MEK kinase 1 interacts with focal adhesion kinase and regulates insulin receptor substrate-1 expression
MEK kinase 1 interacts with focal adhesion kinase and regulates insulin receptor substrate-1 expression
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DOI：
10.1074/jbc.m206087200
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发表时间：
2003-02-07
影响因子：
4.8
通讯作者：
Oka, Y
中科院分区：
文献类型：
--
作者：
Yujiri, T;Nawata, R;Oka, Y
MEK激酶1（MEKK 1）已被证明有助于调节细胞迁移，而粘着斑激酶（FAK）是参与细胞迁移和整合素信号传导的主要参与者。在这里，我们表明MEKK 1和FAK是从小鼠成纤维细胞中免疫共沉淀的。此外，MEKK 1和FAK之间的关联似乎是生理相关的，因为它通过表皮生长因子（EGF）治疗而增强。将FAK靶向膜也增强了其与MEKK 1的结合，表明MEKK 1定位于膜相关的亚细胞结构域，可能是粘着斑。有趣的是，胰岛素受体底物-1（IRS-1）的表达在MEKK 1缺陷的成纤维细胞中减少，这与FAK缺陷的成纤维细胞中的早期发现相似。胰岛素样生长因子1（IGF-1）诱导的ERK激活减少MEKK 1缺陷细胞，但磷脂酰肌醇3-激酶/Akt激活没有。尽管据报道整合素通过FAK介导的JNK活化调节IRS-1基因的转录，但在MEKK 1缺陷细胞中未观察到纤连蛋白刺激的FAK、ERK或JNK活化受损。MEKK 1表达的重建恢复了IRS-1表达以及IGF-1诱导的ERK激活。总之，这些发现表明MEKK 1与粘着斑相互作用，并调节IRS-1的表达。
MEK kinase 1 (MEKK1) has been shown to contribute to the regulation of cell migration, whereas focal adhesion kinase (FAK) is a major player involved in both cell migration and integrin signaling. Here we show that MEKK1 and FAK are co-immunoprecipitated from mouse fibroblasts. Moreover, the association between MEKK1 and FAK appears to be physiologically relevant, as it is enhanced by treatment with epidermal growth factor (EGF). Targeting FAK to the membrane also enhanced its association with MEKK1, indicating that MEKK1 is localized to a membrane-related subcellular domain, perhaps focal adhesions. Interestingly, the expression of insulin receptor substrate-1 (IRS-1) was diminished in MEKK1-deficient fibroblasts, which is similar to an earlier finding in FAK-deficient fibroblasts. Insulin-like growth factor 1 (IGF-1)-induced ERK activation was diminished in MEKK1-deficient cells, but phosphatidylinositol 3-kinase/Akt activation was not. Although integrin reportedly regulates the transcription of the IRS-1 gene via FAK-mediated JNK activation, no impairment of fibronectin-stimulated activation of FAK, ERK, or JNK was observed in MEKK1-deficient cells. Reconstitution of MEKK1 expression restored IRS-1 expression as well as IGF-1-induced ERK activation. Taken together, these findings indicate that MEKK1 interacts with FAK in focal adhesions and regulates IRS-1 expression.