The Role of Drosophila Heparan Sulfate 6-O-Endosulfatase in Sulfation Compensation*

Dejima, Katsufumi; Kleinschmit, Adam; Takemura, Masahiko; Choi, Pui Yee; Kinoshita-Toyoda, Akiko; Toyoda, Hidenao; Nakato, Hiroshi

doi:10.1074/jbc.m112.404830

Cited by 10 publications

(13 citation statements)

References 45 publications

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“…We have shown previously that the compensatory increase of 6-O-sulfation in Hs2st mutants is critical for the rescue of the mutants and that Hs2st; Hs6st double mutants fail to restore FGF, Wingless, and BMP signaling (4,5). Our disaccharide analysis data revealed a substantial increase 6-O-sulfation in Hsepi mutants as observed in Hs2st mutants (Fig.…”

Section: An Increase In 6-o-sulfation Is Critical For the Rescue Of Tsupporting

confidence: 70%

“…We showed that 6-O-sulfation is dramatically elevated in these mutants. Thus, compensatory up-regulation of 6-O-sulfate groups may be responsible for rescue of HS-dependent pathways in Hsepi mutant flies as observed in Hs2st mutant animals (4,5). Consistent with this idea, Hsepi; Hs6st mutants are completely lethal (Table 1).…”

Section: Discussionsupporting

confidence: 54%

“…In Hs2st mutants, 6-Osulfation is up-regulated in compensation, rescuing morphogenesis and HS-dependent molecular pathways, including FGF, Wnt, and BMP signaling (4,5). Our HS disaccharide analyses revealed that the increase of 6-O-sulfation in Hs2st mutants in the absence of Hsepi was not as remarkable as that in its presence.…”

Section: Discussionmentioning

confidence: 72%

“…We have shown previously that this compensatory increase in 6-O-sulfation restores FGF signaling during tracheal system formation (4). The compensation mechanism also rescues Wingless and BMP signaling (5).…”

Section: D-glucuronyl C5-epimerase In Drosophilamentioning

confidence: 91%

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Analysis of Drosophila Glucuronyl C5-Epimerase

Dejima

Takemura

Nakato

et al. 2013

Journal of Biological Chemistry

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Section: An Increase In 6-o-sulfation Is Critical For the Rescue Of Tsupporting

confidence: 70%

Section: Discussionsupporting

confidence: 54%

Section: Discussionmentioning

confidence: 72%

Section: D-glucuronyl C5-epimerase In Drosophilamentioning

confidence: 91%

See 2 more Smart Citations

Analysis of Drosophila Glucuronyl C5-Epimerase

Dejima

Takemura

Nakato

et al. 2013

Journal of Biological Chemistry

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“…[15] As a result, natural polysaccharides that bind the HBD such as heparan sulfate (HS) have different binding properties for VEGF 165a and VEGF 165b. [9, 16, 17] Taking advantage of the structural differences between the HBDs, a therapeutic aptamer, pegaptanib, has been previously developed that only binds VEGF 165a . [18]…”

Section: Introductionmentioning

confidence: 99%

Selective binding of C-6 OH sulfated hyaluronic acid to the angiogenic isoform of VEGF165

et al. 2016

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Vascular endothelial growth factor 165 (VEGF165) is an important extracellular protein involved in pathological angiogenesis in diseases such as cancer, wet age-related macular degeneration (wet-AMD) and retinitis pigmentosa. VEGF165 exists in two different isoforms: the angiogenic VEGF165a, and the anti-angiogenic VEGF165b. In some angiogenic diseases the proportion of VEGF165b may be equal to or higher than that of VEGF165a. Therefore, developing therapeutics that inhibit VEGF165a and not VEGF165b may result in a greater anti-angiogenic activity and therapeutic benefit. To this end, we report the selective binding properties of sulfated hyaluronic acid (s-HA). Selective biopolymers offer several advantages over antibodies or aptamers including cost effective and simple synthesis, and the ability to make nanoparticles or hydrogels for drug delivery applications or VEGF165a sequestration. Limiting sulfation to the C-6 hydroxyl (C-6 OH) in the N-acetyl-glucosamine repeat unit of hyaluronic acid (HA) resulted in a polymer with strong affinity for VEGF165a but not VEGF165b. Increased sulfation beyond the C-6 OH (i.e. greater than 1 sulfate group per HA repeat unit) resulted in s-HA polymers that bound both VEGF165a and VEGF165b. The C-6 OH sulfated HA (Mw 150 kDa) showed strong binding properties to VEGF165a with a fast association rate constant (Ka; 2.8 × 106 M−1s−1), slow dissociation rate constant (Kd; 2.8 × 10−3 s−1) and strong equilibrium binding constant (KD; ~ 1.0 nM)), which is comparable to the non-selective VEGF165 binding properties of the commercialized therapeutic anti-VEGF antibody (Avastin®). The C-6 OH sulfated HA also inhibited human umbilical vein endothelial cell (HUVEC) survival and proliferation and human dermal microvascular endothelial cell (HMVEC) tube formation. These results demonstrate that the semi-synthetic natural polymer, C-6 OH sulfated HA, may be a promising biomaterial for the treatment of angiogenesis-related disease.

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In vivo activities of heparan sulfate differentially modified by NDSTs during development

Nakato,

Baker,

Kinoshita‐Toyoda

et al. 2024

Proteoglycan Research

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Heparan sulfate proteoglycans (HSPGs) serve as co‐receptors for growth factor signaling during development. It is well known that the level and patterns of sulfate groups of heparan sulfate (HS) chains, or HS fine structures, have a major impact on HSPG function. On the other hand, the physiological significance of other structural features of HS, including NS/NA domain organization, remains to be elucidated. A blueprint of the HS domain structures is mainly controlled by HS N‐deacetylase/N‐sulfotransferases (NDSTs). To analyze in vivo activities of differentially modified HS, we established two knock‐in (KI) Drosophila strains with the insertion of mouse Ndst1 (mNdst1) or Ndst2 (mNdst2) in the locus of sulfateless (sfl), the only Drosophila NDST. In these KI lines, mNDSTs are expressed from the sfl locus, in the level and patterns identical to the endogenous sfl gene. Thus, phenotypes of Ndst1 KI and Ndst2KI animals reflect the ability of HS structures made by these enzymes to rescue sfl mutation. Remarkably, we found that mNdst1 completely rescued the loss of sfl. mNdst2 showed a limited rescue ability, despite a higher level of HS sulfation compared to HS in mNdst1 KI. Our study suggests that independent of sulfation levels, additional HS structural features controlled by NDSTs play key roles during tissue patterning.

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The Role of Drosophila Heparan Sulfate 6-O-Endosulfatase in Sulfation Compensation*

Cited by 10 publications

References 45 publications

Analysis of Drosophila Glucuronyl C5-Epimerase

Analysis of Drosophila Glucuronyl C5-Epimerase

Selective binding of C-6 OH sulfated hyaluronic acid to the angiogenic isoform of VEGF165

In vivo activities of heparan sulfate differentially modified by NDSTs during development

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