A Novel Mechanism of Sequestering Fibroblast Growth Factor 2 by Glypican in Lipid Rafts, Allowing Skeletal Muscle Differentiation
A Novel Mechanism of Sequestering Fibroblast Growth Factor 2 by Glypican in Lipid Rafts, Allowing Skeletal Muscle Differentiation
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DOI：
10.1128/mcb.01164-09
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发表时间：
2010-04-01
影响因子：
5.3
通讯作者：
Brandan, Enrique
中科院分区：
文献类型：
--
作者：
Gutierrez, Jaime;Brandan, Enrique
硫酸乙酰肝素蛋白聚糖（HSPG）是生长因子活性的关键调节剂。成纤维细胞生长因子2（FGF-2）强烈抑制骨骼肌分化。我们已经表明，HSPGs存在于质膜上，在成肌细胞中表达，并在肌肉分化过程中下调。一个例外是磷脂酰肌醇蛋白聚糖-1，它存在于整个生肌过程中。不表达磷脂酰肌醇蛋白聚糖-1的成肌细胞表现出分化缺陷，FGF-2的受体结合增加，伴随着信号传导增加。磷脂酰肌醇蛋白聚糖-1缺陷型成肌细胞显示肌细胞生成素（控制肌生成的主基因）、肌球蛋白和成肌细胞融合指数的表达降低。逆转这些缺陷诱导大鼠磷脂酰肌醇蛋白聚糖-1的表达。磷脂酰肌醇蛋白聚糖-1是唯一定位于成肌细胞脂筏结构域的HSPG，导致FGF-2与位于非筏结构域的FGF-2受体（FGFR）隔离。嵌合磷脂酰肌醇蛋白聚糖-1，含有多配体蛋白聚糖-1跨膜和胞质结构域，位于非筏结构域与FGFR-IV-和增强的FGF-2-依赖性信号相互作用。因此，磷脂酰肌醇蛋白聚糖-1作为肌肉分化的正调节剂，通过隔离脂肪筏中的FGF-2并阻止其结合和依赖性信号传导。
Heparan sulfate proteoglycans (HSPGs) are critical modulators of growth factor activities. Skeletal muscle differentiation is strongly inhibited by fibroblast growth factor 2 (FGF-2). We have shown that HSPGs present at the plasma membrane are expressed in myoblasts and are downregulated during muscle differentiation. An exception is glypican-1, which is present throughout the myogenic process. Myoblasts that do not express glypican-1 exhibit defective differentiation, with an increase in the receptor binding of FGF-2, concomitant with increased signaling. Glypican-1-deficient myoblasts show decreased expression of myogenin, the master gene that controls myogenesis, myosin, and the myoblast fusion index. Reversion of these defects was induced by expression of rat glypican-1. Glypican-1 is the only HSPG localized in lipid raft domains in myoblasts, resulting in the sequestration of FGF-2 away from FGF-2 receptors (FGFRs) located in nonraft domains. A chimeric glypican-1, containing syndecan-1 transmembrane and cytoplasmic domains, is located in nonraft domains interacting with FGFR-IV- and enhanced FGF-2-dependent signaling. Thus, glypican-1 acts as a positive regulator of muscle differentiation by sequestering FGF-2 in lipid rafts and preventing its binding and dependent signaling.