnt Signalling?

Gagliardi, Maria; Piddini, Eugenia; Vincent, Jean‐Paul

doi:10.1111/j.1600-0854.2007.00662.x

Cited by 73 publications

(61 citation statements)

References 76 publications

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“…Somewhat contradictory data are published on clathrinmediated endocytosis [292]. For example, in the ventral cuticle of Drosophila larvae, clathrin-mediated endocytosis was reported to be required for the removal of the Wingless protein leading to a downregulation of the signal [293].…”

Section: The Roles Of Endocytosis In Wnt/ -Catenin Signalingmentioning

confidence: 95%

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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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Section: The Roles Of Endocytosis In Wnt/ -Catenin Signalingmentioning

confidence: 95%

“…Thus, although endocytosis clears the Wnt signalosome from the cellular surface, there is an increasing evidence that clathrindepending endocytosis is in itself an important process in Wnt/ -catenin signal activation [164,290,292].…”

Section: The Roles Of Endocytosis In Wnt/ -Catenin Signalingmentioning

confidence: 99%

Wnt/beta-Catenin Signaling and Small Molecule Inhibitors

Voronkov¹,

Krauß²

2012

CPD

View full text Add to dashboard Cite

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“…However, whether these pathways are upstream or downstream of Wnt/b-catenin signaling has yet to be established. Alternatively, EMMPRIN could increase the bioavailability of various factors in the extracellular milieu (such as Wnts) by increased microvesicle shedding (Bartscherer and Boutros, 2008;Gagliardi et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

EMMPRIN regulates the canonical Wnt/β-catenin signaling pathway, a potential role in accelerating lung tumorigenesis

et al. 2010

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Advances in the field of tumor biology have identified that tumor cells co-opt developmental signaling pathways of embryonic stem cells and thus gain the ability to proliferate, differentiate and alter cell-cell interactions. One such pathway is the Wnt/b-catenin signaling pathway. High levels of EMMPRIN expression have been shown to correlate with poor prognosis and metastasis in a broad range of tumors. Although a variety of functions are attributed to EMMPRIN in tumorigenesis, the specific mechanism(s) through which it can exert its effects have not been elucidated, until now. In this study, we identify EMMPRIN as a novel regulator of the canonical Wnt/ b-catenin signaling pathway in lung cancer. Increasing EMMPRIN expression levels in lung cancer epithelial cells upregulated the b-catenin signaling pathway and silencing EMMPRIN inhibited b-catenin signaling, cell migration, proliferation, anchorage-independent growth and tumor growth in a mouse tumor xenograft model. These results provide a compelling rationale for targeting EMMPRIN for anticancer therapies. Understanding the molecular mechanisms driving EMMPRIN-induced lung tumorigenesis will provide enormous benefits in developing new therapeutic treatments for this and other forms of cancer.

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“…In addition, caveolin does not exist in Drosophila, and therefore a different mechanism has to be envisioned for Wg signaling. Thus, some cautions are warranted, particularly when perturbations of general endocytic pathways are performed and thus broad cellular events beyond Wnt signaling are affected (Gagliardi et al 2008). Indeed, manipulating endocytic molecules in Drosophila has also yielded contradictory results regarding Wg signaling (Piddini et al 2005;Rives et al 2006;Seto and Bellen 2006).…”

Section: Lrp6 Signal Initiation-amplification Signalosomes and Endomentioning

confidence: 99%

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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Endocytosis: A Positive or a Negative Influence on Wnt Signalling?

Cited by 73 publications

References 76 publications

Wnt/beta-Catenin Signaling and Small Molecule Inhibitors

Wnt/beta-Catenin Signaling and Small Molecule Inhibitors

EMMPRIN regulates the canonical Wnt/β-catenin signaling pathway, a potential role in accelerating lung tumorigenesis

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

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