scholarly journals Author response: R-spondins engage heparan sulfate proteoglycans to potentiate WNT signaling

2020 ◽  
Author(s):  
Ramin Dubey ◽  
Peter van Kerkhof ◽  
Ingrid Jordens ◽  
Tomas Malinauskas ◽  
Ganesh V Pusapati ◽  
...  
Keyword(s):  
Heparan Sulfate ◽  
Wnt Signaling ◽  
Heparan Sulfate Proteoglycans ◽  
Author Response

scholarly journals Heparan sulfate proteoglycans are critical for the organization of the extracellular distribution of Wingless

Development ◽  
2001 ◽  
Vol 128 (1) ◽  
pp. 87-94 ◽  
Author(s):  
G.H. Baeg ◽  
X. Lin ◽  
N. Khare ◽  
S. Baumgartner ◽  
N. Perrimon
Keyword(s):  
Heparan Sulfate ◽  
Wnt Signaling ◽  
Heparan Sulfate Proteoglycans ◽  
Gene Activity ◽  
Dramatic Decrease

Recent studies in Drosophila have shown that heparan sulfate proteoglycans (HSPGs) are required for Wingless (Wg/Wnt) signaling. In addition, genetic and phenotypic analyses have implicated the glypican gene dally in this process. Here, we report the identification of another Drosophila glypican gene, dally-like (dly) and show that it is also involved in Wg signaling. Inhibition of dly gene activity implicates a function for DLY in Wg reception and we show that overexpression of DLY leads to an accumulation of extracellular Wg. We propose that DLY plays a role in the extracellular distribution of Wg. Consistent with this model, a dramatic decrease of extracellular Wg was detected in clones of cells that are deficient in proper glycosaminoglycan biosynthesis. We conclude that HSPGs play an important role in organizing the extracellular distribution of Wg.

scholarly journals Perlecan regulates bidirectional Wnt signaling at the Drosophila neuromuscular junction

2013 ◽  
Vol 200 (2) ◽  
pp. 219-233 ◽  
Author(s):  
Keisuke Kamimura ◽  
Kohei Ueno ◽  
Jun Nakagawa ◽  
Rie Hamada ◽  
Minoru Saitoe ◽  
...  
Keyword(s):  
Drosophila Melanogaster ◽  
Neuromuscular Junction ◽  
Heparan Sulfate ◽  
Wnt Signaling ◽  
Nuclear Import ◽  
Heparan Sulfate Proteoglycans ◽  
Down Regulation ◽  
Bidirectional Signaling ◽  
Synaptic Boutons ◽  
Signaling Activity

Heparan sulfate proteoglycans (HSPGs) play pivotal roles in the regulation of Wnt signaling activity in several tissues. At the Drosophila melanogaster neuromuscular junction (NMJ), Wnt/Wingless (Wg) regulates the formation of both pre- and postsynaptic structures; however, the mechanism balancing such bidirectional signaling remains elusive. In this paper, we demonstrate that mutations in the gene of a secreted HSPG, perlecan/trol, resulted in diverse postsynaptic defects and overproduction of synaptic boutons at NMJ. The postsynaptic defects, such as reduction in subsynaptic reticulum (SSR), were rescued by the postsynaptic activation of the Frizzled nuclear import Wg pathway. In contrast, overproduction of synaptic boutons was suppressed by the presynaptic down-regulation of the canonical Wg pathway. We also show that Trol was localized in the SSR and promoted postsynaptic accumulation of extracellular Wg proteins. These results suggest that Trol bidirectionally regulates both pre- and postsynaptic activities of Wg by precisely distributing Wg at the NMJ.

scholarly journals Coordination of Heparan Sulfate Proteoglycans with Wnt Signaling To Control Cellular Migrations and Positioning in Caenorhabditis elegans

Genetics ◽  
2017 ◽  
Vol 206 (4) ◽  
pp. 1951-1967 ◽  
Author(s):  
Kristian Saied-Santiago ◽  
Robert A. Townley ◽  
John D. Attonito ◽  
Dayse S. da Cunha ◽  
Carlos A. Díaz-Balzac ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Heparan Sulfate ◽  
Wnt Signaling ◽  
Heparan Sulfate Proteoglycans

scholarly journals QSulf1 remodels the 6-O sulfation states of cell surface heparan sulfate proteoglycans to promote Wnt signaling

2003 ◽  
Vol 162 (2) ◽  
pp. 341-351 ◽  
Author(s):  
Xingbin Ai ◽  
Anh-Tri Do ◽  
Olga Lozynska ◽  
Marion Kusche-Gullberg ◽  
Ulf Lindahl ◽  
...  
Keyword(s):  
Cell Surface ◽  
Heparan Sulfate ◽  
Wnt Signaling ◽  
Present Model ◽  
Receptor Activation ◽  
Heparan Sulfate Proteoglycans ◽  
Biochemical Studies ◽  
Frizzled Receptors ◽  
Wnt Signal ◽  
Function Cell

The 6-O sulfation states of cell surface heparan sulfate proteoglycans (HSPGs) are dynamically regulated to control the growth and specification of embryonic progenitor lineages. However, mechanisms for regulation of HSPG sulfation have been unknown. Here, we report on the biochemical and Wnt signaling activities of QSulf1, a novel cell surface sulfatase. Biochemical studies establish that QSulf1 is a heparan sulfate (HS) 6-O endosulfatase with preference, in particular, toward trisulfated IdoA2S-GlcNS6S disaccharide units within HS chains. In cells, QSulf1 can function cell autonomously to remodel the sulfation of cell surface HS and promote Wnt signaling when localized either on the cell surface or in the Golgi apparatus. QSulf1 6-O desulfation reduces XWnt binding to heparin and HS chains of Glypican1, whereas heparin binds with high affinity to XWnt8 and inhibits Wnt signaling. CHO cells mutant for HS biosynthesis are defective in Wnt-dependent Frizzled receptor activation, establishing that HS is required for Frizzled receptor function. Together, these findings suggest a two-state “catch or present” model for QSulf1 regulation of Wnt signaling in which QSulf1 removes 6-O sulfates from HS chains to promote the formation of low affinity HS–Wnt complexes that can functionally interact with Frizzled receptors to initiate Wnt signal transduction.

scholarly journals R-spondins engage heparan sulfate proteoglycans to potentiate WNT signaling

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Ramin Dubey ◽  
Peter van Kerkhof ◽  
Ingrid Jordens ◽  
Tomas Malinauskas ◽  
Ganesh V Pusapati ◽  
...  
Keyword(s):  
Heparan Sulfate ◽  
Wnt Signaling ◽  
Cultured Cells ◽  
Heparan Sulfate Proteoglycans ◽  
G Protein Coupled Receptors ◽  
Binding Domains ◽  
Genome Wide ◽  
A Genome ◽  
G Protein Coupled ◽  
In Cells

R-spondins (RSPOs) amplify WNT signaling during development and regenerative responses. We previously demonstrated that RSPOs 2 and 3 potentiate WNT/β-catenin signaling in cells lacking leucine-rich repeat-containing G-protein coupled receptors (LGRs) 4, 5 and 6 (Lebensohn and Rohatgi, 2018). We now show that heparan sulfate proteoglycans (HSPGs) act as alternative co-receptors for RSPO3 using a combination of ligand mutagenesis and ligand engineering. Mutations in RSPO3 residues predicted to contact HSPGs impair its signaling capacity. Conversely, the HSPG-binding domains of RSPO3 can be entirely replaced with an antibody that recognizes heparan sulfate (HS) chains attached to multiple HSPGs without diminishing WNT-potentiating activity in cultured cells and intestinal organoids. A genome-wide screen for mediators of RSPO3 signaling in cells lacking LGRs 4, 5 and 6 failed to reveal other receptors. We conclude that HSPGs are RSPO co-receptors that potentiate WNT signaling in the presence and absence of LGRs.

Localization of cell-surface and basement-membrane heparan-sulfate proteoglycans using the malaria circumsporozoite protein

1994 ◽  
Vol 52 ◽  
pp. 294-295
Author(s):  
U. Frevert ◽  
S. Sinnis ◽  
C. Cerami ◽  
V. Nussenzweig
Keyword(s):  
Heparan Sulfate ◽  
Protein A ◽  
Kidney Tissue ◽  
Plasmodium Species ◽  
Its Region ◽  
Basement Membranes ◽  
Heparan Sulfate Proteoglycans ◽  
Infected Mosquito ◽  
Complement Components ◽  
Region Ii

Malaria sporozoites, which invade hepatocytes within minutes after transmission by an infected mosquito, are covered with the circumsporozoite (CS) protein, which in all Plasmodium species contains the conserved region II-plus. This region is also found as a cell-adhesive motif in a variety of host proteins like thrombospondin, properdin and the terminal complement components.The CS protein with its region II-plus specifically binds to heparan sulfate proteoglycans (HSPG) on the basolateral surface of hepatocytes in the space of Disse (FIG. 1), to certain basolateral cell membranes and basement membranes of the kidney (FIG. 2) as well as to heparin in the granules of connective tissue mast cells. The distribution of the HSPG receptors for the CS protein was examined by incubation of Lowicryl K4M or LR White sections of liver and kidney tissue with the recombinant CS ligand, whose binding sites were detected with a monoclonal anti-CS antibody and protein A gold.

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