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JBC Papers in Press. Published on May 4, 2015 as Manuscript M114. 635755

Ohkawa, Y;Momota, H;Kato, A;Hashimoto, N;Tsuda, Y;Kotani, N;Honke, K;Suzumura, A;Furukawa, K;Ohmi, Y;Natsume, A;Wakabayashi, T;Furukawa, K;

There have been a few studies on the ganglioside expression in human glioma tissues. However, the role of these gangliosides such as GD3 and GD2 has not been well understood. In this study, we employed a genetically engineered mouse model of glioma to clarify the functions of GD3 in gliomas. Forced expression of platelet-derived growth factor B (PDGFB) in cultured astrocytes derived from p53-deficient mice resulted in the expression of GD3 and GD2. GD3-positive astrocytes exhibited increased cell growth and invasion activities along with elevated phosphorylation of Akt and Yes kinase. By enzyme-mediated activation of radical sources (EMARS) reaction and mass spectrometry, we identified PDGF receptor alpha (PDGFR alpha) as a GD3-associated molecule. GD3-positive astrocytes showed significant amount of PDGFR alpha; in glycolipid-enriched microdomains (GEM)/rafts compared with GD3-negative cells. Src kinase family Yes was co-precipitated with PDGFR alpha;, and its pivotal role in the increased cell invasion of GD3-positive astrocytes was demonstrated by silencing with anti-Yes siRNA. Direct association between PDGFR alpha; and GD3 was also shown, suggesting that GD3 forms a ternary complex with PDGFR alpha; and Yes. The fact that GD3, PDGFR alpha; and activated Yes were colocalized in lamellipodia and edge of tumors in cultured cells and glioma tissues, respectively, suggest that GD3 induced by PDGFB enhances PDGF signals in GEM/rafts, leading to the promotion of malignant phenotypes such as cell invasion in gliomas. Copyright 2015, The American Society for Biochemistry and Molecular Biology.