PUBLICATION
N-terminal syndecan-2 domain selectively enhances 6-O heparan sulfate chains sulfation and promotes VEGFA165-dependent neovascularization
- Authors
- Corti, F., Wang, Y., Rhodes, J.M., Atri, D., Archer-Hartmann, S., Zhang, J., Zhuang, Z.W., Chen, D., Wang, T., Wang, Z., Azadi, P., Simons, M.
- ID
- ZDB-PUB-190407-3
- Date
- 2019
- Source
- Nature communications 10: 1562 (Journal)
- Registered Authors
- Simons, Michael
- Keywords
- none
- MeSH Terms
-
- Animals
- Mice
- Neovascularization, Physiologic/genetics*
- Protein Domains
- Retina/growth & development
- Sequence Analysis, Protein
- Syndecan-2/genetics
- Syndecan-2/metabolism
- Syndecan-2/physiology*
- Syndecan-4/genetics
- Syndecan-4/metabolism
- Syndecan-4/physiology
- Vascular Endothelial Growth Factor A/genetics
- Vascular Endothelial Growth Factor A/metabolism
- Vascular Endothelial Growth Factor A/physiology*
- Vascular Endothelial Growth Factor Receptor-2/genetics
- Vascular Endothelial Growth Factor Receptor-2/metabolism
- Vascular Endothelial Growth Factor Receptor-2/physiology
- PubMed
- 30952866 Full text @ Nat. Commun.
Citation
Corti, F., Wang, Y., Rhodes, J.M., Atri, D., Archer-Hartmann, S., Zhang, J., Zhuang, Z.W., Chen, D., Wang, T., Wang, Z., Azadi, P., Simons, M. (2019) N-terminal syndecan-2 domain selectively enhances 6-O heparan sulfate chains sulfation and promotes VEGFA165-dependent neovascularization. Nature communications. 10:1562.
Abstract
The proteoglycan Syndecan-2 (Sdc2) has been implicated in regulation of cytoskeleton organization, integrin signaling and developmental angiogenesis in zebrafish. Here we report that mice with global and inducible endothelial-specific deletion of Sdc2 display marked angiogenic and arteriogenic defects and impaired VEGFA165 signaling. No such abnormalities are observed in mice with deletion of the closely related Syndecan-4 (Sdc4) gene. These differences are due to a significantly higher 6-O sulfation level in Sdc2 versus Sdc4 heparan sulfate (HS) chains, leading to an increase in VEGFA165 binding sites and formation of a ternary Sdc2-VEGFA165-VEGFR2 complex which enhances VEGFR2 activation. The increased Sdc2 HS chains 6-O sulfation is driven by a specific N-terminal domain sequence; the insertion of this sequence in Sdc4 N-terminal domain increases 6-O sulfation of its HS chains and promotes Sdc2-VEGFA165-VEGFR2 complex formation. This demonstrates the existence of core protein-determined HS sulfation patterns that regulate specific biological activities.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping