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-B p65, TRIP6 regulates nuclear translocation and the activation of NF-B 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-B activity, resistance to apoptosis, and Fasmediated cell invasion in glioblastomas.The Fas/CD95/Apo-1 death receptor is a tumor necrosis factor (TNF) receptor superfamily member that mediates apoptosis important for development, immune responses, and tumor surveillance (34,37,41). Fas binds to Fas ligand (FasL) on the cell surface and induces the formation of the death-inducing signaling complex (DISC) by recruiting FADD (Fas-associated death domain-containing protein) and procaspase-8 and -10, which activate downstream effector caspases and commit cells to apoptosis (4,7,18,29,35). Although the main function of Fas is traditionally considered proapoptotic, Fas is also capable of triggering nonapoptotic functions by activating NF-B and mitogen-activated protein (MAP) kinase signaling pathways, leading to cell survival, proliferation, differentiation, and/or tissue regeneration (1,10,25,34). Moreover, the activation of Fas induces tumor growth and invasiveness in apoptosis-resistant tumor cells (2, 6). It was reported that FasLstimulated glioma tumor invasion is regulated via the Fas-mediated recruitment of Yes and the PI3K (phosphatidylinositol 3-kinase) p85 subunit (20), providing evidence that in addition to forming the Fas-FADD death domain (DD) complex, Fas can also recruit other signaling molecules to mediate diverse nonapoptotic effects. In this regard, we have found a novel link between Fas and the adaptor protein TRIP6 (thyroid hormone receptor-interacting protein 6).TRIP6 is a zyxin-related focal adhesion molecule (28). Through the three LIM domains, a PDZ-binding motif, a Crk SH2-binding motif, and/or other protein-interacting domains, TRIP6 serves as a platform for the recruitment of a number of molecules involved in actin assembly, cell motility, survival, and transcriptional control (5,9,13,17,21,23,42,46,47,49).The function of TRIP6 in cell motility is regulated by Srcdependent phosphorylation at ...

Thyroid hormone receptor interacting protein 6 (TRIP6), also known as zyxin-related protein-1 (ZRP-1), is an adaptor protein that belongs to the zyxin family of LIM proteins. TRIP6 is primarily localized in the cytosol or focal adhesion plaques, and may associate with the actin cytoskeleton. Additionally, it is capable of shuttling to the nucleus to serve as a transcriptional coregulator. Structural and functional analyses have revealed that through multidomain-mediated protein-protein interactions, TRIP6 serves as a platform for the recruitment of a wide variety of signaling molecules involved in diverse cellular responses, such as actin cytoskeletal reorganization, cell adhesion and migration, antiapoptotic signaling, osteoclast sealing zone formation and transcriptional control. Although the physiological functions of TRIP6 remain largely unknown, it has been implicated in cancer progression and telomere protection. Together, these studies suggest that TRIP6 plays multifunctional roles in different cellular responses, and thus may represent a novel target for therapeutic intervention.

TRIP6 is an adaptor protein that regulates cell motility and antiapoptotic signaling. Although it has been implicated in tumorigenesis, the underlying mechanism remains largely unknown. Here we provide evidence that TRIP6 promotes tumorigenesis by serving as a bridge to promote the recruitment of p27 KIP1 to AKT in the cytosol. TRIP6 regulates the membrane translocation and activation of AKT and facilitates AKT-mediated recognition and phosphorylation of p27 KIP1 specifically at T157, thereby promoting the cytosolic mislocalization of p27 KIP1 . This is required for p27 KIP1 to enhance lysophosphatidic acid (LPA)-induced ovarian cancer cell migration. TRIP6 also promotes serum-induced reduction of nuclear p27 KIP1 expression levels through Skp2-dependent and -independent mechanisms. Consequently, knockdown of TRIP6 in glioblastoma or ovarian cancer xenografts restores nuclear p27 KIP1 expression and impairs tumor proliferation. As TRIP6 is upregulated in gliomas and its levels correlate with poor clinical outcomes in a dose-dependent manner, it may represent a novel prognostic marker and therapeutic target in gliomas.T hyroid hormone receptor-interacting protein 6 (TRIP6) is a zyxin-related adaptor protein and focal adhesion molecule (1). Through its three LIM domains, PDZ-binding motif, Crk SH2-binding motif, and several putative SH3-binding domains, TRIP6 associates with a variety of molecules from the cell surface to the nucleus to regulate actin reorganization, focal adhesion assembly/disassembly, cell migration/invasion, antiapoptotic signaling, and transcriptional control. Notably, TRIP6 binds to lysophophatidic acid (LPA) receptor 2 (LPA 2 ) and the Fas/CD95 receptor to promote LPA-and Fas ligand-induced cell migration in a c-Src-dependent manner (2-4). TRIP6 can also regulate prosurvival signaling via activation of NF-B, extracellular signal-regulated kinase (ERK), and phosphatidylinositol 3-kinase (PI3K)/ AKT (3, 5), and nuclear TRIP6 acts as a transcriptional coregulator of AP-1 and NF-B (6). These data suggest that TRIP6 functions at a point of convergence of multiple signaling pathways critical for cancer development.We recently showed that TRIP6 is overexpressed in glioblastomas (3). By analyzing the survival of glioma patients, we found that the increased expression level of TRIP6 correlates significantly with poor clinical outcomes. Although these findings implicate a role for TRIP6 in cancer progression, the precise function of TRIP6 in tumorigenesis remains largely unknown. To address this issue, we examined the effect of TRIP6 knockdown on the proliferation of glioblastoma and ovarian cancer cell lines that express TRIP6 at high levels. These studies reveal a novel role for TRIP6 in tumorigenesis by promoting the loss of nuclear p27 KIP1

Small cell lung cancer (SCLC) accounts for approximately 15% of all lung cancers and demands effective targeted therapeutic strategies. In this meta-analysis study, we aim to identify significantly mutated genes and regulatory pathways to help us better understand the progression of SCLC and to identify potential biomarkers. Besides ranking genes based on their mutation frequencies, we sought to identify statistically significant mutations in SCLC with the MutSigCV software. Our analysis identified several genes with relatively low mutation frequency, including PTEN, as highly significant (p<0.001), suggesting these genes may play an important role in the progression of SCLC. Our results also indicated mutations in genes involved in the axon guidance pathways likely play an important role in SCLC progression. In addition, we observed that the mutation rate was significantly higher in samples with RB1 gene mutated when compared to samples with wild type RB1, suggesting that RB1 status has significant impact on the mutation profile and disease progression in SCLC.