title: Tax-interacting protein 1 coordinates the spatiotemporal activation of Rho GTPases and regulates the infiltrative growth of human glioblastoma.
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.
authors.affiliation: 1] Department of Radiation Oncology, Vanderbilt University School of Medicine, Nashville, TN, USA [2] Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: H
authors.initials: H
authors.lastname: Wang
authors.affiliation: 1] Department of Radiation Oncology, Vanderbilt University School of Medicine, Nashville, TN, USA [2] Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Science, Kunming, China [3] Graduate School, Chinese Academy of Sciences, Beijing, China.
authors.forename: M
authors.initials: M
authors.lastname: Han
authors.affiliation: Department of Pathology, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: W
authors.initials: W
authors.lastname: Whetsell
authors.affiliation: 1] Department of Neurological Surgery, Vanderbilt University School of Medicine, Nashville, TN, USA [2] Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: J
authors.initials: J
authors.lastname: Rich
authors.affiliation: Department of Radiation Oncology, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: D
authors.initials: D
authors.lastname: Hallahan
authors.affiliation: 1] Department of Radiation Oncology, Vanderbilt University School of Medicine, Nashville, TN, USA [2] Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, USA [3] Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Han
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001932:Brain Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D004789:Enzyme Activation; D005260:Female; D019204:GTP-Binding Proteins; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D005909:Glioblastoma / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D058990:Molecular Targeted Therapy; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D011379:Prognosis; D021381:Protein Transport; D064067:Rho Guanine Nucleotide Exchange Factors / Q000378:metabolism; D062211:Spatio-Temporal Analysis; D051176:beta Catenin / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism*
chemical_list: C576606:ARHGEF7 protein, human; D051017:Apoptosis Regulatory Proteins; D047908:Intracellular Signaling Peptides and Proteins; C100494:RTKN protein, human; D064067:Rho Guanine Nucleotide Exchange Factors; C421249:TAX1BP3 protein, human; D051176:beta Catenin; D019204:GTP-Binding Proteins; D020741:rho GTP-Binding Proteins
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