PMID- 23775076 OWN - NLM STAT- MEDLINE DCOM- 20131104 LR - 20211021 IS - 1083-351X (Electronic) IS - 0021-9258 (Print) IS - 0021-9258 (Linking) VI - 288 IP - 30 DP - 2013 Jul 26 TI - 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. PG - 21887-97 LID - 10.1074/jbc.M113.468686 [doi] AB - 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. FAU - Fortin Ensign, Shannon P AU - Fortin Ensign SP AD - Cancer and Cell Biology Division, The Translational Genomics Research Institute, Phoenix, Arizona 85004, USA. FAU - Mathews, Ian T AU - Mathews IT FAU - Eschbacher, Jennifer M AU - Eschbacher JM FAU - Loftus, Joseph C AU - Loftus JC FAU - Symons, Marc H AU - Symons MH FAU - Tran, Nhan L AU - Tran NL LA - eng GR - P50 CA108961/CA/NCI NIH HHS/United States GR - R01 CA130940/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20130617 PL - United States TA - J Biol Chem JT - The Journal of biological chemistry JID - 2985121R RN - 0 (ARHGEF26 protein, human) RN - 0 (Cytokine TWEAK) RN - 0 (Guanine Nucleotide Exchange Factors) RN - 0 (RAC1 protein, human) RN - 0 (Receptors, Tumor Necrosis Factor) RN - 0 (TNF Receptor-Associated Factor 2) RN - 0 (TNFRSF12A protein, human) RN - 0 (TNFSF12 protein, human) RN - 0 (TWEAK Receptor) RN - 0 (Tumor Necrosis Factors) RN - 147605-13-8 (RHOG protein, human) RN - EC 3.6.5.2 (rac1 GTP-Binding Protein) RN - EC 3.6.5.2 (rho GTP-Binding Proteins) SB - IM MH - Blotting, Western MH - Cell Line, Tumor MH - Cell Movement/drug effects/*genetics MH - Cytokine TWEAK MH - Gene Expression Regulation, Neoplastic MH - Glioma/*genetics/metabolism/pathology MH - Guanine Nucleotide Exchange Factors/*genetics/metabolism MH - HEK293 Cells MH - Humans MH - Immunohistochemistry MH - Microscopy, Fluorescence MH - Neoplasm Invasiveness MH - Protein Binding/drug effects MH - Pseudopodia/genetics/metabolism MH - RNA Interference MH - Receptors, Tumor Necrosis Factor/*genetics/metabolism MH - Reverse Transcriptase Polymerase Chain Reaction MH - Signal Transduction/drug effects/genetics MH - TNF Receptor-Associated Factor 2/*genetics/metabolism MH - TWEAK Receptor MH - Tumor Necrosis Factors/pharmacology MH - rac1 GTP-Binding Protein/genetics/metabolism MH - rho GTP-Binding Proteins/genetics/metabolism PMC - PMC3724644 OTO - NOTNLM OT - Cell Invasion OT - Cell Signaling OT - Glioblastoma OT - Guanine Nucleotide Exchange Factor (GEF) OT - Rho GTPases EDAT- 2013/06/19 06:00 MHDA- 2013/11/05 06:00 PMCR- 2014/07/26 CRDT- 2013/06/19 06:00 PHST- 2013/06/19 06:00 [entrez] PHST- 2013/06/19 06:00 [pubmed] PHST- 2013/11/05 06:00 [medline] PHST- 2014/07/26 00:00 [pmc-release] AID - S0021-9258(20)45485-7 [pii] AID - M113.468686 [pii] AID - 10.1074/jbc.M113.468686 [doi] PST - ppublish SO - J Biol Chem. 2013 Jul 26;288(30):21887-97. doi: 10.1074/jbc.M113.468686. Epub 2013 Jun 17.