The Adaptor Protein TRIP6 Antagonizes Fas-Induced Apoptosis but Promotes Its Effect on Cell Migration

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.

We thank Tim Townes for providing the pDL171 expression vector and Susan Nozell for the NF-κB p65 expression plasmid.

This work was supported by NIH grant NS066332 (F.-T.L.), the Southeastern Brain Tumor Foundation (F.-T.L.), and the NCI CA13148-35 UAB Comprehensive Cancer Center collaborative programmatic development grant (E.N.B. and F.-T.L.). Y.-J.L. is a recipient of a UAB Brain Tumor Training Program postdoctoral fellowship (NIH T32-NS48039).

We declare that we have no conflicts of interest.