title: Ligands Binding to Cell Surface Ganglioside GD2 Cause Src-Dependent Activation of N-Methyl-D-Aspartate Receptor Signaling and Changes in Cellular Morphology.
abstract: Ganglioside GD2 is a plasma membrane glycosphinogolipid. In healthy adults it is expressed at low levels, but it is over-expressed in many cancers. For cancer therapy, GD2 is targeted with anti-GD2 monoclonal antibodies (mAbs), and one adverse side effect is severe visceral pain. Pain is not neuropathic, cannot be blocked with morphine, and stops on discontinuation of mAb therapy. Here, we provide evidence that ligand binding to cell surface GD2 induces rapid and transient activation of Src-family kinases, followed by Src-dependent phosphorylation of NMDA-receptor NR2B subunits selectively, activation of Ca++ fluxes, production of cAMP, and changes in cellular morphology. These GD2-ligand activated signals differ in kinetics and in pharmacology from activation of the same signals in the same cells by BDNF, the growth factor agonist of the TrkB receptor, suggesting biological specificity. Hence, cell surface GD2 regulates pathways that can be associated with neoplasia and with morphine-intractable pain; and this can explain why expression of GD2 correlates with these two pathologies.
authors.affiliation: Lady Davis Institute-Jewish General Hospital, McGill University, 3755 Cote St., Catherine, E-535, Montreal, Quebec, Canada; Pharmacology and Therapeutics, McGill University, 3755 Cote St., Catherine, E-535, Montreal, Quebec, Canada.
authors.forename: Wenyong
authors.initials: W
authors.lastname: Tong
authors.affiliation: Lady Davis Institute-Jewish General Hospital, McGill University, 3755 Cote St., Catherine, E-535, Montreal, Quebec, Canada.
authors.forename: Mario
authors.initials: M
authors.lastname: Maira
authors.affiliation: Lady Davis Institute-Jewish General Hospital, McGill University, 3755 Cote St., Catherine, E-535, Montreal, Quebec, Canada; Segal Center for Translational Research, McGill University, 3755 Cote St., Catherine, E-535, Montreal, Quebec, Canada.
authors.forename: Martin
authors.initials: M
authors.lastname: Gagnon
authors.affiliation: Lady Davis Institute-Jewish General Hospital, McGill University, 3755 Cote St., Catherine, E-535, Montreal, Quebec, Canada; Pharmacology and Therapeutics, McGill University, 3755 Cote St., Catherine, E-535, Montreal, Quebec, Canada; Segal Center for Translational Research, McGill University, 3755 Cote St., Catherine, E-535, Montreal, Quebec, Canada.
authors.forename: H Uri
authors.initials: HU
authors.lastname: Saragovi
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism*; D048430:Cell Shape; D000242:Cyclic AMP / Q000378:metabolism; D005732:Gangliosides / Q000378:metabolism*; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D008024:Ligands; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D051966:Phospholipase C gamma / Q000378:metabolism; D010766:Phosphorylation; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D015398:Signal Transduction; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D005732:Gangliosides; D008024:Ligands; C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; C019403:ganglioside, GD2; D000242:Cyclic AMP; D019061:src-Family Kinases; D051966:Phospholipase C gamma; D002118:Calcium