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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.
Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.

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Copyright © 1998 by the American Society for Biochemistry and Molecular Biology.
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