Murray, D. W., Didier, S., Chan, A., Paulino, V., Van Aelst, L., Ruggieri, R., Tran, N. L., Byrne, A. T., Symons, M. (February 2014) Guanine nucleotide exchange factor Dock7 mediates HGF-induced glioblastoma cell invasion via Rac activation. British Journal of Cancer, 110 (5). pp. 1307-1315. ISSN 0007-0920
Abstract
Background:Glioblastoma multiforme (GBM), a highly invasive primary brain tumour, remains an incurable disease. Rho GTPases and their activators, guanine nucleotide exchange factors (GEFs), have central roles in GBM invasion. Anti-angiogenic therapies may stimulate GBM invasion via HGF/c-Met signalling. We aim to identify mediators of HGF-induced GBM invasion that may represent targets in a combination anti-angiogenic/anti-invasion therapeutic paradigm.Methods:Guanine nucleotide exchange factor expression was measured by microarray analysis and western blotting. Specific depletion of proteins was accomplished using siRNA. Cell invasion was determined using matrigel and brain slice assays. Cell proliferation and survival were monitored using sulforhodamine B and colony formation assays. Guanine nucleotide exchange factor and GTPase activities were determined using specific affinity precipitation assays.Results:We found that expression of Dock7, a GEF, is elevated in human GBM tissue in comparison with non-neoplastic brain. We showed that Dock7 mediates serum- and HGF-induced glioblastoma cell invasion. We also showed that Dock7 co-immunoprecipitates with c-Met and that this interaction is enhanced upon HGF stimulation in a manner that is dependent on the adaptor protein Gab1. Dock7 and Gab1 also co-immunoprecipitate in an HGF-dependent manner. Furthermore, Gab1 is required for HGF-induced Dock7 and Rac1 activation and glioblastoma cell invasion.Conclusions:Dock7 mediates HGF-induced GBM invasion. Targeting Dock7 in GBM may inhibit c-MET-mediated invasion in tumours treated with anti-angiogenic regimens.British Journal of Cancer advance online publication, 11 February 2014; doi:10.1038/bjc.2014.39 www.bjcancer.com.
| Item Type: | Paper |
|---|---|
| Subjects: | diseases & disorders > cancer diseases & disorders bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > Rac organs, tissues, organelles, cell types and functions > organs types and functions > brain bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types |
| CSHL Authors: | |
| Communities: | CSHL Cancer Center Program > Signal Transduction CSHL labs > Van Aelst lab CSHL Cancer Center Shared Resources > DNA Sequencing Service |
| Depositing User: | Matt Covey |
| Date: | 11 February 2014 |
| Date Deposited: | 21 Feb 2014 21:38 |
| Last Modified: | 04 Nov 2015 20:29 |
| PMCID: | PMC3950876 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/29541 |
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