Ganglioside GM1 binds to the Trk protein and regulates receptor function.
Several lines of evidence have suggested that ganglioside GM1 stimulates neuronal sprouting and enhances the action of nerve growth factor (NGF), but its precise mechanism is yet to be elucidated. We report here that GM1 directly and tightly associates with Trk, the high-affinity tyrosine kinase-type receptor for NGF, and strongly enhances neurite outgrowth and neurofilament expression in rat PC12 cells elicited by a low dose of NGF that alone is insufficient to induce neuronal differentiation. The potentiation of NGF activity by GM1 appears to involve tyrosine-autophosphorylation of Trk, which contains intrinsic tyrosine kinase activity that has been localized to the cytoplasmic domain. In the presence of GM1 in culture medium, there is a > 3-fold increase in NGF-induced autophosphorylation of Trk as compared with NGF alone. We also found that GM1 could directly enhance NGF-activated autophosphorylation of immunoprecipitated Trk in vitro. Monosialoganglioside GM1, but not polysialogangliosides, is tightly associated with immunoprecipitated Trk. Furthermore, such tight association of GM1 with Trk appears to be specific, since a similar association was not observed with other growth factor receptors, such as low-affinity NGF receptor (p75NGR) and epidermal growth factor receptor (EGFR). Thus, these results strongly suggest that GM1 functions as a specific endogenous activator of NGF receptor function, and these enhanced effects appear to be due, at least in part, to tight association of GM1 with Trk.
Mutoh
T
T
Second Department of Internal Medicine, Fukui Medical School, Japan.
Tokuda
A
A
Miyadai
T
T
Hamaguchi
M
M
Fujiki
N
N
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D005677:G(M1) Ganglioside / Q000378:metabolism* / Q000494:pharmacology*; D007700:Kinetics; D009414:Nerve Growth Factors / Q000494:pharmacology; D016501:Neurites / Q000187:drug effects / Q000502:physiology; D016900:Neurofilament Proteins / Q000096:biosynthesis / Q000187:drug effects; D016716:PC12 Cells; D010766:Phosphorylation; D010768:Phosphoserine / Q000032:analysis; D010769:Phosphothreonine / Q000032:analysis; D019000:Phosphotyrosine; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000302:isolation & purification / Q000378:metabolism*; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000302:isolation & purification / Q000378:metabolism*; D020917:Receptor, trkA; D017475:Receptors, Nerve Growth Factor / Q000302:isolation & purification / Q000378:metabolism*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000032:analysis
D009414:Nerve Growth Factors; D016900:Neurofilament Proteins; D011518:Proto-Oncogene Proteins; D017475:Receptors, Nerve Growth Factor; D010769:Phosphothreonine; D010768:Phosphoserine; D019000:Phosphotyrosine; D005677:G(M1) Ganglioside; D014443:Tyrosine; D020794:Receptor Protein-Tyrosine Kinases; D020917:Receptor, trkA