Ganglioside GD3 Enhances Invasiveness of Gliomas by Forming a Complex with Platelet-derived Growth Factor Receptor α and Yes Kinase.
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 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 reaction and mass spectrometry, we identified PDGF receptor α (PDGFRα) as a GD3-associated molecule. GD3-positive astrocytes showed a significant amount of PDGFRα in glycolipid-enriched microdomains/rafts compared with GD3-negative cells. Src kinase family Yes was co-precipitated with PDGFRα, and its pivotal role in the increased cell invasion of GD3-positive astrocytes was demonstrated by silencing with anti-Yes siRNA. Direct association between PDGFRα and GD3 was also shown, suggesting that GD3 forms ternary complex with PDGFRα and Yes. The fact that GD3, PDGFRα, and activated Yes were colocalized in lamellipodia and the edge of tumors in cultured cells and glioma tissues, respectively, suggests that GD3 induced by platelet-derived growth factor B enhances PDGF signals in glycolipid-enriched microdomain/rafts, leading to the promotion of malignant phenotypes such as cell proliferation and invasion in gliomas.
From the Department of Biochemistry II, the Department of Neurosurgery, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, Nagoya 466-0065, Japan, the Department of Biomedical Sciences, Chubu University College of Life and Health Sciences, 1200 Matsumoto-cho, Kasugai 487-8501, Japan.
Yuki
Y
Ohkawa
the Department of Neurosurgery, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, Nagoya 466-0065, Japan.
Hiroyuki
H
Momota
the Department of Neurosurgery, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, Nagoya 466-0065, Japan.
Akira
A
Kato
From the Department of Biochemistry II.
Noboru
N
Hashimoto
From the Department of Biochemistry II.
Yusuke
Y
Tsuda
the Department of Biochemistry, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama-machi, Iruma-gun, Saitama 350-0495, Japan.
Norihiro
N
Kotani
the Department of Biochemistry, Kochi University Medical School, Kohasu, Okou-cho, Nankoku, Kochi 783-8505, Japan.
Koichi
K
Honke
the Department of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University, Furou-cho, Chikusa-ku, Nagoya 464-8601, Japan, and.
Akio
A
Suzumura
From the Department of Biochemistry II, the Department of Biomedical Sciences, Chubu University College of Life and Health Sciences, 1200 Matsumoto-cho, Kasugai 487-8501, Japan.
Keiko
K
Furukawa
From the Department of Biochemistry II.
Yuhsuke
Y
Ohmi
the Department of Neurosurgery, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, Nagoya 466-0065, Japan.
Atsushi
A
Natsume
the Department of Neurosurgery, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, Nagoya 466-0065, Japan.
Toshihiko
T
Wakabayashi
From the Department of Biochemistry II, the Department of Biomedical Sciences, Chubu University College of Life and Health Sciences, 1200 Matsumoto-cho, Kasugai 487-8501, Japan koichi@med.nagoya-u.ac.jp.
Koichi
K
Furukawa
D000818:Animals; D001932:Brain Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D005732:Gangliosides / Q000378:metabolism*; D005910:Glioma / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009361:Neoplasm Invasiveness; D011485:Protein Binding; D051575:Proto-Oncogene Proteins c-yes / Q000235:genetics / Q000378:metabolism*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics / Q000378:metabolism*
D005732:Gangliosides; C026226:ganglioside, GD3; D020796:Receptor, Platelet-Derived Growth Factor alpha; D051575:Proto-Oncogene Proteins c-yes; C496639:Yes1 protein, mouse
animal model; cell invasion; ganglioside; glioblastoma; invasion; lipid raft