Repression of myogenic differentiation by aFGF, bFGF, and K-FGF is dependent on cellular heparan sulfate.
Repression of myogenic differentiation by aFGF, bFGF, and K-FGF is dependent on cellular heparan sulfate.
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DOI：
10.1083/jcb.118.3.631
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发表时间：
1992-08
期刊：
影响因子：
--
通讯作者：
Rapraeger A
中科院分区：
文献类型：
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作者：
Olwin BB;Rapraeger A
我们已经提出了一个模型，在这个模型中，成纤维细胞生长因子信号需要成纤维细胞生长因子与至少两个成纤维细胞生长因子受体、硫酸乙酰肝素蛋白多糖(HSPG)和酪氨酸激酶相互作用。由于成纤维细胞生长因子可能是骨骼肌分化的关键介质，我们研究了MM14骨骼肌成肌细胞中糖胺多糖的合成及其参与成纤维细胞生长因子信号转导的作用。增殖和分化的MM14细胞表现出相似的HSPG水平，而分化的细胞表现出硫酸软骨素蛋白多糖和硫酸乙酰肝素链的水平降低。存在于增殖细胞中的HSPG，包括Syndecan，与bFGF结合，而大多数硫酸软骨素和硫酸肝素链不结合。用氯酸盐处理骨骼肌细胞，氯酸盐是糖胺多聚糖硫酸化的可逆抑制剂，用来检测硫酸蛋白多聚糖对成纤维细胞生长因子信号的需求。氯酸盐处理减少了90%的糖胺聚糖硫酸盐化和80%的成纤维细胞生长因子与高亲和力部位的结合。氯酸盐处理MM14成肌细胞后，酸性、碱性和卡波西肉瘤FGFs的生物活性降低，导致终末分化。同时加入硫酸钠或肝素可逆转氯酸盐对成纤维细胞生长因子信号的抑制作用。通过肝素酶抑制基本的成纤维细胞生长因子结合和生物活性的能力，进一步支持了硫酸乙酰肝素蛋白多糖在成纤维细胞生长因子信号转导中的直接作用。这些结果表明，酸性、碱性或卡波西氏肉瘤成纤维细胞生长因子激活成纤维细胞生长因子受体需要同时与HSPG和酪氨酸激酶受体结合。骨骼肌在体内的分化可能依赖于成纤维细胞生长因子、成纤维细胞生长因子酪氨酸激酶受体和热休克蛋白。这些分子的调控可能会对骨骼肌的发育和再生产生重要的影响。
We have proposed a model in which fibroblast growth factor (FGF) signalling requires the interaction of FGF with at least two FGF receptors, a heparan sulfate proteoglycan (HSPG) and a tyrosine kinase. Since FGF may be a key mediator of skeletal muscle differentiation, we examined the synthesis of glycosaminoglycans in MM14 skeletal muscle myoblasts and their participation in FGF signalling. Proliferating and differentiated MM14 cells exhibit similar levels of HSPG, while differentiated cells exhibit reduced levels of chondroitin sulfate proteoglycans and heparan sulfate chains. HSPGs, including syndecan, present in proliferating cells bind bFGF, while the majority of chondroitin sulfate and heparan sulfate chains do not. Treatment of skeletal muscle cells with chlorate, a reversible inhibitor of glycosaminoglycan sulfation, was used to examine the requirement of sulfated proteoglycans for FGF signalling. Chlorate treatment reduced glycosaminoglycan sulfation by 90% and binding of FGF to high affinity sites by 80%. Chlorate treatment of MM14 myoblasts abrogated the biological activity of acidic, basic, and Kaposi's sarcoma FGFs resulting in terminal differentiation. Chlorate inhibition of FGF signalling was reversed by the simultaneous addition of sodium sulfate or heparin. Further support for a direct role of heparan sulfate proteoglycans in fibroblast growth factor signal transduction was demonstrated by the ability of heparitinase to inhibit basic FGF binding and biological activity. These results suggest that activation of FGF receptors by acidic, basic or Kaposi's sarcoma FGF requires simultaneous binding to a HSPG and the tyrosine kinase receptor. Skeletal muscle differentiation in vivo may be dependent on FGFs, FGF tyrosine kinase receptors, and HSPGs. The regulation of these molecules may then be expected to have important implications for skeletal muscle development and regeneration.