Abstract
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.
Highlights
Resulting in a failure of receptor-interacting protein (RIP) to recruit the IKK complex in FAK؊/؊ cells
Defective TNF-␣-induced IL-6 Production in the FAKϪ/Ϫ Fibroblasts—It is well documented that FAK plays important roles in the integrin signaling in cell migration, cell survival, or cell cycle regulation
In order to study the role of FAK, we obtained FAKϩ/Ϫ and FAKϪ/Ϫ embryonic fibroblasts from FAK-deficient mice, which were originally established by Ilic and co-workers [19, 20]
Summary
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-B activation and subsequent IL-6 production. To date, no reports have described the role of FAK in inflammatory and immune responses, whereas proline-rich tyrosine kinase 2, a related adhesion focal tyrosine kinase, was found to be activated by TNF or by ultraviolet irradiation [17]. Mechanisms of FAK activation are multiple, and other tyrosine-phosphorylated proteins such as proline-rich tyrosine kinase 2 are present in the cells [3, 5, 18]. Cellular focal adhesion contains structural and signaling proteins that in many cases are modified by tyrosine phosphorylation (rethe role of FAK because FAK deficiency in mice was embryonic lethal as a result of defective developmental gastrulation events with deficits in cell migration (18 –20). We have uncovered the role of FAK in TNF␣-mediated NF-B activation through its association with receptor-interacting protein (RIP), a serine/threonine kinase
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