Department of Cell Biology, University of Alabama at Birmingham, Birmingham, Alabama 35294-0005, USA.
Mol Cell Biol. 2010 Dec;30(23):5582-96. doi: 10.1128/MCB.00134-10. Epub 2010 Sep 27.
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.
Fas/CD95 受体介导细胞凋亡，但也能够触发非凋亡信号。然而，选择性调节这些相反效应的机制尚不完全清楚。在这里，我们证明 Fas 的激活或溶血磷脂酸 (LPA) 的刺激诱导细胞骨架重排，导致 Fas 与肌动蛋白应力纤维和衔接蛋白 TRIP6 相关联。TRIP6 结合 Fas 的细胞质近膜域，并干扰 FADD 向 Fas 的募集。此外，通过与 NF-κB p65 的物理相互作用，TRIP6 调节 Fas 激活或 LPA 刺激时 NF-κB 的核易位和激活。结果，TRIP6 拮抗 Fas 诱导的细胞凋亡，并进一步增强在高表达 TRIP6 的细胞中 LPA 的抗凋亡作用。另一方面，TRIP6 促进 Fas 介导的在抗凋亡的神经胶质瘤细胞中的细胞迁移。这种效应通过 TRIP6 在 Tyr-55 处的Src 依赖性磷酸化来调节。由于 TRIP6 在神经胶质瘤中过表达，这可能对增强 NF-κB 活性、对凋亡的抗性以及 Fas 介导的神经胶质瘤细胞侵袭有重大影响。
