Developmental roles of heparan sulfate proteoglycans in Drosophila

Lin, Xinhua; Perrimon, Norbert

doi:10.1023/a:1025329323438

Cited by 63 publications

(43 citation statements)

References 35 publications

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“…HSPGs have been shown to affect distribution and signaling of several secreted growth factors, including FGF, Wnt, TGFβ, and Hh family members in Drosophila and vertebrates (Perrimon and Bernfield 2000;Lin and Perrimon 2002;Nybakken and Perrimon 2002). Studies carried out with Ext1 and Ext2 null mice show that HSPGs are required for developing embryos to survive and that haploinsufficiency of HS is the main cause of exostoses (Koziel et al 2004;Stickens et al 2005).…”

Section: Discussionmentioning

confidence: 99%

Functional conservation of the human EXT1 tumor suppressor gene and its Drosophila homolog tout velu

et al. 2007

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Heparan sulfate proteoglycans play a vital role in signaling of various growth factors in both Drosophila and vertebrates. In Drosophila, mutations in the tout velu (ttv) gene, a homolog of the mammalian EXT1 tumor suppressor gene, leads to abrogation of glycosaminoglycan (GAG) biosynthesis. This impairs distribution and signaling activities of various morphogens such as Hedgehog (Hh), Wingless (Wg), and Decapentaplegic (Dpp). Mutations in members of the exostosin (EXT) gene family lead to hereditary multiple exostosis in humans leading to bone outgrowths and tumors. In this study, we provide genetic and biochemical evidence that the human EXT1 (hEXT1) gene is conserved through species and can functionally complement the ttv mutation in Drosophila. The hEXT1 gene was able to rescue a ttv null mutant to adulthood and restore GAG biosynthesis.

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Section: Discussionmentioning

confidence: 99%

Functional conservation of the human EXT1 tumor suppressor gene and its Drosophila homolog tout velu

et al. 2007

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“…HSPGs are ECM and cell surface proteins possessing a protein core to which heparin sulfate GAG chains are attached (Lin and Perrimon, 2002 Figure 1 In Wnt-producing cells, the Wnt protein becomes palmitoylated in the ER by the porcupine acyl-transferase. Further transport and secretion of the Wnt protein in secretory vesicles is controlled by the multi-pass transmembrane protein Wntless/Evi, which is present in the Golgi and/or on the plasma membrane.…”

Section: Wnts As Morphogensmentioning

confidence: 99%

Wnts as ligands: processing, secretion and reception

2006

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“…These growth factors and cytokines form tight complexes with heparin and HSPGs, an interaction that has critical effects on the signaling activity of the ligand (1). Among the ligands known to bind to heparin or heparan sulfate are the fibroblast growth factor (FGF) family of growth factors (2), the transforming growth factor-␤ family of growth factors (3), vascular endothelial growth factor (4), interleukin-3 (5), granulocyte-macrophage colony-stimulating factor (5), interferon-␥ (6), Hedgehog (7), and Wnt (7). Many classes of receptors, including receptor serine/threonine kinases and seven pass transmembrane receptors, have now been shown to be modulated by HSPGs (1).…”

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confidence: 99%

Suppression of the Biological Activities of the Epidermal Growth Factor (EGF)-like Domain by the Heparin-binding Domain of Heparin-binding EGF-like Growth Factor

Takazaki

Shishido²,

Iwamoto

et al. 2004

Journal of Biological Chemistry

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Heparin-binding EGF-like growth factor (HB-EGF) is a member of the EGF family of growth factors that has a high affinity for heparin and heparan sulfate. While interactions with heparin are thought to modulate the biological activity of HB-EGF, the precise role of the heparin-binding domain has remained unclear. We analyzed the activity of wild-type HB-EGF and a mutant form lacking the heparin-binding domain (⌬HB) in the presence or absence of heparin. The activity of the EGFlike domain of HB-EGF was determined by measuring binding to diphtheria toxin (DT) as well as the growth factor activity in EGF receptor-expressing cells. The binding affinity of ⌬HB for DT was much higher than that of wild-type HB-EGF in the absence of heparin. The binding affinity of HB-EGF for DT was increased by addition of exogenous heparin and reached the level close to the affinity of ⌬HB, whereas that of ⌬HB was not affected. Moreover, the growth factor activity of ⌬HB was much higher than that of wild-type HB-EGF in the absence of heparin but was not affected by addition of exogenous heparin, whereas HB-EGF had increased growth factor activity with added heparin. These results indicate that the heparin-binding domain suppresses the activity of the EGF-like domain of HB-EGF and that association of heparin with HB-EGF via this domain removes the suppressive effect. Thus, we conclude that the heparin-binding domain serves as a negative regulator of this growth factor.Cell surface heparan sulfate proteoglycans (HSPGs) 1 have been implicated in a variety of cell signaling pathways involving heparin-binding growth factors or cytokines. These growth factors and cytokines form tight complexes with heparin and

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Developmental roles of heparan sulfate proteoglycans in Drosophila

Cited by 63 publications

References 35 publications

Functional conservation of the human EXT1 tumor suppressor gene and its Drosophila homolog tout velu

Functional conservation of the human EXT1 tumor suppressor gene and its Drosophila homolog tout velu

Wnts as ligands: processing, secretion and reception

Suppression of the Biological Activities of the Epidermal Growth Factor (EGF)-like Domain by the Heparin-binding Domain of Heparin-binding EGF-like Growth Factor

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