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(Received for publication, March 15, 1995; and in revised form, May 2, 1995) From the Insulin-like growth factor I (IGF-I) is a mitogenic peptide that
is produced in most tissues and cell lines and plays an important role
in embryonic development and postnatal growth. IGF-I is initially
synthesized as a prohormone precursor that is converted to mature IGF-I
by endoproteolytic removal of the carboxyl-terminal E-domain.
Regulation of the conversion of proIGF-I to mature IGF-I is a potential
mechanism by which the biological activity of this growth factor might
be modulated. Endoproteolysis of the IGF-I prohormone occurs at the
unique pentabasic motif
Lys-X-X-Lys-X-X-Arg
Volume 270,
Number 29,
Issue of July 21, pp. 17566-17574, 1995
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
-X-X-Arg-X-X-Arg.
Recently, a family of enzymes which cleave prohormone precursors at
sites containing multiple basic residues has been discovered. The goals
of this study were 1) to determine which basic residues in the
pentabasic proIGF-I processing site were necessary for proper cleavage
and 2) to examine the role that subtilisin-related proprotein
convertase 1 (SPC1/furin) might play in proIGF-I processing. We have
shown that an expression vector coding for an epitope-tagged proIGF-I
directs synthesis and secretion of mature IGF-I-(1-70), extended
IGF-I-(1-76), proIGF-I, and N-glycosylated proIGF-I in
human embryonic kidney 293 cells. Extended IGF-I-(1-76) is
produced by cleavage at Arg
and requires both Arg
(P4) and Arg
(P1). Cleavage at Arg
does
not occur in the SPC1-deficient cell lines RPE.40 and LoVo, suggesting
that processing at this site is mediated by SPC1. Mature
IGF-I-(1-70) is produced by cleavage at Arg
and
requires both Lys
(P4) and Arg
(P1).
Lys
in the P7 position is important for efficient
cleavage. SPC1 is not required for processing at Arg
since
this cleavage occurs in RPE.40 and LoVo cells. These data suggest the
existence of a processing enzyme which is specific for the
Lys-X-X-Arg motif of proIGF-I.
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