Activating and inhibitory heparin sequences for FGF-2 (basic FGF). Distinct requirements for FGF-1, FGF-2, and FGF-4

• Published in: The Journal of biological chemistry 1993-11, Vol.268 (32), p.23906-23914
• Main Authors: GUIMOND, S, MACCARANA, M, OLWIN, B. B, LINDAHL, U, RAPRAEGER, A. C
• Format: Article
• Language: English
• Subjects: 3T3 Cells; Animals; Biological and medical sciences; Cattle; Cell Differentiation; Cell physiology; Fibroblast Growth Factor 1 - antagonists & inhibitors; Fibroblast Growth Factor 1 - metabolism; Fibroblast Growth Factor 2 - antagonists & inhibitors; Fibroblast Growth Factor 2 - metabolism; Fibroblast Growth Factor 4; Fibroblast Growth Factors - antagonists & inhibitors; Fibroblast Growth Factors - metabolism; Fundamental and applied biological sciences. Psychology; Heparin - chemistry; Heparin - metabolism; Humans; Mice; Molecular and cellular biology; Muscles - cytology; Proto-Oncogene Proteins - antagonists & inhibitors; Proto-Oncogene Proteins - metabolism; Signal Transduction
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1016/s0021-9258(20)80471-2

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.