Cdc42 and the guanine nucleotide exchange factors Ect2 and trio mediate Fn14-induced migration and invasion of glioblastoma cells

• Published in: Molecular cancer research 2012-07, Vol.10 (7), p.958-968
• Main Authors: Fortin, Shannon P, Ennis, Matthew J, Schumacher, Cassie A, Zylstra-Diegel, Cassandra R, Williams, Bart O, Ross, Julianna T D, Winkles, Jeffrey A, Loftus, Joseph C, Symons, Marc H, Tran, Nhan L
• Format: Article
• Language: English
• Subjects: Animals; Astrocytoma - genetics; Astrocytoma - metabolism; cdc42 GTP-Binding Protein - genetics; cdc42 GTP-Binding Protein - metabolism; Cell Movement - genetics; Cytokine TWEAK; Glioblastoma - genetics; Glioblastoma - metabolism; Guanine Nucleotide Exchange Factors - metabolism; Humans; Mice; Neoplasm Invasiveness - genetics; Neuropeptides - metabolism; Phosphoproteins - metabolism; Protein-Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; rac GTP-Binding Proteins - metabolism; rac1 GTP-Binding Protein; Receptors, Tumor Necrosis Factor - genetics; Receptors, Tumor Necrosis Factor - metabolism; Signal Transduction; Tumor Necrosis Factors - pharmacology; TWEAK Receptor
• ISSN: 1541-7786; 1557-3125
• DOI: 10.1158/1541-7786.mcr-11-0616

Malignant glioblastomas are characterized by their ability to infiltrate into normal brain. We previously reported that binding of the multifunctional cytokine TNF-like weak inducer of apoptosis (TWEAK) to its receptor fibroblast growth factor-inducible 14 (Fn14) induces glioblastoma cell invasion via Rac1 activation. Here, we show that Cdc42 plays an essential role in Fn14-mediated activation of Rac1. TWEAK-treated glioma cells display an increased activation of Cdc42, and depletion of Cdc42 using siRNA abolishes TWEAK-induced Rac1 activation and abrogates glioma cell migration and invasion. In contrast, Rac1 depletion does not affect Cdc42 activation by Fn14, showing that Cdc42 mediates TWEAK-stimulated Rac1 activation. Furthermore, we identified two guanine nucleotide exchange factors (GEF), Ect2 and Trio, involved in TWEAK-induced activation of Cdc42 and Rac1, respectively. Depletion of Ect2 abrogates both TWEAK-induced Cdc42 and Rac1 activation, as well as subsequent TWEAK-Fn14-directed glioma cell migration and invasion. In contrast, Trio depletion inhibits TWEAK-induced Rac1 activation but not TWEAK-induced Cdc42 activation. Finally, inappropriate expression of Fn14 or Ect2 in mouse astrocytes in vivo using an RCAS vector system for glial-specific gene transfer in G-tva transgenic mice induces astrocyte migration within the brain, corroborating the in vitro importance of the TWEAK-Fn14 signaling cascade in glioblastoma invasion. Our results suggest that the TWEAK-Fn14 signaling axis stimulates glioma cell migration and invasion through two GEF-GTPase signaling units, Ect2-Cdc42 and Trio-Rac1. Components of the Fn14-Rho GEF-Rho GTPase signaling pathway present innovative drug targets for glioma therapy.