Guanine nucleotide exchange factor Dock7 mediates HGF-induced glioblastoma cell invasion via Rac activation
Open accessAbstract
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.
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DOCK7 is upregulated in astrocytoma human glioblastoma compared with nonneoplastic brain.
“DOCK7-controlled migration can also be pathological; it was identified to be required for human hepatocyte growth factor (HGF)-induced glioblastoma tumor cell invasion, with upregulated DOCK7 found in astrocytoma human glioblastoma compared with nonneoplastic brain (108).”
From RHO to the DOCK for GDP disembarking: Structural insights into the DOCK GTPase nucleotide exchange factors (2021) · cites this paper as [108]
DOCK7 is required for human hepatocyte growth factor (HGF)-induced glioblastoma tumor cell invasion.
“DOCK7-controlled migration can also be pathological; it was identified to be required for human hepatocyte growth factor (HGF)-induced glioblastoma tumor cell invasion, with upregulated DOCK7 found in astrocytoma human glioblastoma compared with nonneoplastic brain (108).”
From RHO to the DOCK for GDP disembarking: Structural insights into the DOCK GTPase nucleotide exchange factors (2021) · cites this paper as [108]
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Cited by
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Thompson, A. P., Bitsina, C., Gray, J. L., von Delft, F., & Brennan, P. E. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.100521 · Cited by 21 · see citing works
“DOCK7-controlled migration can also be pathological; it was identified to be required for human hepatocyte growth factor (HGF)-induced glioblastoma tumor cell invasion, with upregulated DOCK7 found in astrocytoma human glioblastoma compared with nonneoplastic brain (108).”
Background
- Authors
- Murray, D. W., Didier, S., Chan, A., Paulino, V, Van Aelst, L., Ruggieri, R., Tran, N. L., Byrne, A. T., & Symons, M.
- Affiliations
- Northwell Health (US)
- Translational Genomics Research Institute (US)
- University College Dublin (IE)
- Corresponding author
- Symons, M
- Venue
- British Journal of Cancer
- Published
- 2014-02-11
- Volume
- 110
- Issue
- 5
- Pages
- 1307-1315
- ISSN
- 0007-0920 (ISSN-L)
- 1532-1827
- PMC
- PMC3950876
- OpenAlex
- W2018240980
- Cited by
- 39
- References
- 0
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 1 · 2023: 6 · 2022: 5 · 2021: 3 · 2020: 5 · 2019: 4 · 2018: 4 · 2017: 3 · 2016: 2 · 2015: 1 · 2014: 2
- FWCI
- 1.34
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc-sa
- www.springer.com/tdm (unspecified)
- Locations
- British Journal of Cancer (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
- Funders
- Health Research Board
- European Commission
- National Institutes of Health (5p30ca045508-35)
- National Institute of Mental Health (R01MH082808)
- National Cancer Institute (R01CA130940, P30-CA045508, P50CA108961)
- National Institute of Neurological Disorders and Stroke (R21NS060023)
- Topics
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cancer Mechanisms and Therapy
- Keywords
- DOCK7, guanine nucleotide exchange factor, glioblastoma, cell invasion, hepatocyte growth factor, c-Met, Gab1, Rac1 activation, Rho GTPases, anti-angiogenic therapy, tumor invasion
- MeSH terms
- Brain Neoplasms, Cell Movement, Cell Survival, Glioblastoma, Humans, Hepatocyte Growth Factor, Proto-Oncogene Proteins c-met, Angiogenesis Inhibitors, Guanine Nucleotide Exchange Factors, GTPase-Activating Proteins, rho GTP-Binding Proteins, rac1 GTP-Binding Protein, Cell Line, Tumor, Cell Growth Processes, Adaptor Proteins, Signal Transducing
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