Abstract
Glioblastoma (GBM), the most aggressive primary brain tumors, are highly infiltrative. Although GBM express high Ras activity and Ras proteins have been implicated in gliomagenesis, Ras-activating mutations are not frequent in these tumors. RasGRP3, an important signaling protein responsive to diacylglycerol (DAG), increases Ras activation. Here, we examined the expression and functions of RasGRP3 in GBM and glioma cells. RasGRP3 expression was upregulated in GBM specimens and glioma stem cells compared with normal brains and neural stem cells, respectively. RasGRP3 activated Ras and Rap1 in glioma cells and increased cell migration and invasion partially via Ras activation. Using pull-down assay and mass spectroscopy we identified the actin-related protein, Arp3, as a novel interacting protein of RasGRP3. The interaction of RasGRP3 and Arp3 was validated by immunofluorescence staining and co-immunoprecipitation, and PMA, which activates RasGRP3 and induces its translocation to the peri-nuclear region, increased the association of Arp3 and RasGRP3. Arp3 was upregulated in GBM, regulated cell spreading and migration and its silencing partially decreased these effects of RasGRP3 in glioma cells. In summary, RasGRP3 acts as an important integrating signaling protein of the DAG and Ras signaling pathways and actin polymerization and represents an important therapeutic target in GBM.
Highlights
Glioblastoma (GBM), the most malignant of the primary brain tumors, are characterized by increased proliferation and invasion into the surrounding normal brain tissue [1]
Gene expression profiling has identified five GBM subtypes, which are classified based on their www.impactjournals.com/oncotarget pathways coupled to DAG generation are highly active in glioma, mainly downstream of activated epidermal growth factor (EGF) and platelet-derived growth factor (PDGF)
We found that GBM tumors expressed RasGRP3 mRNA
Summary
Glioblastoma (GBM), the most malignant of the primary brain tumors, are characterized by increased proliferation and invasion into the surrounding normal brain tissue [1]. Understanding the mechanisms that regulate glioma cell migration is crucial for the development of novel effective interventions. Gene expression profiling has identified five GBM subtypes, which are classified based on their www.impactjournals.com/oncotarget pathways coupled to DAG generation are highly active in glioma, mainly downstream of activated epidermal growth factor (EGF) and platelet-derived growth factor (PDGF). While the different RasGRP proteins generally share similar mechanisms of regulation, they exhibit distinct patterns of tissue expression and specificity for Ras and Rap GTPases [12, 14,15,16]. The role of the RasGRP proteins in carcinogenesis and malignant transformation is just beginning to be understood. Recent studies have reported that RasGRPs can function as oncogenes in multiple cancers, inducing tumorigenesis in both mouse models and in humans [17,18,19], Elevated
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