Wnt/Frizzled signaling in Ewing sarcoma

Üren, Aykut; Wolf, Vladimir; Sun, Ye; Azari, Amir A.; Rubin, Jeffrey S.; Toretsky, Jeffrey A.

doi:10.1002/pbc.20124

Cited by 65 publications

(51 citation statements)

References 39 publications

(42 reference statements)

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“…Earlier we observed that Wnt-3a CM induced the formation of long cytoplasmic extensions in TC-32 cells, an ESFT cell line (38). In the current study, we reproduced these results with purified recombinant Wnt-3a and further characterized the morphological changes.…”

Section: Resultssupporting

confidence: 83%

Wnt-3a and Dickkopf-1 Stimulate Neurite Outgrowth in Ewing Tumor Cells via a Frizzled3- and c-Jun N-Terminal Kinase-Dependent Mechanism

Endo

Beauchamp

Woods

et al. 2008

Molecular and Cellular Biology

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Recombinant Wnt-3a stimulated the rapid formation of elongated processes in Ewing sarcoma family tumor (ESFT) cells that were identified as neurites. The processes stained positively for polymerized actin and microtubules as well as synapsin I and growth-associated protein 43. Inhibition of the Wnt receptor, Frizzled3 (Fzd3), with antiserum or by short interfering RNA (siRNA) markedly reduced neurite extension. Knockdown of Dishevelled-2 (Dvl-2) and Dvl-3 also suppressed neurite outgrowth. Surprisingly, disruption of the Wnt/ Fzd/lipoprotein receptor-related protein (LRP) complex and the associated ␤-catenin signaling by treating cells either with the Wnt antagonist Dickkopf-1 (Dkk1) or LRP5/LRP6 siRNA enhanced neuritogenesis. Neurite outgrowth induced by Dkk1 or with LRP5/LRP6 siRNA was inhibited by secreted Fzd-related protein 1, a Wnt antagonist that binds directly to Wnt. Moreover, Dkk1 stimulation of neurite outgrowth was blocked by Fzd3 siRNA. These results suggested that Dkk1 shifted endogenous Wnt activity from the ␤-catenin pathway to Fzd3-mediated, noncanonical signaling that is responsible for neurite formation. In particular, c-Jun amino-terminal kinase (JNK) was important for neurite outgrowth stimulated by both Wnt-3a and Dkk1. Our data demonstrate that Fzd3, Dvl, and JNK activity mediate Wnt-dependent neurite outgrowth and that ESFT cell lines will be useful experimental models for the study of Wnt-dependent neurite extension.The Wnts comprise a large family of secreted glycoproteins that have a variety of activities during embryonic development and promote tissue homeostasis in the adult. At the cellular level, Wnts control proliferation, differentiation, survival, motility, and polarity. They also affect the organization of the developing embryo by regulating tissue patterning, organogenesis, and specification of the body plan (43).Wnts are particularly important in the development of the nervous system, where they are required for several morphogenetic events, including neural tube closure and the formation of specific brain structures as well as induction and migration of neural crest cells (23,25). Wnt signaling has also been shown to stimulate axonal remodeling, pathfinding, dendritic arborization, and neuronal connectivity in the central nervous system (2,6,9,14,32,41,42). Targeted disruption of the gene encoding the Wnt receptor, Frizzled3 (Fzd3), caused severe defects in several major axon tracts of the forebrain, including a complete loss of the thalamocortical, corticothalamic, and nigrostriatal tracts and the anterior commissure as well as variable loss of the corpus callosum (41). Derailed/Ryk, a Wntbinding atypical receptor tyrosine kinase, regulates axon pathfinding in mammalian systems by eliciting either neurite-repulsive (15,18,33) or -attractive (19) responses, depending on the setting. Multiple downstream components of Wnt signaling pathways have been shown to function in neurite outgrowth, although their mechanisms of action have not been fully delineated. The inhibition of gl...

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Section: Resultssupporting

confidence: 83%

Wnt-3a and Dickkopf-1 Stimulate Neurite Outgrowth in Ewing Tumor Cells via a Frizzled3- and c-Jun N-Terminal Kinase-Dependent Mechanism

Endo

Beauchamp

Woods

et al. 2008

Molecular and Cellular Biology

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“…The mouse cells were grown on TripleFlasks (Fisher Scientific, Newark, DE, USA) with 500 cm 2 culture area until they were 80% confluent, and then the medium was changed to 100 ml serum-free DMEM. Two successive 72-h harvests of conditioned medium were collected and pooled (Uren et al 2004, Chen et al 2008. Typically, CM was stored at K80 8C; once thawed, medium was kept refrigerated and retained activity for several weeks.…”

Section: Reagentsmentioning

confidence: 99%

“…Immunofluorescence was performed on C18-4 cells using phalloidin-FITC for actin filament staining. The number of extensions longer than the cell body was counted for each condition and represented in a graph (Uren et al 2004). Human germ cells cultured in the presence and absence of WNT3A CM were analyzed every day and the number of colonies in each well was counted using an inverted microscope.…”

Section: Morphological Analysismentioning

confidence: 99%

Wnt signaling promotes proliferation and stemness regulation of spermatogonial stem/progenitor cells

Golestaneh¹,

Beauchamp²,

Fallen³

et al. 2009

Reproduction

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115

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Spermatogonial stem cells (SSCs) self-renew throughout life to produce progenitor cells that are able to differentiate into spermatozoa. However, the mechanisms underlying the cell fate determination between self-renewal and differentiation have not yet been delineated. Culture conditions and growth factors essential for self-renewal and proliferation of mouse SSCs have been investigated, but no information is available related to growth factors that affect fate determination of human spermatogonia. Wnts form a large family of secreted glycoproteins, the members of which are involved in cell proliferation, differentiation, organogenesis, and cell migration. Here, we show that Wnts and their receptors Fzs are expressed in mouse spermatogonia and in the C18-4 SSC line. We demonstrate that WNT3A induces cell proliferation, morphological changes, and cell migration in C18-4 cells. Furthermore, we show that b-catenin is activated during testis development in 21-day-old mice. In addition, our study demonstrates that WNT3A sustained adult human embryonic stem (ES)-like cells derived from human germ cells in an undifferentiated stage, expressing essential human ES cell transcription factors. These results demonstrate for the first time that Wnt/b-catenin pathways, especially WNT3A, may play an important role in the regulation of mouse and human spermatogonia.

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“…It can act as either an agonist or antagonist of WNT/β-catenin signaling, depending on the cellular context and the presence of the co-factor Kremen 2 [12][13][14]. In ES Kremen 2 is absent and DKK2 stimulates canonical β-catenin signaling.…”

Section: Introductionmentioning

confidence: 99%

The posterior HOXD locus: Its contribution to phenotype and malignancy of Ewing sarcoma

Heyking¹,

Roth²,

Ertl³

et al. 2016

European Journal of Cancer

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Wnt/Frizzled signaling in Ewing sarcoma

Cited by 65 publications

References 39 publications

Wnt-3a and Dickkopf-1 Stimulate Neurite Outgrowth in Ewing Tumor Cells via a Frizzled3- and c-Jun N-Terminal Kinase-Dependent Mechanism

Wnt-3a and Dickkopf-1 Stimulate Neurite Outgrowth in Ewing Tumor Cells via a Frizzled3- and c-Jun N-Terminal Kinase-Dependent Mechanism

Wnt signaling promotes proliferation and stemness regulation of spermatogonial stem/progenitor cells

The posterior HOXD locus: Its contribution to phenotype and malignancy of Ewing sarcoma

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