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J. Biol. Chem., Vol. 281, Issue 30, 21052-21061, July 28, 2006

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Control of Fibroblast Growth Factor (FGF) 7- and FGF1-induced Mitogenesis and Downstream Signaling by Distinct Heparin Octasaccharide Motifs^*

Yongde Luo, Sheng Ye, Mikio Kan^¶, and Wallace L. McKeehan^||1

From the ^||Department of Biochemistry and Biophysics, Texas A&M University, Center for Cancer Biology and Nutrition, Institute of Biosciences and Technology, The Texas A&M University System Health Science Center, Houston, Texas 77030-3303, the Department of Physiology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390-9040, and ^¶Zeria Pharmaceutical Co., Ltd., GS PlatZ., 2512-1, Oshikiri, Kohnan-Machi, Ohsato-Gun, Saitama 360-0111, Japan

Variation in length, disaccharide composition, and sulfation of heparan sulfate (HS) affects fibroblast growth factor (FGF) signaling. However, it is unclear whether the specific distribution of groups within oligosaccharides or random variations in charge density underlies the effects. Recently we showed that a mixture of undersulfated octasaccharides exhibiting 7 and 8 sulfates (7,8-S-OctaF7) generated from heparin had the highest affinity for FGF7 monitored by salt resistance (>0.60 M salt) of octasaccharide-FGF7 complexes. 7,8-S-OctaF7 also had the highest specific activity for formation of a complex with dimeric FGFR2IIIb competent to bind FGF7. Here we show that when endogenous HS was inhibited by chlorate treatment, 7,8-S-OctaF7 specifically supported FGF7-stimulated DNA synthesis and downstream signaling in FGFR2IIIb-expressing mouse keratinocytes. It failed to support FGF1 signaling in both HS-deficient mouse keratinocytes and 3T3 fibroblasts. In contrast, abundant, more highly sulfated and heterogenous mixtures of octasaccharides with lower affinity (0.30-0.60 M salt) for FGF7 supported FGF1-induced signaling in both cell types. In contrast to the two-component 7,8-S-OctaF7 mixture from FGF7, the high affinity octasaccharide fraction from FGF1 was a heterogeneous mixture with components ranging from 8 to 12 sulfates with 11-S-octasaccharides the most abundant. The high affinity fraction exhibited similar properties to the lower affinity fractions from both FGF1 and FGF7. Octasaccharide mixtures eluting from FGF1 between 0.30 and 0.60 M and above 0.60 M salt were nearly equal in support of FGF1 signaling in fibroblasts and keratinocytes. Both were deficient in support of FGF7-induced signaling in keratinocytes. The results show that both variations in overall charge density and specific distribution of charged groups within HS motifs exhibit FGF-specific control over formation of FGF-HS-FGFR complexes and downstream signaling.

Received for publication, February 17, 2006 , and in revised form, May 5, 2006.

^* This work was supported by United States Public Health Service National Institutes of Health, NIDDK Grant DK35310 and NCI Grant CA59971 and by GS PlatZ, Ltd. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: 2121 W. Holcombe Blvd., Houston, TX 77030-3303. Tel.: 713-677-7522; Fax: 713-677-7512; E-mail: wmckeehan{at}ibt.tamhsc.edu.

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