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J. Biol. Chem., Vol. 268, Issue 32, 23906-23914, 11, 1993
S Guimond, M Maccarana, BB Olwin, U Lindahl and AC Rapraeger
Chlorate-treated Swiss 3T3 fibroblasts, with impaired synthesis of heparan
sulfate proteoglycan, were used as target cells in assessing the ability of
exogenous heparin-derived saccharides to promote the mitogenic activity of
basic fibroblast growth factor 2 (FGF-2). Full- size native heparin
(carrying iduronosyl 2-O-sulfate and glucosaminyl 6- O-sulfate groups), as
well as a dodecasaccharide fraction isolated after limited deaminative
cleavage of heparin, were efficient promoters, whereas the corresponding
decasaccharides, or smaller oligosaccharides, were inactive. Neither
selectively 2-O-desulfated nor preferentially 6-O-desulfated heparin were
active. However, the latter derivative competed with native heparin for
binding to FGF-2 and thus blocked the ability of native heparin to promote
the mitogenic activity of FGF-2. The 6-O-desulfated heparin also prevented
the ability of FGF- 2 to suppress myogenic differentiation in MM14 mouse
myoblasts. The binding region for FGF-2 has been identified as a
pentasaccharide sequence containing a single essential O-sulfate group, at
C2 of iduronic acid (1). It is proposed that the dodecasaccharide sequence
required to promote receptor signaling by FGF-2 encompasses this
pentasaccharide region, which binds the growth factor, and a site
interacting with the receptor that contains essential 2-O- and 6-O- sulfate
groups. Similar studies involving the related growth factors, FGF-1 and
FGF-4, revealed differential effects of saccharides. The mitogenic effect
induced by FGF-1 thus was not blocked by either the 2- O- or the
6-O-desulfated heparins. However, both of these derivatives, at high
concentrations, promote mitogenic activity of FGF-4. It is concluded that
specific saccharide sequences within heparan sulfate glycosaminoglycan
chains favor the signaling by distinct members of the FGF family.
Activating and inhibitory heparin sequences for FGF-2 (basic FGF). Distinct requirements for FGF-1, FGF-2, and FGF-4
Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison 53706.
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