Fibroblast Growth Factor-2-induced Signaling through Lipid Raft-associated Fibroblast Growth Factor Receptor Substrate 2 (FRS2)*
Fibroblast Growth Factor-2-induced Signaling through Lipid Raft-associated Fibroblast Growth Factor Receptor Substrate 2 (FRS2)*
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DOI：
10.1074/jbc.m210245200
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发表时间：
2003-04
期刊：
影响因子：
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通讯作者：
M. Ridyard;S. Robbins
中科院分区：
文献类型：
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作者：
M. Ridyard;S. Robbins
质膜是不均匀的，但含有特定的亚室，其特征在于其独特的脂质和蛋白质组成。基于它们在各种信号分子中的富集，这些膜微区被认为是许多细胞外刺激的局部信号转导位点。我们以前已经表明，成纤维细胞生长因子-2（FGF 2）诱导的脂筏膜微结构域内的人神经母细胞瘤细胞的特征是由酪氨酸磷酸化的p80磷蛋白的特异性信号转导反应。在这里，我们表明，这种蛋白质是信号适配器FRS 2，它是专门定位于脂筏在体外和体内。我们已经研究了脂筏内FRS 2的酪氨酸磷酸化和丝氨酸-苏氨酸磷酸化如何影响细胞对FGF 2信号传导的反应。我们的数据表明，蛋白激酶C，Src家族激酶和MEK 1/2的激活参与调节FRS 2的丝氨酸-苏氨酸磷酸化，这可以间接影响FRS 2磷酸酪氨酸水平。我们还表明，Grb 2被招募到脂筏在信号转导事件和MEK 1/2的激活脂筏内的不同机制可能会导致不同的细胞反应。这项工作表明，脂筏内的区室化信号传导可能为生长因子信号传导提供一定水平的特异性。
The plasma membrane is not homogenous but contains specific subcompartments characterized by their unique lipid and protein composition. Based on their enrichment in various signaling molecules, these membrane microdomains are recognized to be sites of localized signal transduction for a number of extracellular stimuli. We have previously shown that fibroblast growth factor-2 (FGF2) induced a specific signaling response within a lipid raft membrane microdomain in human neuroblastoma cells characterized by the tyrosine phosphorylation of a p80 phosphoprotein. Herein, we show that this protein is the signaling adaptor FRS2 and that it is localized exclusively to lipid rafts in vitro and in vivo. We have examined how the tyrosine phosphorylation and serine-threonine phosphorylation of FRS2 within lipid rafts affect the response of cells to FGF2 signaling. Our data suggest that activation of protein kinase C, Src family kinases, and MEK1/2 are involved in regulating serine-threonine phosphorylation of FRS2, which can indirectly affect FRS2 phosphotyrosine levels. We also show that Grb2 is recruited to lipid rafts during signaling events and that activation of MEK1/2 by different mechanisms within lipid rafts may lead to different cellular responses. This work suggests that compartmentalized signaling within lipid rafts may provide a level of specificity for growth factor signaling.