The cell-surface proteoglycan Dally regulates Wingless signalling in Drosophila

Tsuda, Manabu; Kamimura, Kazuo; Nakato, Hiroshi; Archer, Michael; Staatz, William D.; Fox, Bethany; Humphrey, Melanie; Olson, Sara; Futch, Tracy A.; Kaluza, Vesna; Siegfried, Esther; Stam, Lynn F.; Selleck, Scott B.

doi:10.1038/22336

Cited by 367 publications

(253 citation statements)

References 28 publications

(11 reference statements)

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“…The specific functions of glypicans are still not well understood, but their localization on the cell surface and experimental data indicate that glypicans are involved in the regulation of interactions between growth factors and their receptors (overviews in David, 1993;Bernfield et al, 1999;Perrimon and Bernfield, 2000). For example, human glypican-1 (GPC1) can stimulate 'heparin-binding' growth factors such as basic fibroblast growth factor (FGF) and growth factor receptor interactions and signalling (Steinfeld et al, 1996); or dally, the Drosophila melanogaster homologue to human glypicans, controls cellular responses to decapentaplegic, a TGF (transforming growth factor) b-related morphogen (Jackson et al, 1997), and can influence signalling mediated by wingless, a member of the Wnt family of growth factors, secreted proteins that control proliferation and differentiation during development (Tsuda et al, 1999). It has been proposed that GPC3 negatively regulates insulinlike growth factor-II (IGF-II) activity by competing for IGF-II binding with the signalling receptor for IGF-II, IGF-I receptor .…”

Section: Discussionmentioning

confidence: 99%

Glypican-3 is involved in cellular protection against mitoxantrone in gastric carcinoma cells

et al. 2003

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Elevated expression of the heparan sulphate proteoglycan glypican-3 (GPC3) was found on mRNA and protein levels in the atypical multidrug-resistant gastric carcinoma cell line EPG85-257RNOV, which was established by in vitro selection against mitoxantrone. In order to elucidate a putative role of GPC3 in the drug-resistant phenotype, the mitoxantrone-resistant cell line EPG85-257RNOV was transfected with an expression vector construct carrying an anti-GPC3 hammerhead ribozyme. It could be demonstrated that in anti-GPC3 ribozymetransfected cell clones, the GPC3-specific mRNA and corresponding protein expression levels were decreased to levels that are similar to those observed in nonresistant, parental cells. The anti-GPC3 ribozyme-containing clones reduced the mitoxantrone resistance level up to 21% of the original resistance and the crossresistance against etoposide to 33% of the original value. This reversal of drug resistance was accompanied by an increased cellular mitoxantrone accumulation in the anti-GPC3 ribozymeexpressing cells. In conclusion, it was verified that GPC3 is involved in the cellular protection against mitoxantrone in the atypical multidrug-resistant gastric carcinoma cell line EPG85-257RNOV. Oncogene (2004) 23, 945-955.

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Section: Discussionmentioning

confidence: 99%

Glypican-3 is involved in cellular protection against mitoxantrone in gastric carcinoma cells

et al. 2003

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“…Given that glypicans have been shown to regulate both canonical or non-canonical signaling (21,22,47), and given that non-canonical Wnt signaling can inhibit canonical signaling (48 -54), it is possible that the increase in canonical Wnt signaling observed in the GPC3-null embryos could be the result of either the direct stimulation of the canonical Wnt pathway or an indirect consequence of the inhibition of a non-canonical Wnt pathway. We therefore decided to investigate whether there are alterations in non-canonical Wnt signaling in the mice lacking GPC3.…”

Section: Gpc3 Knockout Mice Exhibit Alterations In Wntmentioning

confidence: 99%

The Loss of Glypican-3 Induces Alterations in Wnt Signaling

Song

Shi

Yun

et al. 2005

Journal of Biological Chemistry

196

165

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Loss-of-function mutations of the GPC3 gene are the cause of the human Simpson-Golabi-Behmel syndrome. Based on the overgrowth phenotype of the SimpsonGolabi-Behmel syndrome patients and the key role played by the insulin-like growth factor (IGF) signaling system in regulating embryonic growth, it was speculated that GPC3 regulates IGF signaling. In order to test the validity of this hypothesis, we mated GPC3 knockout mice with insulin receptor substrate-1 (IRS-1) nullizygous mice. We found that GPC3 regulates organism growth independent of IRS-1, suggesting that GPC3 does not modulate IGF signaling. Instead, we found that GPC3 knockout mice exhibit alterations in the Wnt signaling pathway, which is also associated with the regulation of cell proliferation. In particular, the loss of GPC3 led to the inhibition of the non-canonical Wnt/JNK signaling pathway, while concomitantly causing the activation of canonical Wnt/␤-catenin signaling. These in vivo findings were confirmed in vitro upon the ectopic overexpression of GPC3 in mesothelioma cells. In these cells, the GPC3-induced increase in JNK activity was associated with an enhanced response to Wnt5a. Most interestingly, the heparan sulfate chains of GPC3 were not required for its stimulatory activity on Wnt5a signaling and for the formation of GPC3-Wnt5a complexes. We propose that at least in some cell types GPC3 serves as a selective regulator of Wnt signaling, by potentiating non-canonical Wnt signaling, while inhibiting the canonical Wnt signaling pathway.

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“…Recent studies on Drosophila demonstrated that the mutation of some genes required for proteoglycan biosynthesis, dally (27,28), sugarless (29 -32), and tout-velu (32,33), resulted in defective signaling during development. A number of reports have suggested that heparan sulfate proteoglycans are involved in a variety of signaling pathways, in particular those of fibroblast growth factor (34), Wnt/Wingless (35), Decapentaplegic (27), and Hedgehog (36). Heparan sulfate proteoglycans are thought to be required for stabilizing the complex between a ligand and its receptors or restricting the extracellular diffusion of ligands (35).…”

Section: Fig 2 Subcellular Localization Of Papst1 Proteinmentioning

confidence: 99%

Molecular Cloning and Identification of 3′-Phosphoadenosine 5′-Phosphosulfate Transporter

Kamiyama

Suda

Ueda

et al. 2003

Journal of Biological Chemistry

124

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Nucleotide sulfate, namely 3 -phosphoadenosine 5 -phosphosulfate (PAPS), is a universal sulfuryl donor for sulfation. Although a specific PAPS transporter is present in Golgi membrane, no study has reported the corresponding gene. We have identified a novel human gene encoding a PAPS transporter, which we have named PAPST1, and the Drosophila melanogaster ortholog, slalom (sll). The amino acid sequence of PAPST1 (432 amino acids) exhibited 48.1% identity with SLL (465 amino acids), and hydropathy analysis predicted the two to be type III transmembrane proteins. The transient expression of PAPST1 in SW480 cells showed a subcellular localization in Golgi membrane. The expression of PAPST1 and SLL in yeast Saccharomyces cerevisiae significantly increased the transport of PAPS into the Golgi membrane fraction. In human tissues, PAPST1 is highly expressed in the placenta and pancreas and present at lower levels in the colon and heart. An RNA interference fly of sll produced with a GAL4-UAS system revealed that the PAPS transporter is essential for viability. It is well known that mutations of some genes related to PAPS synthesis are responsible for human inherited disorders. Our findings provide insights into the significance of PAPS transport and post-translational sulfation.Glycosylation, phosphorylation, and sulfation are essential post-translational alterations of glycoproteins, proteoglycans, and glycolipids for normal growth and development. For sulfation, an activated form of sulfate, 3Ј-phosphoadenosine 5Ј-phosphosulfate (PAPS), 1 is used as a common sulfate donor (1). Sulfate is transferred from PAPS to a defined position on the sugar residue by sulfotransferases. In higher organisms, PAPS is synthesized in the cytosol (2, 3) by a bifunctional PAPS synthetase having both ATP-sulfurylase and adenosine-phosphosulfate kinase activities (4). Since sulfation occurs in the lumens of the endoplasmic reticulum and Golgi apparatus (5), PAPS must be translocated from the cytosol into the Golgi lumen through a specific transporter localized in the microsomal membrane.Earlier studies had shown a saturable transport activity of PAPS using isolated Golgi vesicles (6) or reconstituted proteoliposome (7). To identify this transporter protein, the proteins responsible for PAPS translocating activity have been purified (8 -10). The characterization of these purified proteins revealed the kinetic behavior of a PAPS-specific transport through an antiport mechanism (8 -10); however, cloning of the transporter has not been reported.Recently, several nucleotide-sugar transporters (NSTs) have been cloned and characterized in mammals, yeast, protozoa, and plants (11-13). Nucleotide-sugars are the donor substrates for glycosylation, which is catalyzed by glycosyltransferases. These NST proteins are highly hydrophobic Type III multitransmembrane proteins localized in the Golgi or endoplasmic reticulum membrane and provide a specific substrate for the glycosylation. The structural conservation among NSTs has contributed to the identifi...

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The cell-surface proteoglycan Dally regulates Wingless signalling in Drosophila

Cited by 367 publications

References 28 publications

Glypican-3 is involved in cellular protection against mitoxantrone in gastric carcinoma cells

Glypican-3 is involved in cellular protection against mitoxantrone in gastric carcinoma cells

The Loss of Glypican-3 Induces Alterations in Wnt Signaling

Molecular Cloning and Identification of 3′-Phosphoadenosine 5′-Phosphosulfate Transporter

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