Ganglioside modulation of the PDGF receptor. A model for ganglioside functions.
Gangliosides are a family of glycolipids that are present at the cell surface of all mammalian cells. Patterns of gangliosides are different in gliomas than normal brain, and exogenously added gangliosides affect the growth of cultured glioma cells. Gangliosides inhibit the activities of several kinases, including protein kinase C (PKC) and cAMP-kinase. U-1242 MG cells (derived from a human malignant glioma) have receptors for platelet-derived growth factor (PDGF) that become phosphorylated on tyrosine when exposed to PDGF. Exposure of these cells to PDGF also causes an increase in intracellular calcium concentration ([Ca2+]i) and induces a translocation of PKC to the membrane. Preincubation of U-1242 MG cells with several species of gangliosides inhibits the increase in ([Ca2+]i) and PKC translocation in response to PDGF, but GM3 is much less effective than other species tested. This is due to a lack of activation of the receptor tyrosine kinase as monitored by phosphorylation of the receptor on tyrosine residues, but is not due to an inhibition of binding of PDGF to its receptors. The lack of activation of the PDGF receptor tyrosine kinase is due to an inhibition of dimerization of the receptor monomers by gangliosides GM1, GM2, GD1a, GT1b, but not GM3. Therefore, gangliosides may be involved in coordinating the activities of multiple trophic factors simultaneously acting on a cell by regulating the dimerization of their respective receptor monomers.
Yates
A J
AJ
Division of Neuropathology, Ohio State University, Columbus 43210, USA.
Saqr
H E
HE
Van Brocklyn
J
J
D001932:Brain Neoplasms / Q000503:physiopathology*; D002455:Cell Division / Q000502:physiology; D005732:Gangliosides / Q000502:physiology*; D005910:Glioma / Q000503:physiopathology; D006801:Humans; D008954:Models, Biological; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000494:pharmacology; D017479:Receptors, Platelet-Derived Growth Factor / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
D005732:Gangliosides; D010982:Platelet-Derived Growth Factor; D017479:Receptors, Platelet-Derived Growth Factor