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Papers In Press, published online ahead of print May 15, 2004
Department of Biochemistry II, Nagoya University School of Medicine, Nagoya 466-0065
Corresponding Author: koichi{at}med.nagoya-u.ac.jp
Ganglioside GM1 has been considered to have a neurotrohic factor-like activity. To analyse the effects of endogenously-generated GM1, a rat pheochromocytoma cell line PC12 was transfected with GM1/GD1b/GA1 synthase gene, and showed increased expression levels of GM1. To our surprise, GM1+-transfectant cells (GM1+-cells) showed no neurite formation after stimulation with nerve growth factor (NGF). Auto-phosphorylation of NGF receptor TrkA and activation of ERK1/2 after NGF treatment were scarcely detected in GM1+-cells. Binding of 125I-NGF to PC12 cells was almost equivalent between GM1+-cells and controls. However, dimer formation of TrkA upon NGF treatment was markedly suppressed in GM1+-cells in both cross-linking analysis with BS3 and 125I-NGF binding assay. The sucrose density gradient fractionation of the cell lysate revealed that TrkA primarily located in the lipid raft fraction moved to the non-raft fraction in GM1+-cells. p75NTR and Ras also moved from the raft to non-raft fraction in GM1+-cells, while flotillin and GM1 persistently resided in the lipid raft. TrkA kinase activity was differentially regulated with added GM1 to the kinase assay system in vitro, suggesting suppressive/enhancing effects of GM1 on NGF signals based on the concentration. Mesurement of fluorescence recovery after photobleaching revealed that the membrane fluidity reduced in GM1+-cells. These results suggested that over-expressed GM1 suppresses the differentiation signals mediated by NGF/TrkA by modulating the properties of the lipid raft and the intra-cellular localization of NGF receptors and relevant signaling molecules.
J. Biol. Chem, 10.1074/jbc.M403816200
Submitted on April 6, 2004
Revised on May 14, 2004
Accepted on May 14, 2004
Over-expressed GM1 suppresses NGF signals by modulating the intra-cellular localization of NGF receptors and membrane fluidity in PC12 cells
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