GM1 ganglioside activates the high-affinity nerve growth factor receptor trkA.
The monosialoganglioside GM1 has been shown to possess neurotrophic activity in vitro and in vivo and is now used as an experimental treatment for a variety of neurological disorders and trauma. Little is known about the mechanism of action used by GM1. Because GM1 appears to enhance nerve growth factor (NGF) activity, we have used C6trk+ cells, a derivative of C6-2B glioma cells that express the high-affinity receptor for NGF trkA, to determine whether the neurotrophic effects of GM1 occurs through induction of trkA activity. Exposure of C6trk+ cells to NGF (10-50 ng/ml) resulted in a five- to 10-fold increase in trkA tyrosine phosphorylation within 5 min. Incubation of cells with GM1 resulted in a threefold increase in trkA phosphorylation beginning within 1 h and peaking between 3 and 6 h. Optimal responses to GM1 were obtained using 80-100 microM concentrations. Moreover, tyrosine phosphorylation of known trkA target proteins, such as extracellular signal-regulated kinases, and suc-associated neurotrophic factor-induced tyrosine-phosphorylated target, were activated upon stimulation of C6trk+ cells with GM1. In addition, GM1 potentiated the NGF-mediated activation of tyrosine phosphorylation of trkA. GM1 failed to induce phosphorylation of trkA and target proteins in mock transfected cells. Thus, our data demonstrate that GM1 mimics some of the effects of NGF and suggest that the neurotrophic properties of GM1 may be attributed to its activation of trkA signal transduction.
Rabin
S J
SJ
Department of Cell Biology, Georgetown University, School of Medicine, Washington, D.C. 20007, USA.
Mocchetti
I
I
D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005677:G(M1) Ganglioside / Q000494:pharmacology*; D006023:Glycoproteins / Q000378:metabolism; D006133:Growth Substances / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1; D009414:Nerve Growth Factors / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D020917:Receptor, trkA; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism
C033904:GP 140; D006023:Glycoproteins; D006133:Growth Substances; D009414:Nerve Growth Factors; D011518:Proto-Oncogene Proteins; D017475:Receptors, Nerve Growth Factor; D005677:G(M1) Ganglioside; D014443:Tyrosine; D020794:Receptor Protein-Tyrosine Kinases; D020917:Receptor, trkA; D017346:Protein Serine-Threonine Kinases; D019950:Mitogen-Activated Protein Kinase 1