GD3 synthase gene expression in PC12 cells results in the continuous activation of TrkA and ERK1/2 and enhanced proliferation.
A rat pheochromocytoma cell line (PC12) transfected with ganglioside GD3 synthase gene showed a marked change in the ganglioside profile and enhanced proliferation and no response of neurite extension to nerve growth factor (NGF) stimulation. In these transfectant cells, a continuous phosphorylation of TrkA and the activation of ERK1/2 without NGF treatment were observed. Proliferation inhibition experiments with kinase inhibitors such as herbimycin A, K-252a, and PD98059 revealed that the enhanced proliferation was actually due to the activation of the Ras/MEK/ERK pathway. A TrkA dimer was detected in the GD3 synthase transfectant cells regardless of NGF treatment by cross-linking and immunoblotting. The increased expression of GD1b and GT1b in these transfectant cells might induce the conformational change of TrkA to form a dimer and to be activated continuously. These results may indicate regulatory roles of gangliosides in cell proliferation under physiological and malignant processes.
Fukumoto
S
S
Department of Biochemistry II, Nagoya University School of Medicine, Nagoya 466-0065, Japan.
Mutoh
T
T
Hasegawa
T
T
Miyazaki
H
H
Okada
M
M
Goto
G
G
Furukawa
K
K
Urano
T
T
D000818:Animals; D015153:Blotting, Western; D002455:Cell Division; D003432:Cross-Linking Reagents / Q000494:pharmacology; D019281:Dimerization; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D005732:Gangliosides / Q000378:metabolism; D015870:Gene Expression; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D020932:Nerve Growth Factor / Q000494:pharmacology; D016501:Neurites / Q000187:drug effects; D016716:PC12 Cells; D010766:Phosphorylation; D051381:Rats; D020917:Receptor, trkA / Q000378:metabolism*; D012799:Sialyltransferases / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection
D003432:Cross-Linking Reagents; D004791:Enzyme Inhibitors; D005732:Gangliosides; D020932:Nerve Growth Factor; D012799:Sialyltransferases; C043662:alpha-N-acetylneuraminate alpha-2,8-sialyltransferase; D020917:Receptor, trkA; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases