Department of Comparative Biomedical Sciences, Royal Veterinary College, University of London, London NW1 OTU, UK.
Department of Physiology, Anatomy & Genetics, University of Oxford, South Parks Road, Oxford OX1 3PT, UK.
Int J Mol Sci. 2022 Mar 29;23(7):3769. doi: 10.3390/ijms23073769.
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 β (TGFβ) cell signalling activities. Unlike Sulf2, Sulf1 over-expression in dermal microvascular HMec1 cells promotes TGFβ 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 TGFβ and VEGF signalling while Sulf2 over-expression maintains the control phenotype. Exposure of these cells to VEGF-A, TGFβ1, 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 TGFβ cell signalling activities.
信号活动受到严格调控以控制细胞反应。细胞膜和细胞外基质中的硫酸乙酰肝素蛋白聚糖 (HSPG) 调节配体的可用性，并与一系列关键受体相互作用。SULF1 和 SULF2 酶通过去除 6-O 硫酸盐来修饰 HSPG 硫酸化，从而调节细胞信号转导，但被认为具有相同的功能。然而，我们对两种不同的人内皮细胞系的体外 mRNA 和蛋白质分析突出了它们通过反馈调节 HS 6-O 转移酶 (HS6ST) 活性来维持特定 HSPG 硫酸化模式的明显不同的调节作用，以及在血管内皮生长因子 (VEGF) 和转化生长因子β (TGFβ) 细胞信号转导活性中高度不同的作用。与 Sulf2 不同，在真皮微血管 HMec1 细胞中过表达 Sulf1 会同时上调 HS6ST1 活性，从而促进 TGFβ 和 VEGF 细胞信号转导。相比之下，Sulf1 在静脉 ea926 细胞中的过表达会产生相反的效果，因为它会减弱 TGFβ 和 VEGF 信号转导，而 Sulf2 的过表达则维持对照表型。这些细胞暴露于 VEGF-A、TGFβ1 及其抑制剂进一步突出了它们的内皮细胞类型特异性反应和整合生长因子相互作用，以调节细胞信号转导，并对 HSPG 硫酸化进行选择性反馈调节，此外还利用替代的 Sulf2 RNA 剪接来调节净 VEGF-A 和 TGFβ 细胞信号转导活性。
