Context Dependent Sulf1/Sulf2 Functional Divergence in Endothelial Cell Activity

Justo, T; Smart, N; Dhoot, GK

Abstract

Signalling activities are tightly regulated to control cellular responses. Heparan sulfate proteoglycans (HSPGs) at the cell membrane and extracellular matrix regulate ligand availability and interaction with a range of key receptors. SULF1 and SULF2 enzymes modify HSPG sulfation by removing 6-O sulfates to regulate cell signalling but are considered functionally identical. Our in vitro mRNA and protein analyses of two diverse human endothelial cell lines, however, highlight their markedly distinct regulatory roles of maintaining specific HSPG sulfation patterns through feedback regulation of HS 6-O transferase (HS6ST) activities and highly divergent roles in vascular endothelial growth factor (VEGF) and Transforming growth factor beta (TGF beta) cell signalling activities. Unlike Sulf2, Sulf1 over-expression in dermal microvascular HMec1 cells promotes TGF beta and VEGF cell signalling by simultaneously upregulating HS6ST1 activity. In contrast, Sulf1 over-expression in venous ea926 cells has the opposite effect as it attenuates both TGF beta and VEGF signalling while Sulf2 over-expression maintains the control phenotype. Exposure of these cells to VEGF-A, TGF beta 1, and their inhibitors further highlights their endothelial cell type-specific responses and integral growth factor interactions to regulate cell signalling and selective feedback regulation of HSPG sulfation that additionally exploits alternative Sulf2 RNA-splicing to regulate net VEGF-A and TGF beta cell signalling activities.

Citation

Justo, T., Smart, N., & Dhoot, G. (2022). Context Dependent Sulf1/Sulf2 Functional Divergence in Endothelial Cell Activity. International Journal of Molecular Sciences, 23(7), https://doi.org/10.3390/ijms23073769

• Journal Article Type: Article
• Acceptance Date: Mar 28, 2022
• Publication Date: 2022
• Deposit Date: Aug 19, 2022
• Publicly Available Date: Aug 19, 2022
• Print ISSN: 1661-6596
• Publisher: MDPI
• Peer Reviewed: Peer Reviewed
• Volume: 23
• Issue: 7
• DOI: https://doi.org/10.3390/ijms23073769
• Keywords: Sulf1; Sulf2; angiogenesis; VEGF cell signalling; TGF beta cell signalling; HEPARAN-SULFATE 6-O-ENDOSULFATASE; TUMOR; EXPRESSION; CARTILAGE; SULF-2; QSULF1