title: Focal adhesion kinase determines the fate of death or survival of cells in response to TNFalpha in the presence of actinomycin D.
abstract: We speculated that focal adhesion kinase (FAK) might play a critical role in the TNFalpha-induced cell death. In this study, we found that FAK-/- cells are more sensitive to TNFalpha-induced apoptosis in the presence of actinomycin D (Act D) compared to FAK+/- cells. Prosurvival pathways are activated by the rapid recruitment of complex I, comprising TNFR1, TRADD, RIP and TRAF2, which leads to the activation of the NF-kappaB pathway. On the other hand, proapoptotic pathways are activated by complex II, the death-inducing signaling complex (DISC), which contains TNFR1, TRADD, RIP, and FADD, and procaspase-8 proteins. As TNFR1, TRADD, and RIP are included in both Complex I and DISC, we speculated that RIP might be a key protein. Coimmunoprecipitation assays revealed that RIP is included in complex I in FAK+/- cells, and FAK was associated with RIP. On the other hand, RIP is included in DISC in FAK-/- cells. FAK might be a key protein in the formation of complex I and the activation of NF-kappaB. Furthermore, Akt was activated in FAK+/- cells, but not FAK-/- cells. In conclusion, we first demonstrated that FAK determines the pathway leading to death or survival in TNFalpha/ActD-stimulated fibroblasts.
authors.affiliation: Department of Biochemistry, Kyoritsu University of Pharmacy, Shibakoen 1-5-30, Minato-ku, Tokyo 105-8512, Japan.
authors.forename: Reiko
authors.initials: R
authors.lastname: Takahashi
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Sonoda
authors.forename: Daiju
authors.initials: D
authors.lastname: Ichikawa
authors.forename: Naomi
authors.initials: N
authors.lastname: Yoshida
authors.forename: Aizu-Yokota
authors.initials: AY
authors.lastname: Eriko
authors.forename: Kasahara
authors.initials: K
authors.lastname: Tadashi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003609:Dactinomycin / Q000494:pharmacology*; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D051417:Focal Adhesion Kinase 1 / Q000235:genetics / Q000378:metabolism*; D047468:Immunoprecipitation; D020128:Inhibitory Concentration 50; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity*
chemical_list: D053418:Death Domain Receptor Signaling Adaptor Proteins; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D003609:Dactinomycin; D051417:Focal Adhesion Kinase 1; C496051:Ptk2 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D048670:MAP Kinase Kinase 4; D053148:Caspase 3; D053181:Caspase 8