RasGRP3 regulates the migration of glioma cells via interaction with Arp3
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Hae Kyung Lee1,2, Susan Finniss1,2, Simona Cazacu1,2, Cunli Xiang1,2, Laila M. Poisson2,3, Peter M. Blumberg4, Chaya Brodie1,2,5
1Davidson Laboratory of Cell Signaling and Tumorigenesis, Department of Neurosurgery, Hermelin Brain Tumor Center, Henry Ford Hospital, Detroit, MI, USA
2Hermelin Brain Tumor Center, Henry Ford Hospital, Detroit, MI, USA
3Department of Public Health Sciences, Center for Bioinformatics, Henry Ford Hospital, Detroit, MI, USA
4Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
5Everard and Mina Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel
Chaya Brodie, e-mail: [email protected]
Received: July 07, 2014 Accepted: October 06, 2014 Published: February 11, 2015
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.
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