Tes, a Specific Mena Interacting Partner, Breaks the Rules for EVH1 Binding

Cell Motility Laboratory, Cancer Research UK, London Research Institute, 44 Lincoln's Inn Fields, London, WC2A 3PX, UK.
Molecular Cell (Impact Factor: 14.02). 01/2008; 28(6):1071-82. DOI: 10.1016/j.molcel.2007.10.033
Source: PubMed


The intracellular targeting of Ena/VASP family members is achieved via the interaction of their EVH1 domain with FPPPP sequence motifs found in a variety of cytoskeletal proteins, including lamellipodin, vinculin, and zyxin. Here we show that the LIM3 domain of Tes, which lacks the FPPPP motif, binds to the EVH1 domain of Mena, but not to those of VASP or Evl. The structure of the LIM3:EVH1 complex reveals that Tes occludes the FPPPP-binding site and competes with FPPPP-containing proteins for EVH1 binding. Structure-based gain-of-function experiments define the molecular basis for the specificity of the Tes-Mena interaction. Consistent with in vitro observations, the LIM3 domain displaces Mena, but not VASP, from the leading edge and focal adhesions. It also regulates cell migration through a Mena-dependent mechanism. Our observations identify Tes as an atypical EVH1 binding partner and a regulator specific to a single Ena/VASP family member.

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Available from: David Christopher Briggs, Oct 04, 2015
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    • "TES tumor suppressor gene was first described in 2001 as a gene located on the human chromosome 7q31.1 that encodes a 421-amino acid protein localized in the cell-cell contact areas, with a role in focal cellular adhesion; its upregulation reduced the tumor growth in case of ovarian and cervical carcinoma cell lines [38, 39]. To produce actin assembly, TES interacts with zyxin, similar to Mena protein [39], but not with VASP protein [40], although VASP and Mena seem to share similar cellular localization and functions [31]. Based on these observations, Boëda et al. suggested that TES can be attached to Mena and block its interactions, resulting in inhibition of tumor cells invasion in a Mena-dependent mechanism [40]. "
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    ABSTRACT: The Ena/VASP (enabled/vasodilator stimulated phosphoprotein) family includes the binding actin proteins such as mammalian Ena (Mena), VASP, and Ena-VASP-like. It is known that the perturbation of actin cycle could determine alteration in the mobility of cells and in consequence of organogenesis. Few recent studies have revealed that Mena protein could play a role in breast or pancreatic carcinogenesis. Based on our researches, we observed that the intensity of Mena expression increased from premalignant to malignant lesions in some organs such as large bowel, stomach, cervix, and salivary glands. These findings prove that Mena could be a marker of premalignant epithelial lesions. In premalignant lesions, it could be helpful to define more accurately the risk for malignant transformation. In malignant tumors, correlation of expression of its splice variants could indicate metastatic behavior. In conclusion, we consider that it is necessary to analyze the expression of Mena splice variants in a higher number of cases, in different epithelial lesions, and also in experimental studies to define its exact role in carcinogenesis and also its possible prognostic and predictive values.
    07/2013; 2013(3):365192. DOI:10.1155/2013/365192
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    • "One molecular explanation for this could be the sustained expression of CDKN1C and TES within the mesodermal progenitors. CDKN1C and TES are known regulators of cell cycle and cell motility, respectively (Pateras et al. 2006; Boeda et al. 2007), and we demonstrated that knockdown of TES in M-iG7 cells reduces their motility in vitro (Supplemental Fig. 4C). In NS-like cells derived from the GiPSCs, expression of CDKN1C and TES were not sustained despite removal of DNA hypermethylation. "
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    ABSTRACT: Epigenetic changes are frequently observed in cancer. However, their role in establishing or sustaining the malignant state has been difficult to determine due to the lack of experimental tools that enable resetting of epigenetic abnormalities. To address this, we applied induced pluripotent stem cell (iPSC) reprogramming techniques to invoke widespread epigenetic resetting of glioblastoma (GBM)-derived neural stem (GNS) cells. GBM iPSCs (GiPSCs) were subsequently redifferentiated to the neural lineage to assess the impact of cancer-specific epigenetic abnormalities on tumorigenicity. GiPSCs and their differentiating derivatives display widespread resetting of common GBM-associated changes, such as DNA hypermethylation of promoter regions of the cell motility regulator TES (testis-derived transcript), the tumor suppressor cyclin-dependent kinase inhibitor 1C (CDKN1C; p57KIP2), and many polycomb-repressive complex 2 (PRC2) target genes (e.g., SFRP2). Surprisingly, despite such global epigenetic reconfiguration, GiPSC-derived neural progenitors remained highly malignant upon xenotransplantation. Only when GiPSCs were directed to nonneural cell types did we observe sustained expression of reactivated tumor suppressors and reduced infiltrative behavior. These data suggest that imposing an epigenome associated with an alternative developmental lineage can suppress malignant behavior. However, in the context of the neural lineage, widespread resetting of GBM-associated epigenetic abnormalities is not sufficient to override the cancer genome.
    Genes & development 03/2013; 27(6):654-69. DOI:10.1101/gad.212662.112 · 10.80 Impact Factor
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    • "Through Tag-seq expression profiling of normal and cancer stem cells followed by qRT-PCR validation in a wider panel of 22 cell lines, we identified 29 genes strongly discriminating GNS from NS cells. Some of these genes have previously been implicated in glioma, including four with a role in adhesion and/or migration, CD9, ST6GALNAC5, SYNM and TES [49-52], and two transcriptional regulators, FOXG1 and CEBPB. FOXG1, which has been proposed to act as an oncogene in glioblastoma by suppressing growth-inhibitory effects of transforming growth factor β [53], showed remarkably strong expression in all 16 GNS cell lines assayed by qRT-PCR. "
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    ABSTRACT: Background Glioblastoma multiforme, the most common type of primary brain tumor in adults, is driven by cells with neural stem (NS) cell characteristics. Using derivation methods developed for NS cells, it is possible to expand tumorigenic stem cells continuously in vitro. Although these glioblastoma-derived neural stem (GNS) cells are highly similar to normal NS cells, they harbor mutations typical of gliomas and initiate authentic tumors following orthotopic xenotransplantation. Here, we analyzed GNS and NS cell transcriptomes to identify gene expression alterations underlying the disease phenotype. Methods Sensitive measurements of gene expression were obtained by high-throughput sequencing of transcript tags (Tag-seq) on adherent GNS cell lines from three glioblastoma cases and two normal NS cell lines. Validation by quantitative real-time PCR was performed on 82 differentially expressed genes across a panel of 16 GNS and 6 NS cell lines. The molecular basis and prognostic relevance of expression differences were investigated by genetic characterization of GNS cells and comparison with public data for 867 glioma biopsies. Results Transcriptome analysis revealed major differences correlated with glioma histological grade, and identified misregulated genes of known significance in glioblastoma as well as novel candidates, including genes associated with other malignancies or glioma-related pathways. This analysis further detected several long non-coding RNAs with expression profiles similar to neighboring genes implicated in cancer. Quantitative PCR validation showed excellent agreement with Tag-seq data (median Pearson r = 0.91) and discerned a gene set robustly distinguishing GNS from NS cells across the 22 lines. These expression alterations include oncogene and tumor suppressor changes not detected by microarray profiling of tumor tissue samples, and facilitated the identification of a GNS expression signature strongly associated with patient survival (P = 1e-6, Cox model). Conclusions These results support the utility of GNS cell cultures as a model system for studying the molecular processes driving glioblastoma and the use of NS cells as reference controls. The association between a GNS expression signature and survival is consistent with the hypothesis that a cancer stem cell component drives tumor growth. We anticipate that analysis of normal and malignant stem cells will be an important complement to large-scale profiling of primary tumors.
    Genome Medicine 10/2012; 4(10):76. DOI:10.1186/gm377 · 5.34 Impact Factor
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