Specific inhibition of FGF-2 signaling with 2-O-sulfated octasaccharides of heparan sulfate
Specific inhibition of FGF-2 signaling with 2-O-sulfated octasaccharides of heparan sulfate
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DOI：
10.1093/glycob/cwp031
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发表时间：
2009-06-01
期刊：
影响因子：
4.3
通讯作者：
Kimata, Koji
中科院分区：
文献类型：
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作者：
Ashikari-Hada, Satoko;Habuchi, Hiroko;Kimata, Koji
在成纤维细胞生长因子-2信号转导中，成纤维细胞生长因子受体-1、酪氨酸激酶成纤维细胞生长因子受体-1和细胞表面硫酸乙酰肝素蛋白多糖三元复合体的形成对成纤维细胞生长因子受体-1的激活和下游信号转导起关键作用。外源性肝素聚合物和一些八糖可抑制成纤维细胞生长因子-2诱导的中国仓鼠卵巢(CHO)-K1细胞FGFR-1和细胞外信号调节激酶(ERK1/2)的磷酸化，FGFR-1在细胞表面呈现HS。八糖的抑制作用依赖于分子中2-O-硫酸盐基团的数量，而与6-O-硫酸盐基团的数量无关。2-O-位的硫酸化不仅是HS与Fgf-2结合的先决条件，也是调节Fgf-2信号和与内源性HS竞争抑制的先决条件。有趣的是，只有含有结合成纤维细胞生长因子-4所必需的2-O-和6-O-硫酸基团的特定八糖才能阻止成纤维细胞生长因子-4诱导的磷酸化。在HS生物合成缺乏的CHO-677细胞中，肝素可促进成纤维细胞生长因子-2诱导的ERK1/2的磷酸化，而成纤维细胞生长因子-2结合的八糖则抑制该磷酸化。我们的数据表明，特定的肝素结合因子的活性可以被独特的寡糖抑制，这些寡糖可以结合这些因子，但不能形成功能信号复合体，无论细胞是否有正常的HS补充或缺乏HS。
In fibroblast growth factor (FGF)-2 signaling, the formation of a ternary complex of FGF-2, tyrosine-kinase fibroblast growth factor receptor (FGFR)-1, and cell surface heparan sulfate (HS) proteoglycan is known to be critical for the activation of FGFR-1 and downstream signal transduction. Exogenous heparin polymer and some octasaccharides inhibited FGF-2-induced phosphorylation both of FGFR-1 and of extracellular signal-regulated kinase (ERK1/2) in Chinese hamster ovary (CHO)-K1 cells transfected with FGFR-1, which present HS on their cell surface. The inhibitory effect of octasaccharide was dependent on the number of 2-O-sulfate groups within a molecule but independent of the number of 6-O-sulfate groups. Sulfation at the 2-O-position was a prerequisite not only for the binding of HS to FGF-2 but also for regulation of FGF-2 signaling and competitive inhibition with endogenous HS. Interestingly, FGF-4-induced phosphorylation was impeded only by specific octasaccharides containing both 2-O- and 6-O-sulfated groups, which were necessary for binding FGF-4. In CHO-677 cells deficient in HS biosynthesis, heparin enhanced FGF-2-induced phosphorylation of ERK1/2. On the other hand, an FGF-2-binding octasaccharide inhibited the phosphorylation. Our data suggest that the activity of particular heparin-binding factors can be inhibited by distinctive oligosaccharides that can bind the factors but cannot form functional signaling complexes irrespective of whether cells have a normal complement of HS or lack HS.