Ganglioside modulates ligand binding to the epidermal growth factor receptor.
Ganglioside modulates ligand binding to the epidermal growth factor receptor.
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DOI：
10.1046/j.1523-1747.2001.00222.x
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发表时间：
2001
期刊：
影响因子：
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通讯作者：
X. Wang;Z. Rahman;P. Sun;E. Meuillet;D. George;E. Bremer;A. Al-Qamari;A. Paller
中科院分区：
文献类型：
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作者：
X. Wang;Z. Rahman;P. Sun;E. Meuillet;D. George;E. Bremer;A. Al-Qamari;A. Paller
而以前的研究表明，药理学添加神经节苷脂抑制角质形成细胞增殖下调表皮生长因子受体磷酸化，潜在的生化基础和生理相关性是未知的。使用Scatchard和位移图，我们已经表明，补充纯化的神经节苷脂减少（125）I-标记的表皮生长因子的角质形成细胞衍生的SCC 12细胞的结合。相反，用唾液酸酶转染并因此耗尽神经节苷脂的SCC 12细胞显示与表皮生长因子受体的配体结合增加，这与它们响应于表皮生长因子和转化生长因子-α的增殖增加以及表皮生长因子受体和下游信号转导途径组分的磷酸化增加一致。改变结合的机制似乎主要涉及完整膜内可用受体的数量减少，但不改变受体蛋白表达。这些研究提供证据表明，神经节苷脂对角质形成细胞增殖的影响至少部分来自神经节苷脂与受体的直接结合和受体-配体相互作用的破坏。操纵膜神经节苷脂含量可能是一个强大的新手段，改变表皮生长因子受体依赖的细胞增殖。
Whereas previous investigations have shown that pharmacologic addition of gangliosides inhibits keratinocyte proliferation by downregulating epidermal growth factor receptor phosphorylation, the underlying biochemical basis and physiologic relevance are unknown. Using Scatchard and displacement plots, we have shown that supplemental purified gangliosides decrease the binding of (125)I-labeled epidermal growth factor to keratinocyte-derived SCC12 cells. Conversely, SCC12 cells transfected with sialidase and thus depleted of gangliosides show increased ligand binding to the epidermal growth factor receptor, which is consistent with their increased proliferation in response to epidermal growth factor and transforming growth factor-alpha, and increased phosphorylation of the epidermal growth factor receptor, and downstream signal transduction pathway components. The mechanism of the altered binding appears to involve primarily decreased numbers of available receptors within the intact membrane, but not altered receptor protein expression. These studies provide evidence that the effect of gangliosides on keratinocyte proliferation results, at least in part, from the direct binding of ganglioside to the receptor and disruption of the receptor-ligand interaction. Manipulation of membrane ganglioside content may be a powerful new means to alter epidermal growth factor receptor-dependent cell proliferation.