Drosophila Heparan Sulfate 6-O-Endosulfatase Sulf1 Facilitates Wingless (Wg) Protein Degradation

Kleinschmit, Adam; Takemura, Masahiko; Dejima, Katsufumi; Choi, Pui Yee; Nakato, Hiroshi

doi:10.1074/jbc.m112.447029

Cited by 28 publications

(27 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Interaction of HSPGs with Frizzled (Fz) receptors and Wnt ligands is thought to promote internalization of receptor-ligand complexes, which in turn either positively or negatively regulate extracellular Wnt ligand distribution and Wnt signaling (Gagliardi et al, 2008;Ohkawara et al, 2011). This biphasic activity of HSPGs is influenced by the ratio of ligand to receptor and co-receptors (Yan et al, 2009), the stability of free ligand (Kleinschmit et al, 2013) and possibly by specific HS structures (Ai et al, 2003). Additionally, the HSPG core protein can modulate signaling independently of or in conjunction with its HS side chains.…”

Section: Introductionmentioning

confidence: 99%

Syndecan defines precise spindle orientation by modulating Wnt signaling in C. elegans

et al. 2014

Self Cite

View full text Add to dashboard Cite

Wnt signals orient mitotic spindles in development, but it remains unclear how Wnt signaling is spatially controlled to achieve precise spindle orientation. Here, we show that C. elegans syndecan (SDN-1) is required for precise orientation of a mitotic spindle in response to a Wnt cue. We find that SDN-1 is the predominant heparan sulfate (HS) proteoglycan in the early C. elegans embryo, and that loss of HS biosynthesis or of the SDN-1 core protein results in misorientation of the spindle of the ABar blastomere. The ABar and EMS spindles both reorient in response to Wnt signals, but only ABar spindle reorientation is dependent on a new cell contact and on HS and SDN-1. SDN-1 transiently accumulates on the ABar surface as it contacts C, and is required for local concentration of Dishevelled (MIG-5) in the ABar cortex adjacent to C. These findings establish a new role for syndecan in Wnt-dependent spindle orientation.

show abstract

Section: Introductionmentioning

confidence: 99%

Syndecan defines precise spindle orientation by modulating Wnt signaling in C. elegans

et al. 2014

Self Cite

View full text Add to dashboard Cite

show abstract

“…Previous studies have shown that Sulf1-catalyzed decrease in 6-O sulfation lowers the affinity between heparan sulfate and ligand proteins (Kleinschmit et al, 2013). This can positively or negatively regulate signal transduction in a context-dependent manner (Ai et al, 2003;Kleinschmit et al, 2013;Wojcinski et al, 2011). In the Drosophila wing disc, Sulf1 negatively regulates the FGF, Wg, EGFR and Hh pathways (Butchar et al, 2012;Kamimura et al, 2006;Kleinschmit et al, 2013Kleinschmit et al, , 2010Wojcinski et al, 2011;You et al, 2011).…”

Section: Heparan Sulfate Regulates Damage-induced Activation Of Isc Dmentioning

confidence: 99%

“…This fine-tuning of heparan sulfate sulfation plays an important role in modulating the function of HSPGs (Ai et al, 2003;Dhoot et al, 2001;Lamanna et al, 2006;Morimoto-Tomita et al, 2002;Wang et al, 2004). Previous studies have shown that Sulf1-catalyzed decrease in 6-O sulfation lowers the affinity between heparan sulfate and ligand proteins (Kleinschmit et al, 2013). This can positively or negatively regulate signal transduction in a context-dependent manner (Ai et al, 2003;Kleinschmit et al, 2013;Wojcinski et al, 2011).…”

Section: Heparan Sulfate Regulates Damage-induced Activation Of Isc Dmentioning

confidence: 99%

“…This can positively or negatively regulate signal transduction in a context-dependent manner (Ai et al, 2003;Kleinschmit et al, 2013;Wojcinski et al, 2011). In the Drosophila wing disc, Sulf1 negatively regulates the FGF, Wg, EGFR and Hh pathways (Butchar et al, 2012;Kamimura et al, 2006;Kleinschmit et al, 2013Kleinschmit et al, , 2010Wojcinski et al, 2011;You et al, 2011). Given that some of the signaling ligands known to regulate ISC division in the midgut are heparan-sulfate-dependent factors, including Vein (Vn; an EGFR ligand), Hh, and Wg, we hypothesized that dynamic regulation of 6-O sulfation might be important for controlling ISC mitotic activity during regeneration.…”

Section: Heparan Sulfate Regulates Damage-induced Activation Of Isc Dmentioning

confidence: 99%

“…Sulfs specifically remove 6-O sulfate groups from highly sulfated regions of heparan sulfate. In Drosophila, the single Sulf gene, Sulf1, modulates FGF, Wg, Hh and EGFR signaling during development (Butchar et al, 2012;Dani et al, 2012;Kamimura et al, 2006;Kleinschmit et al, 2013Kleinschmit et al, , 2010Wojcinski et al, 2011;You et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Drosophila Sulf1 is required for the termination of intestinal stem cell division during regeneration

Takemura

Nakato

2017

Journal of Cell Science

Self Cite

View full text Add to dashboard Cite

Stem cell division is activated to trigger regeneration in response to tissue damage. The molecular mechanisms by which this stem cell mitotic activity is properly repressed at the end of regeneration are poorly understood. Here, we show that a specific modification of heparan sulfate is crucial for regulating Drosophila intestinal stem cell (ISC) division during normal midgut homeostasis and regeneration. Loss of the extracellular heparan sulfate endosulfatase Sulf1 resulted in increased ISC division during normal homeostasis, which was caused by upregulation of mitogenic signaling including the JAK-STAT, EGFR and Hedgehog pathways. Using a regeneration model, we found that ISCs failed to properly halt division at the termination stage in Sulf1 mutants, showing that Sulf1 is required for terminating ISC division at the end of regeneration. We propose that posttranscriptional regulation of mitogen signaling by heparan sulfate structural modifications provides a new regulatory step for precise temporal control of stem cell activity during regeneration.

show abstract

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

Nakato,

Baker,

Kinoshita‐Toyoda

et al. 2024

Proteoglycan Research

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Drosophila Heparan Sulfate 6-O-Endosulfatase Sulf1 Facilitates Wingless (Wg) Protein Degradation

Cited by 28 publications

References 49 publications

Syndecan defines precise spindle orientation by modulating Wnt signaling in C. elegans

Syndecan defines precise spindle orientation by modulating Wnt signaling in C. elegans

Drosophila Sulf1 is required for the termination of intestinal stem cell division during regeneration

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

Contact Info

Product

Resources

About