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Tax-interacting protein 1 coordinates the spatiotemporal activation of Rho GTPases and regulates the infiltrative growth of human glioblastoma

Oncogene volume 33, pages 1558–1569 (2014)Cite this article

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Abstract

PDZ domains represent one group of the major structural units that mediate protein interactions in intercellular contact, signal transduction and assembly of biological machineries. Tax-interacting protein (TIP)-1 protein is composed of a single PDZ domain that distinguishes TIP-1 from other PDZ domain proteins that more often contain multiple protein domains and function as scaffolds for protein complex assembly. However, the biological functions of TIP-1, especially in cell transformation and tumor progression, are still controversial as observed in a variety of cell types. In this study, we have identified ARHGEF7, a guanine nucleotide exchange factor for Rho GTPases, as one novel TIP-1-interacting protein in human glioblastoma cells. We found that the presence of TIP-1 protein is essential to the intracellular redistribution of ARHGEF7 and rhotekin, one Rho effector and the spatiotemporally coordinated activation of Rho GTPases (RhoA, Cdc42 and Rac1) in migrating glioblastoma cells. TIP-1 knockdown resulted in both aberrant localization of ARHGEF7 and rhotekin, as well as abnormal activation of Rho GTPases that was accompanied with impaired motility of glioblastoma cells. Furthermore, TIP-1 knockdown suppressed tumor cell dispersal in orthotopic glioblastoma murine models. We also observed high levels of TIP-1 expression in human glioblastoma specimens, and the elevated TIP-1 levels are associated with advanced staging and poor prognosis in glioma patients. Although more studies are needed to further dissect the mechanism(s) by which TIP-1 modulates the intracellular redistribution and activation of Rho GTPases, this study suggests that TIP-1 holds potential as both a prognostic biomarker and a therapeutic target of malignant gliomas.

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Acknowledgements

We thank Drs Barbara Fingleton, Steven K Hanks and Mike Freeman (Vanderbilt) for critical reading and discussions of this manuscript. We are grateful to Dr Paul A Welling at University of Maryland for the kind gift of TIP-1-expressing constructs. We appreciate the technical assistance and advices from Dr Ling Geng (Pathology, Vanderbilt University) in the animal studies, Dr Heping Yan (Washington University at St Louis) in the antibody development, Dr Bret Mobley (Pathology, Vanderbilt University) in the microscopic examination of tissue blocks and the technical staffs at the Cell Imaging, Histology and Genomics Cores of the Vanderbilt-Ingram Cancer Center. This study was supported in part by NIH Grants R01CA127482 (Z Han), P50 CA128323 (Gore) and R01CA112385 (DE Hallahan).

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Authors and Affiliations

  1. Department of Radiation Oncology, Vanderbilt University School of Medicine, Nashville, TN, USA

    H Wang, M Han & Z Han

  2. Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, USA

    H Wang & Z Han

  3. Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Science, Kunming, China

    M Han

  4. Graduate School, Chinese Academy of Sciences, Beijing, China

    M Han

  5. Department of Pathology, Vanderbilt University School of Medicine, Nashville, TN, USA

    W Whetsell Jr

  6. Department of Neurological Surgery, Vanderbilt University School of Medicine, Nashville, TN, USA

    J Wang

  7. Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA

    J Wang & Z Han

  8. Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA

    J Rich

  9. Department of Radiation Oncology, Washington University School of Medicine, St Louis, MO, USA

    D Hallahan

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  1. H Wang
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Correspondence to Z Han.

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Wang, H., Han, M., Whetsell, W. et al. Tax-interacting protein 1 coordinates the spatiotemporal activation of Rho GTPases and regulates the infiltrative growth of human glioblastoma. Oncogene 33, 1558–1569 (2014). https://doi.org/10.1038/onc.2013.97

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