The heparanome—The enigma of encoding and decoding heparan sulfate sulfation

Dynamic expression patterns of 6‐O endosulfatases during zebrafish development suggest a subfunctionalisation event for sulf2

“…Since the discovery of a novel sulfatase in the quail embryo as an HS-specific 6-O-endosulfatase (Dhoot et al, 2001), many in vitro and in vivo studies have examined the functional roles and expression patterns of sulf homologs in humans, rat, mice, quail, chick, and frog (Lamanna et al, 2007;Freeman et al, 2008). In this study, we report the phylogenetic analysis and in situ expression of sulf11, sulf2a, and sulf2 in zebrafish.…”

Organ-specific Sulfation Patterns of Heparan Sulfate Generated by Extracellular Sulfatases Sulf1 and Sulf2 in Mice

“…Given that the cleavage of Sulf proteins by furin-type proteinases affects the accumulation of Sulf proteins in lipid-rich domains as well as Wnt activation (44), Sulf1 and Sulf2 may undergo different protein cleavage in vivo. Although Sulf1 and Sulf2 show overall sequence similarity, the hydrophilic domains in their middle portions are divergent (22). Because the hydrophilic domains are required for secretion and cell surface localization of Sulf proteins (13,22), these sequences may give rise to the functional differences between these two Sulf proteins.…”

“…Although Sulf1 and Sulf2 show overall sequence similarity, the hydrophilic domains in their middle portions are divergent (22). Because the hydrophilic domains are required for secretion and cell surface localization of Sulf proteins (13,22), these sequences may give rise to the functional differences between these two Sulf proteins. Fourth, Sulf2 may be localized apart from the target HS.…”

“…By removing 6-O-sulfates in HS, Sulf1 and Sulf2 activate Wnt, Shh, bone morphogenetic protein (BMP), and glial cell line-derived neurotrophic factor (GDNF) and attenuate the signaling of FGF, VEGF, hepatocyte growth factor (HGF), and heparinbinding EGF-like growth factor (HB-EGF) (8, 11, 14 -21). Therefore, Sulf1 and Sulf2 are thought to be key regulators of cell proliferation, differentiation, and migration and are also implicated in cancer progression and metastasis (22,23). Biochemical studies have demonstrated that Sulf1 and Sulf2 are most active in the UA2S-GlcNS6S trisulfated disaccharide unit, which is present in the NS domain (9,11,13,16,24,25).…”

Short SULF1/SULF2 splice variants predominate in mammary tumours with a potential to facilitate receptor tyrosine kinase-mediated cell signalling

“…Changes in their HS sulfation patterns can exert differential functional effects on cell signalling and thus drive not only regulated normal development but also dysregulated tumour growth. Of particular interest amongst these changes is the 6-O sulfate group of the HS chains that has been shown to be associated with the regulation of a number of growth factor signalling pathways (Lamanna et al 2007). The significance of 6-O sulfation in cell signalling has been further highlighted by the discovery of extracellular editing of HS sulfation by two cell surface sulfatases, Sulf1 (qSulf1) and Sulf2, which specifically hydrolyse glucosamine-6S groups of the HS chain (Dhoot et al 2001;Morimoto-Tomita et al 2002).…”