Guanine nucleotide exchange factor Dock7 mediates HGF-induced glioblastoma cell invasion via Rac activation

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.

The Role of Rho GTPases in Motility and Invasion of Glioblastoma Cells

“…Of note is that DOCK1 also plays a central role in the aforementioned EGF-promoted EGFR-DOCK180/ELMO1-RAC1-MLK3-JNK signaling axis [66]. Additionally, DOCK 7 is reported to play a critical role in the invasive behavior of the glioblastoma and mediates Rac1 activation following HGF stimulation [90]. Another Rac GEF that promotes Rac1-mediated invasion in glioblastoma cells is PREX1, which is overexpressed in GBM and responds to the presence of the upregulated Pi3K pathway [91].…”

Glioma infiltration and extracellular matrix: key players and modulators

“…A proteome study has shown that Rac1 protein levels are increased in high‐grade (85%) versus low‐grade (20%) gliomas and correlate with poor survival (Iwadate, ; Salhia et al, ). Direct or indirect depletion of Rac1 significantly inhibits glioblastoma cell invasion (Chuang et al, ; Murray et al, ), indicating the importance of this GTPase in glioblastoma invasiveness.…”

Spontaneous mutation of Dock7 results in lower trabecular bone mass and impaired periosteal expansion in aged female Misty mice

“…Although, we did not find an increase in resorption at 52 wks dynamically or by bone turnover markers/gene expression in our study, it remains unclear whether higher SNS tone is responsible for the non-cell autonomous effects on bone with age in m/m [43]. In fact, Dock7 has been studied for its role in brain and nervous system [8, 9, 14, 18, 19, 44, 45], but it remains unclear if any of these alterations in the nervous system may affect bone development or remodeling. Propranolol treatment, a β2AR antagonist, has been shown to partially rescue m/m bone phenotype in young mice, suggesting that the SNS may indeed be contributing to bone loss in the m/m [4].…”