title: The Src homology 3 domain-containing guanine nucleotide exchange factor is overexpressed in high-grade gliomas and promotes tumor necrosis factor-like weak inducer of apoptosis-fibroblast growth factor-inducible 14-induced cell migration and invasion via tumor necrosis factor receptor-associated factor 2.
abstract: Glioblastoma (GB) is the highest grade of primary adult brain tumors, characterized by a poorly defined and highly invasive cell population. Importantly, these invading cells are attributed with having a decreased sensitivity to radiation and chemotherapy. TNF-like weak inducer of apoptosis (TWEAK)-Fn14 ligand-receptor signaling is one mechanism in GB that promotes cell invasiveness and survival and is dependent upon the activity of multiple Rho GTPases, including Rac1. Here we report that Src homology 3 domain-containing guanine nucleotide exchange factor (SGEF), a RhoG-specific guanine nucleotide exchange factor, is overexpressed in GB tumors and promotes TWEAK-Fn14-mediated glioma invasion. Importantly, levels of SGEF expression in GB tumors inversely correlate with patient survival. SGEF mRNA expression is increased in GB cells at the invasive rim relative to those in the tumor core, and knockdown of SGEF expression by shRNA decreases glioma cell migration in vitro and invasion ex vivo. Furthermore, we showed that, upon TWEAK stimulation, SGEF is recruited to the Fn14 cytoplasmic tail via TRAF2. Mutation of the Fn14-TRAF domain site or depletion of TNF receptor-associated factor 2 (TRAF2) expression by siRNA oligonucleotides blocked SGEF recruitment to Fn14 and inhibited SGEF activity and subsequent GB cell migration. We also showed that knockdown of either SGEF or RhoG diminished TWEAK activation of Rac1 and subsequent lamellipodia formation. Together, these results indicate that SGEF-RhoG is an important downstream regulator of TWEAK-Fn14-driven GB cell migration and invasion.
authors.affiliation: Cancer and Cell Biology Division, The Translational Genomics Research Institute, Phoenix, Arizona 85004, USA.
authors.forename: Shannon P
authors.initials: SP
authors.lastname: Fortin Ensign
authors.forename: Ian T
authors.initials: IT
authors.lastname: Mathews
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Eschbacher
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Loftus
authors.forename: Marc H
authors.initials: MH
authors.lastname: Symons
authors.forename: Nhan L
authors.initials: NL
authors.lastname: Tran
mesh_terms: D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics*; D000074049:Cytokine TWEAK; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry; D008856:Microscopy, Fluorescence; D009361:Neoplasm Invasiveness; D011485:Protein Binding / Q000187:drug effects; D011554:Pseudopodia / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D047992:TNF Receptor-Associated Factor 2 / Q000235:genetics* / Q000378:metabolism; D000074050:TWEAK Receptor; D048069:Tumor Necrosis Factors / Q000494:pharmacology; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C473930:ARHGEF26 protein, human; D000074049:Cytokine TWEAK; D020662:Guanine Nucleotide Exchange Factors; C107953:RAC1 protein, human; D018124:Receptors, Tumor Necrosis Factor; D047992:TNF Receptor-Associated Factor 2; C000613297:TNFRSF12A protein, human; C109743:TNFSF12 protein, human; D000074050:TWEAK Receptor; D048069:Tumor Necrosis Factors; C075397:RHOG protein, human; D020830:rac1 GTP-Binding Protein; D020741:rho GTP-Binding Proteins
keywords: Cell Invasion; Cell Signaling; Glioblastoma; Guanine Nucleotide Exchange Factor (GEF); Rho GTPases