The Retinoic Acid and cAMP-dependent Up-regulation of 3-O-Sulfotransferase-1 Leads to a Dramatic Augmentation of Anticoagulantly Active Heparan Sulfate Biosynthesis in F9 Embryonal Carcinoma Cells

Zhang, Lijuan; Schwartz, John J.; Miller, J. Hillis; Liu, Jian; Fritze, Linda M.S.; Shworak, Nicholas W.; Rosenberg, Robert D.

doi:10.1074/jbc.273.43.27998

Cited by 34 publications

(33 citation statements)

References 30 publications

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“…As far as we know, this is the first report showing that a particular molecule, i.e., Epac, can enhance NDST-1 expression. On the other hand, a report showed that cAMP upregulates 3-O-sulfotransferase-1, a HS-biosynthesis enzyme, in F9 embryonic carcinoma cells (47); however, this is not the case in our study. We did not find that 3-Osulfotransferase-1 was increased by Epac (data not shown).…”

Section: Discussioncontrasting

confidence: 55%

Epac increases melanoma cell migration by a heparan sulfate-related mechanism

Baljinnyam

Iwatsubo

Kurotani

et al. 2009

American Journal of Physiology-Cell Physiology

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2009.-Melanoma, the most malignant form of human skin cancer, has a poor prognosis due to its strong metastatic ability. It was recently demonstrated that Epac, an effector molecule of cAMP, is involved in regulating cell migration; however, the role of Epac in melanoma cell migration remains unclear. We thus examined whether Epac regulates cell migration and metastasis of melanoma. Epac activation, by either specific agonist or overexpression of Epac, increased melanoma cell migration. Deletion of endogenous Epac with small interfering RNA decreased basal melanoma cell migration. These data suggested a major role of Epac in melanoma cell migration. Epac-induced cell migration was mediated by translocation of syndecan-2, a cell-surface heparan sulfate proteoglycan, to lipid rafts. This syndecan-2 translocation was regulated by tubulin polymerization via the Epac/phosphoinositol-3 kinase pathway. Epacinduced cell migration was also regulated by the production of heparan sulfate, a major extracellular matrix. Epac-induced heparan sulfate production was attributable to the increased expression of N-deacetylase/N-sulfotransferase-1 (NDST-1) accompanied by an increased NDST-1 translation rate. Finally, Epac overexpression enhanced lung colonization of melanoma cells in mice. Taken together, these data indicate that Epac regulates melanoma cell migration/ metastasis mostly via syndecan-2 translocation and heparan sulfate production. metastasis; phosphoinositol-3 kinase; N-deacetylase/N-sulfotransferase-1

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Section: Discussioncontrasting

confidence: 55%

Epac increases melanoma cell migration by a heparan sulfate-related mechanism

Baljinnyam

Iwatsubo

Kurotani

et al. 2009

American Journal of Physiology-Cell Physiology

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“…In the final step of the reaction, the amount of 3-OST-1 is up-regulated at a transcriptional level which completes the formation of the antithrombin-binding site and controls the supply of this site present on the cell surface (40). It appears likely that parallel reaction pathways might exist in which other precursor structures, of different monosaccharide sequences, are generated.…”

Section: -O-sulfation Of Heparan Sulfatementioning

confidence: 99%

Expression of Heparan Sulfate d-Glucosaminyl 3-O-Sulfotransferase Isoforms Reveals Novel Substrate Specificities

Liu

Shworak

Sînaÿ

et al. 1999

Journal of Biological Chemistry

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172

163

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The 3-O-sulfation of glucosamine residues is an important modification during the biosynthesis of heparan sulfate (HS). Our previous studies have led us to purify and molecularly clone the heparan sulfate D-glucosaminyl 3-O-sulfotransferase (3-OST-1), which is the key enzyme converting nonanticoagulant heparan sulfate (HS inact ) to anticoagulant heparan sulfate (HS act ). In this study, we expressed and characterized the fulllength cDNAs of 3-OST-1 homologous genes, designated as 3-OST-2, 3-OST-3 A , and 3-OST-3 B as described in the accompanying paper ( 35 S]HS suggested that 3-OST-2 transfers sulfate to GlcA2S-GlcNS and IdoA2S-GlcNS; 3-OST-3 A transfers sulfate to IdoA2S-GlcNS. Our results demonstrate that the 3-O-sulfation of glucosamine is generated by different isoforms depending on the saccharide structures around the modified glucosamine residue. This discovery has provided evidence for a new cellular mechanism for generating a defined saccharide sequence in structurally complex HS polysaccharide.

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“…When 3-OST-1 activity is limiting, levels of these 3-O-sulfated residues from iHS are typically Ͼ10-fold lower than that from aHS (31,32,35,52). Conversely, a transition in 3-OST-1 levels from being limiting to being in excess was accompanied by a 50-fold rise in GlcA-AnMan3SϮ6S derived from iHS, as found during differentiation of F9 cells (42). Second, exhaustive modification of hGEC iHS with 3-OST-1 revealed an extremely small pool of residual aHS-precursor, amounting to 1% of total HS, indicating consumption of the pool by excess 3-OST-1.…”

Section: Discussionmentioning

confidence: 99%

“…Second, exhaustive modification of hGEC iHS with 3-OST-1 revealed an extremely small pool of residual aHS-precursor, amounting to 1% of total HS, indicating consumption of the pool by excess 3-OST-1. When cellular 3-OST-1 activity is limiting, the aHS-precursor pool typically represents 10 -30% of total HS chains (35,42). Conversely, minimal pools have been observed in HS from differentiated F9 cells (42) and in heparin (62,63), which both are produced under conditions of 3-OST-1 excess.…”

Section: Discussionmentioning

confidence: 99%

“…Similar to the procedure of Guo and Conrad (41), the samples were eluted at 0.5 ml/min with 1 mM tetrabutylammonium phosphate, pH 3.6, containing acetonitrile at 4.8 (45 min), 9 (15 min), and 11.7%. The identification of each disaccharide was confirmed by co-chromatography on ion pairing reverse phase HPLC with 3 H-labeled disaccharide standards, as described in prior publications (34,41,42).…”

Section: Methodsmentioning

confidence: 99%

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Synthesis of Anticoagulantly Active Heparan Sulfate Proteoglycans by Glomerular Epithelial Cells Involves Multiple 3-O-Sulfotransferase Isoforms and a Limiting Precursor Pool

Girardin

Hajmohammadi

Birmelé

et al. 2005

Journal of Biological Chemistry

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Endothelial and other select cell types synthesize a subpopulation of heparan sulfate (HS) proteoglycans (HSPGs), anticoagulant HSPGs (aHSPGs) that bear aHS-HS chains with the cognate 3-Osulfated pentasaccharide motif that can bind and activate antithrombin (AT). Endothelial cells regulate aHSPG production by limiting levels of HS 3-O-sulfotransferase-1 (3-OST-1), which modifies a non-limiting pool of aHS-precursors. By probing kidney cryosections with 125 I-AT and fluorescently tagged AT we found that the glomerular basement membrane contains aHSPGs, with the staining pattern implicating synthesis by glomerular epithelial cells (GECs). Indeed, cultured GECs synthesized aHS with high AT affinity that was comparable with the endothelial product. Disaccharide analyses of human GEC (hGEC) HS in conjunction with transcript analyses revealed that hGECs express predominantly 3-OST-1 and 3-OST-3 A . aHS production has not been previously examined in cells expressing multiple 3-OST isoforms. This unusual situation appears to involve novel mechanisms to regulate aHS production, as HS structural analyses suggest hGECs exhibit excess levels of 3-OST-1 and an extremely limiting pool of aHS-precursor. A limiting aHS-precursor pool may serve to minimize aHS synthesis by non-3-OST-1 isoforms. Indeed, we show that high in vitro levels of 3-OST-3 A can efficiently generate aHS. Non-3-OST-1 isoforms can generate aHS in vivo, as the probing of kidney sections from 3-OST-1-deficient mice revealed GEC synthesis of aHSPGs. Surprisingly, Hs3st1 ؊/؊ kidney only expresses 3-OST isoforms having a low specificity for aHS synthesis. Thus, our analyses reveal a cell type that expresses multiple 3-OST isoforms and produces minimal amounts of aHS-precursor. In part, this mechanism should prevent aHS overproduction by non-3-OST-1 isoforms. Such a role may be essential, as 3-OST isoforms that have a low specificity for aHS synthesis can generate substantial levels of aHSPGs in vivo.The majority of mammalian cell types express heparan sulfate proteoglycans (HSPGs), 2 which are comprised of a protein core to which is attached linear chains of heparan sulfate (HS). These pericellular components regulate a myriad of biologic processes (1-6). Tremendous functional diversity stems from the structural complexity of the HS component. The HS chains have a repeated disaccharide unit of N-acetylglucosamine ␤1 3 4 glucuronic/iduronic acid ␤1 3 4 (GlcNAc 3 GlcA/IdoA) that is partially decorated with Nand O-sulfate groups. The specific arrangement of these substituents, in large part, gives rise to distinct binding motifs that activate an array of important biologic effector molecules. HS motifs arise through the remodeling of the copolymer backbone by a relatively ordered series of reactions involving an epimerase and four families of sulfotransferases (reviewed in Refs. 1, 3, 7, and 8). 3-O-Sulfation of glucosamine residues is the rarest modification, yet is accomplished by the largest family of HS sulfotransferases, comprised of seven distinct 3-O-sulfotr...

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The Retinoic Acid and cAMP-dependent Up-regulation of 3-O-Sulfotransferase-1 Leads to a Dramatic Augmentation of Anticoagulantly Active Heparan Sulfate Biosynthesis in F9 Embryonal Carcinoma Cells

Cited by 34 publications

References 30 publications

Epac increases melanoma cell migration by a heparan sulfate-related mechanism

Epac increases melanoma cell migration by a heparan sulfate-related mechanism

Expression of Heparan Sulfate d-Glucosaminyl 3-O-Sulfotransferase Isoforms Reveals Novel Substrate Specificities

Synthesis of Anticoagulantly Active Heparan Sulfate Proteoglycans by Glomerular Epithelial Cells Involves Multiple 3-O-Sulfotransferase Isoforms and a Limiting Precursor Pool

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