Cell adhesion and focal adhesion kinase regulate insulin receptor substrate-1 expression
Cell adhesion and focal adhesion kinase regulate insulin receptor substrate-1 expression
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DOI：
10.1074/jbc.m006162200
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发表时间：
2000-12-08
影响因子：
4.8
通讯作者：
Van Obberghen, E
中科院分区：
文献类型：
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作者：
Lebrun, P;Baron, V;Van Obberghen, E
整合素是参与细胞与细胞外基质蛋白相互作用的跨膜受体。在这里，我们表明，细胞粘附调节胰岛素受体底物-1（IRS-1）mRNA的合成，当成纤维细胞保持在悬浮液中时，IRS-1 mRNA的水平较低，但IRS-2 mRNA的水平没有被检测到，这种影响是由于IRS-1转录的负调控，而不是mRNA稳定性降低。在纤连蛋白或玻连蛋白介导的整合素刺激后，IRS-1 mRNA的水平在4小时内恢复。已知粘着斑激酶（FAK）在整合素刺激后被激活，并且我们发现IRS-1在FAK（-/-）细胞中不表达。表位标记的FAK在FAK（-/-）成纤维细胞（DA 2细胞）中的稳定再表达恢复了IRS-1表达的正常水平，证实IRS-1 mRNA表达受FAK调节。然而，在粘附的FAK（-/-）细胞中，我们没有检测到JNK的激活，而在DA 2细胞中，JNK被激活，这证实了FAK在整合素诱导的JNK激活中的作用。在FAK（-/-）细胞和悬浮的FAK（-/-）细胞中，茴香霉素均能不依赖于FAR刺激JNK，这证实了JNK可以部分调节IRS-1 mRNA的转录。我们认为，整合素可以通过调节细胞中IRS-1的水平来调节胰岛素和胰岛素样生长因子-1信号通路，而FAR介导的JNK信号通路是参与这一过程的通路之一。
Integrins are transmembrane receptors involved in interactions between cells and extracellular matrix proteins. Here we show that cell adhesion regulates insulin receptor substrate-1 (IRS-1) mRNA synthesis, When fibroblasts are held in suspension, lower levels of IRS-1 mRNA, but not of IRS-2 mRNA, are detected, and this effect is due to the negative regulation of IRS-1 transcription rather than to decreased mRNA stability. Upon fibronectin- or vitronectin-mediated integrin stimulation, the level of IRS-1 mRNA was restored within 4 h, The focal adhesion kinase (FAK) is known to be activated upon integrin stimulation, and we found that IRS-1 was not expressed in FAK(-/-) cells. Stable re-expression of epitope-tagged FAK in FAK(-/-) fibroblasts (DA2 cells) restored normal levels of IRS-1 expression, confirming that IRS-1 mRNA expression is regulated by FAK, It is known that integrins activate the JNK pathway. However, in adherent FAK(-/-) cells, we failed to detect activation of JNK, whereas JNK was stimulated in DA2 cells, This confirms the role of FAK in integrin-induced JNK stimulation. FAR-independent stimulation of JNK with anisomycin treatment both in FAK(-/-) cells and in suspended FAK(-/-) cells confirmed that IRS-1 mRNA transcription can be partially regulated by JNK, We suggest that integrins can modulate insulin and insulin-like growth factor-1 signaling pathways by regulating the levels of IRS-1 in cells and that FAR-mediated signaling to JNK is one pathway involved in this process.