Proteolytic cleavage of the rat heparan sulfate 6-O-endosulfatase SulfFP2 by furin-type proprotein convertases

Heparan sulfate 6-O-endosufatases Sulf1 and Sulf2 hydrolyze the 6-O-sulfate of the glucosamine residues in heparin and heparan sulfate, thereby regulating multiple signaling pathways. A previous study reported that human Sulf1 and Sulf2 were proteolytically processed in a manner sensitive to a furin inhibitor. However, the exact sites of cleavage, the sequence motifs for proteolysis, and the effect of the cleavage on enzyme activity remain unknown. Here we show that the cleavage of rat Sulf2 (also called SulfFP2) occurs at two arginine residues, 543 and 570, in the hydrophilic domain. Both sites reside in the consensus sequence for the cleavage by furin-type proprotein convertases, and the consensus motifs are essential for cleavages. The cleavage at arginine 570 is sensitive to a furin inhibitor. Furthermore, the uncleavable form of SulfFP2 shows sulfatase activity comparable to the cleavable SulfFP2, indicating that the cleavage is not indispensable for activation of SulfFP2.