Tumor necrosis factor-induced nuclear factor kappaB activation is impaired in focal adhesion kinase-deficient fibroblasts.
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.
Department of Biochemistry, Kyoritsu College of Pharmacy, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan.
Megumi
M
Funakoshi-Tago
Yoshiko
Y
Sonoda
Saeko
S
Tanaka
Kenichiro
K
Hashimoto
Kenji
K
Tago
Shin-Ichi
S
Tominaga
Tadashi
T
Kasahara
D000818:Animals; D004622:Embryo, Mammalian; D005347:Fibroblasts / Q000378:metabolism*; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D006579:Heterozygote; D006720:Homozygote; D051550:I-kappa B Kinase; D015850:Interleukin-6 / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000502:physiology*; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D011506:Proteins / Q000378:metabolism; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D015850:Interleukin-6; D016328:NF-kappa B; D011506:Proteins; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496051:Ptk2 protein, mouse; D017346:Protein Serine-Threonine Kinases; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506251:Ripk1 protein, mouse; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse; D020928:Mitogen-Activated Protein Kinases