Tumor necrosis factor-induced nuclear factor κB activation is impaired in focal adhesion kinase-deficient fibroblasts
Tumor necrosis factor-induced nuclear factor κB activation is impaired in focal adhesion kinase-deficient fibroblasts
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DOI：
10.1074/jbc.m213115200
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发表时间：
2003-08-01
影响因子：
4.8
通讯作者：
Kasahara, T
中科院分区：
文献类型：
--
作者：
Funakoshi-Tago, M;Sonoda, Y;Kasahara, T
Focal adhesion kinase （FAK）广泛参与重要的细胞功能，如增殖、迁移和存活，尽管其在免疫和炎症反应中的作用尚未被探索。我们利用FAK缺陷（FAK-/-）胚胎成纤维细胞，证明了FAK在肿瘤坏死因子（TNF）诱导的核因子(NF)- κ b激活中的关键作用。有趣的是，tnf诱导的白细胞介素(IL)-6的产生在FAK -/-成纤维细胞中几乎被消除，而在FAK -/-或FAK +/+成纤维细胞中获得正常水平的产生。FAK缺乏不影响三种类型的丝裂原活化蛋白激酶，ERK， JNK和p38。同样，tnf诱导的激活蛋白1或NF-IL-6的激活在FAK -/-细胞中也未受损。值得注意的是，TNF诱导的NF-kappaB DNA结合活性和IkappaB激酶（IKKs）的激活在FAK -/-细胞中明显受损，而TNF受体1或其他信号分子如受体相互作用蛋白（RIP）、肿瘤坏死因子受体相关因子2 （TRAF2）、IKKalpha、IKKbeta和IKKgamma的表达不变。此外，未观察到tnf诱导的FAK与RIP的关联以及随后RIP与TRAF2的关联，导致RIP无法在FAK -/-细胞中招募IKK复合物。将野生型FAK重新引入FAK -/-细胞恢复RIP与TRAF2和IKK复合物的相互作用，并恢复NF-kappaB的激活和随后的IL-6的产生。因此，我们提出了FAK在NF-kappaB激活途径中导致细胞因子产生的新作用。
Focal adhesion kinase (FAK) is widely involved in important cellular functions such as proliferation, migration, and survival, although its roles in immune and inflammatory responses have yet to be explored. We demonstrate a critical role for FAK in the tumor necrosis factor (TNF)-induced activation of nuclear factor (NF)-kappaB, using FAK-deficient (FAK-/-) embryonic fibroblasts. Interestingly, TNF-induced interleukin (IL)-6 production was nearly abolished in FAK -/- fibroblasts, whereas a normal level of production was obtained in FAK -/- or FAK +/+ fibroblasts. FAK deficiency did not affect the three types of mitogen-activated protein kinases, ERK, JNK, and p38. Similarly, TNF-induced activation of activator protein 1 or NF-IL-6 was not impaired in FAK -/- cells. Of note, TNF-induced NF-kappaB DNA binding activity and activation of IkappaB kinases (IKKs) were markedly impaired in FAK -/- cells, whereas the expression of TNF receptor I or other signaling molecules such as receptor-interacting protein (RIP), tumor necrosis factor receptor-associated factor 2 (TRAF2), IKKalpha, IKKbeta, and IKKgamma was unchanged. Also, TNF-induced association of FAK with RIP and subsequent association of RIP with TRAF2 were not observed, resulting in a failure of RIP to recruit the IKK complex in FAK -/- cells. The reintroduction of wild type FAK into FAK -/- cells restored the interaction of RIP with TRAF2 and the IKK complex and allowed recovery of NF-kappaB activation and subsequent IL-6 production. Thus, we propose a novel role for FAK in the NF-kappaB activation pathway leading to the production of cytokines.