Pathway Specificity by the Bifunctional Receptor Frizzled Is Determined by Affinity for Wingless

Rulifson, Eric; Wu, Chi-hwa; Nusse, Roel

doi:10.1016/s1097-2765(05)00018-3

Cited by 110 publications

(76 citation statements)

References 48 publications

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“…7A-A′′). The apparent difference between our observations and the previous work (Rulifson et al, 2000) most probably reflects a difference in the sensitivity of detection methods rather than in the affinity of two versions of Fz for Wg. Overexpression of Fz2, however, leads to increased Wg levels in the central zone of the P compartment (Fig.…”

Section: Fig 3 Notum Suppresses Wg Signaling Mainly Through Dally contrasting

confidence: 99%

“…Previous studies have shown that overexpression of Fz-GPI has no effect on the Wg gradient when examined by conventional staining (Rulifson et al, 2000). However, we found that the extracellular Wg levels are enhanced, and the Wg gradient becomes broader and flatter in the P compartment when overexpressing wild-type Fz (Fig.…”

Section: Fig 3 Notum Suppresses Wg Signaling Mainly Through Dally supporting

confidence: 48%

“…Fz2 has been proposed to play a major role in Wg gradient formation in the wing disc by ectopic expression studies (Cadigan et al, 1998). Although several previous studies as well as our data in this work demonstrated the high capacity of Fz2 in stabilizing Wg (Cadigan, 2002;Lecourtois et al, 2001;Rulifson et al, 2000), our loss-offunction results clearly show that extracellular Wg levels were not reduced in clones mutant fz2. This is apparently not due to the overlapping function of Fz as the extracellular Wg level is enhanced, rather than reduced in the absence of both Fz and Fz2 functions.…”

Section: Roles Of Fz Fz2 and Arr In Wg Gradient Formationsupporting

confidence: 45%

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Drosophilaglypicans Dally and Dally-like shape the extracellular Wingless morphogen gradient in the wing disc

et al. 2005

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Drosophila Wingless (Wg) is the founding member of the Wnt family of secreted proteins. During the wing development, Wg acts as a morphogen whose concentration gradient provides positional cues for wing patterning. The molecular mechanism(s) of Wg gradient formation is not fully understood. Here,we systematically analyzed the roles of glypicans Dally and Dally-like protein(Dlp), the Wg receptors Frizzled (Fz) and Fz2, and the Wg co-receptor Arrow(Arr) in Wg gradient formation in the wing disc. We demonstrate that both Dally and Dlp are essential and have different roles in Wg gradient formation. The specificities of Dally and Dlp in Wg gradient formation are at least partially achieved by their distinct expression patterns. To our surprise,although Fz2 was suggested to play an essential role in Wg gradient formation by ectopic expression studies, removal of Fz2 activity does not alter the extracellular Wg gradient. Interestingly, removal of both Fz and Fz2, or Arr causes enhanced extracellular Wg levels, which is mainly resulted from upregulated Dlp levels. We further show that Notum, a negative regulator of Wg signaling, downregulates Wg signaling mainly by modifying Dally. Last, we demonstrate that Wg movement is impeded by cells mutant for both dally and dlp. Together, these new findings suggest that the Wg morphogen gradient in the wing disc is mainly controlled by combined actions of Dally and Dlp. We propose that Wg establishes its concentration gradient by a restricted diffusion mechanism involving Dally and Dlp in the wing disc.

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Section: Fig 3 Notum Suppresses Wg Signaling Mainly Through Dally contrasting

confidence: 99%

Section: Fig 3 Notum Suppresses Wg Signaling Mainly Through Dally supporting

confidence: 48%

Section: Roles Of Fz Fz2 and Arr In Wg Gradient Formationsupporting

confidence: 45%

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Drosophilaglypicans Dally and Dally-like shape the extracellular Wingless morphogen gradient in the wing disc

et al. 2005

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“…There have been reports that Wnt ligands bind to multiple FZD receptors and vice versa [48,49]. In particular, Wnt5a and Wnt11 also activate the non-canonical Wnt signaling upon binding to FZD7 [50,51].…”

Section: Discussionmentioning

confidence: 99%

Functional interaction between Wnt3 and Frizzled-7 leads to activation of the Wnt/β-catenin signaling pathway in hepatocellular carcinoma cells

Kim¹,

Lee²,

Tsedensodnom³

et al. 2008

Journal of Hepatology

171

173

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Background/Aims-The canonical Wnt signaling is frequently activated in human hepatocellular carcinoma (HCC). We previously demonstrated that up-regulation of Frizzled-7 receptor (FZD7) in HCC was associated with nuclear accumulation of wild-type β-catenin. Here, we investigated Wnt ligand(s) that may activate the Wnt/β-catenin pathway through FZD7 in HCC cells. Results-In hepatitis B virus (HBV)-induced HCC, Wnt3 was upregulated in tumor and peritumoral tissues compared to normal liver and downstream β-catenin target genes were also increased in these samples. Activation of the Wnt/β-catenin pathway in FOCUS-Wnt3 cells was demonstrated by β-catenin accumulation, enhanced TCF transcriptional activity and proliferation rate. The activation of Wnt/β-catenin signaling in FOCUS-Wnt3 was abolished by a knockdown of FZD7 expression by siRNA. More important, a specific Wnt3-FZD7 interaction was observed by co-immunoprecipitation experiments, which suggest that the action of Wnt3 was mediated via FZD7. Methods-To identifyConclusions-These findings demonstrate a functional interaction between Wnt3 and FZD7 leading to activation of the Wnt/β-catenin signaling pathway in HCC cells and may play a role during hepatocarcinogenesis.

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“…With the fledgling wingless (wg, Wnt)-dsh (DVL)-zeste white3 (zw3, GSK3) -armadillo (arm, b-catenin) signaling pathway important for embryonic patterning and wing development (Klingensmith and Nusse 1994;Krasnow et al 1995), came along the identification of the second fly Frizzled gene Dfz2 and the finding that Wg is a ligand for Dfz2 and Fz (Bhanot et al 1996). fz(also called Dfz1) and Dfz2 have redundant functions, although Dfz2 has a more prominent role, in Wg signaling, whereas fz/ Dfz1 has a unique role in the PCP pathway (Kennerdell and Carthew 1998;Chen and Struhl 1999;Boutros et al 2000;Rulifson et al 2000).…”

Section: Wnt -Receptor Interactions: Outside the Cell Fzd Receptorsmentioning

confidence: 99%

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

MacDonald

2012

Cold Spring Harbor Perspectives in Biology

533

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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Pathway Specificity by the Bifunctional Receptor Frizzled Is Determined by Affinity for Wingless

Cited by 110 publications

References 48 publications

Drosophilaglypicans Dally and Dally-like shape the extracellular Wingless morphogen gradient in the wing disc

Drosophilaglypicans Dally and Dally-like shape the extracellular Wingless morphogen gradient in the wing disc

Functional interaction between Wnt3 and Frizzled-7 leads to activation of the Wnt/β-catenin signaling pathway in hepatocellular carcinoma cells

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

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