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J Biol Chem, Vol. 273, Issue 29, 18443-18451, July 17, 1998

Post-translational Processing of the Insulin-like Growth Factor-2 Precursor
ANALYSIS OF O-GLYCOSYLATION AND ENDOPROTEOLYSIS

Stephen J. Duguay^§, Yu Jin^§, Jeffrey Stein^§, Amy N. Duguay, Paul Gardner, and Donald F. Steiner^§

From the  Howard Hughes Medical Institute and ^§ Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, Illinois 60637

Insulin-like growth factor-2 (IGF-2) is expressed in most embryonic tissues and is required for normal development during gestation. After birth IGF-2 expression is extinguished in most tissues, but the gene is often reactivated during tumorigenesis. Tumors secrete high molecular weight forms of IGF-2 that result from aberrant post-translational processing of pro-IGF-2. As a first step toward understanding how high molecular weight IGF-2 peptides might contribute to tumor progression, we have characterized the biosynthesis of IGF-2 in a human embryonic cell line. We have found that pro-IGF-2 can initially form two disulfide isomers that undergo rearrangement to a single conformation in vivo. The addition of N-acetylgalactosamine to Ser⁷¹, Thr⁷², Thr⁷⁵, and Thr¹³⁹ likely occurs in the cis- Golgi apparatus. Sialic acid addition begins in the trans- Golgi apparatus, but IGF-2 peptides must reach the trans-Golgi network for oligosaccharide maturation to be completed. Endoproteolysis occurs concomitant to or slightly after oligosaccharide maturation. Cleavage was observed only at Arg¹⁰⁴, resulting in the secretion of IGF-2-(1-104) and free E-peptide. Proteolysis required basic residues in the P1 (Arg¹⁰⁴) and P4 (Arg¹⁰¹) positions, was completely blocked by a furin inhibitor, and was enhanced by coexpression with furin, PACE4, PC6A, PC6B, and LPC. These data suggest that members of the subtilisin-related proprotein convertase family mediate processing of pro-IGF-2 at Arg¹⁰⁴. We did not detect the IGF-2 peptides that are most abundant in normal serum, mature IGF-2, and IGF-2-(1-87), in this expression system, which indicates that novel endoproteases are responsible for generating these products.

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