Abstract
The Fas/CD95 receptor mediates apoptosis but is also capable of triggering nonapoptotic signals. However, the mechanisms that selectively regulate these opposing effects are not yet fully understood. Here we demonstrate that the activation of Fas or stimulation with lysophosphatidic acid (LPA) induces cytoskeletal reorganization, leading to the association of Fas with actin stress fibers and the adaptor protein TRIP6. TRIP6 binds to the cytoplasmic juxtamembrane domain of Fas and interferes with the recruitment of FADD to Fas. Furthermore, through physical interactions with NF-κB p65, TRIP6 regulates nuclear translocation and the activation of NF-κB upon Fas activation or LPA stimulation. As a result, TRIP6 antagonizes Fas-induced apoptosis and further enhances the antiapoptotic effect of LPA in cells that express high levels of TRIP6. On the other hand, TRIP6 promotes Fas-mediated cell migration in apoptosis-resistant glioma cells. This effect is regulated via the Src-dependent phosphorylation of TRIP6 at Tyr-55. As TRIP6 is overexpressed in glioblastomas, this may have a significant impact on enhanced NF-κB activity, resistance to apoptosis, and Fas-mediated cell invasion in glioblastomas.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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ATPases Associated with Diverse Cellular Activities
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Actins / metabolism
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Active Transport, Cell Nucleus
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Adaptor Proteins, Signal Transducing / chemistry
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / physiology*
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Apoptosis / drug effects
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Apoptosis / genetics
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Apoptosis / physiology*
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Cell Line, Tumor
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Cell Movement / drug effects
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Cell Movement / genetics
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Cell Movement / physiology*
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Fas-Associated Death Domain Protein / genetics
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Fas-Associated Death Domain Protein / physiology
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Glioma / genetics
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Glioma / pathology
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Glioma / physiopathology
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HEK293 Cells
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Humans
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LIM Domain Proteins
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Lysophospholipids / pharmacology
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Models, Biological
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Neoplasm Invasiveness / genetics
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Neoplasm Invasiveness / physiopathology
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Phosphorylation
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Proteasome Endopeptidase Complex
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Signal Transduction
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Transcription Factor RelA / genetics
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Transcription Factor RelA / physiology
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Transcription Factors / chemistry
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Transcription Factors / genetics
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Transcription Factors / physiology*
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Tyrosine / chemistry
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fas Receptor / chemistry
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fas Receptor / genetics
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fas Receptor / physiology*
Substances
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Actins
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Adaptor Proteins, Signal Transducing
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FADD protein, human
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FAS protein, human
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Fas-Associated Death Domain Protein
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LIM Domain Proteins
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Lysophospholipids
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PSMC5 protein, human
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RELA protein, human
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Transcription Factor RelA
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Transcription Factors
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fas Receptor
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Tyrosine
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Proteasome Endopeptidase Complex
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ATPases Associated with Diverse Cellular Activities
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lysophosphatidic acid