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Start Over Author "Symons MH" Topic cell movement
2 results on '"Symons MH"'

1. 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.

Author

Fortin Ensign SP, Mathews IT, Eschbacher JM, Loftus JC, Symons MH, and Tran NL

Subjects
Blotting, Western, Cell Line, Tumor, Cell Movement drug effects, Cytokine TWEAK, Gene Expression Regulation, Neoplastic, Glioma metabolism, Glioma pathology, Guanine Nucleotide Exchange Factors metabolism, HEK293 Cells, Humans, Immunohistochemistry, Microscopy, Fluorescence, Neoplasm Invasiveness, Protein Binding drug effects, Pseudopodia genetics, Pseudopodia metabolism, RNA Interference, Receptors, Tumor Necrosis Factor metabolism, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction drug effects, Signal Transduction genetics, TNF Receptor-Associated Factor 2 metabolism, TWEAK Receptor, Tumor Necrosis Factors pharmacology, rac1 GTP-Binding Protein genetics, rac1 GTP-Binding Protein metabolism, rho GTP-Binding Proteins genetics, rho GTP-Binding Proteins metabolism, Cell Movement genetics, Glioma genetics, Guanine Nucleotide Exchange Factors genetics, Receptors, Tumor Necrosis Factor genetics, TNF Receptor-Associated Factor 2 genetics
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.

Published
2013
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2. Modulation of Rac localization and function by dynamin.

Author

Schlunck G, Damke H, Kiosses WB, Rusk N, Symons MH, Waterman-Storer CM, Schmid SL, and Schwartz MA

Subjects
Animals, Cell Adhesion physiology, Cells, Cultured, Dynamin II drug effects, Dynamin II physiology, Fibronectins metabolism, Fluorescence Resonance Energy Transfer, Mice, Mutation, NIH 3T3 Cells, Protein Serine-Threonine Kinases physiology, Proto-Oncogene Proteins c-akt, RNA, Small Interfering pharmacology, Rats, Recombinant Fusion Proteins drug effects, Recombinant Fusion Proteins metabolism, Recombinant Fusion Proteins physiology, Cell Movement physiology, Dynamin II metabolism, Protein Serine-Threonine Kinases metabolism, Pseudopodia metabolism
Abstract

The GTPase dynamin controls a variety of endocytic pathways, participates in the formation of phagosomes, podosomal adhesions, and invadopodia, and in regulation of the cytoskeleton and apoptosis. Rac, a member of the Rho family of small GTPases, controls formation of lamellipodia and focal complexes, which are critical in cell migration and phagocytosis. We now show that disruption of dynamin(-2) function alters Rac localization and inhibits cell spreading and lamellipodia formation even though Rac is activated. Dominant-negative K44A dynamin(-2) inhibited cell spreading and lamellipodia formation on fibronectin without blocking cell adhesion; dynamin(-2) depletion by specific small interfering RNA inhibited lamellipodia in a similar manner. Dyn2(K44A) induced Rac mislocalization away from cell edges, into abnormal dorsal ruffles, and led to increased total Rac activity. Fluorescence resonance energy transfer imaging of Rac activity confirmed its predominant localization to aberrant dorsal ruffles in the presence of dominant-negative dyn2(K44A). Dyn2(K44A) induced the accumulation of tubulated structures bearing membrane-bound Rac-GFP. Constitutively active but not wild-type GFP-Rac was found on macropinosomes and Rac-dependent, platelet-derived growth factor-induced macropinocytosis was abolished by Dyn2(K44A) expression. These data suggest an indispensable role of dynamin in Rac trafficking to allow for lamellipodia formation and cell spreading.

Published
2004
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