Nerve growth factor stimulates the hydrolysis of glycosylphosphatidylinositol in PC-12 cells: a mechanism of protein kinase C regulation.
Treatment of PC-12 pheochromocytoma cells with nerve growth factor (NGF) results in the differentiation of these cells into a sympathetic neuron-like phenotype. Although the initial intracellular signals elicited by NGF remain unknown, some of the cellular effects of NGF are similar to those of other growth factors, such as insulin. We have investigated the involvement of a newly identified inositol-containing glycolipid in signal transduction for the actions of NGF. NGF stimulates the rapid generation of a species of diacylglycerol that is labeled with [3H]myristate but not with [3H]arachidonate. NGF stimulates [3H]myristate- or [32P]phosphate-labeled phosphatidic acid production over the same time course. Although NGF alone has no effect on the turnover of inositol phospholipids, it does stimulate the hydrolysis of glycosylphosphatidylinositol. The NGF-dependent cleavage of this lipid is accompanied by an increase in the accumulation of its polar head group, an inositol phosphate glycan, which is generated within 30-60 sec of NGF treatment. In an unresponsive PC-12 mutant cell line, neither the diacylglycerol nor inositol phosphate glycan response is detected. A possible role for the NGF-stimulated diacylglycerol is suggested by the inhibition of NGF-dependent c-fos induction by staurosporin, a potent inhibitor of protein kinase C. These results suggest that, like insulin, some of the cellular effects of NGF may be mediated by the phospholipase C-catalyzed hydrolysis of glycosylphosphatidylinositol.
Chan
B L
BL
Laboratory of Viral Oncology, Rockefeller University, New York, NY.
Chao
M V
MV
Saltiel
A R
AR
D000310:Adrenal Gland Neoplasms / Q000378:metabolism*; D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids; D004075:Diglycerides / Q000096:biosynthesis; D005786:Gene Expression Regulation / Q000187:drug effects; D006017:Glycolipids / Q000378:metabolism*; D017261:Glycosylphosphatidylinositols; D006868:Hydrolysis; D019814:Myristic Acid; D009227:Myristic Acids / Q000378:metabolism; D009414:Nerve Growth Factors / Q000494:pharmacology*; D010673:Pheochromocytoma / Q000378:metabolism*; D010710:Phosphates / Q000378:metabolism; D010712:Phosphatidic Acids / Q000096:biosynthesis; D010716:Phosphatidylinositols / Q000378:metabolism*; D011134:Polysaccharides / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016760:Proto-Oncogene Proteins c-fos; D051381:Rats; D011956:Receptors, Cell Surface / Q000502:physiology; D017475:Receptors, Nerve Growth Factor; D015398:Signal Transduction; D019311:Staurosporine; D014407:Tumor Cells, Cultured
D000470:Alkaloids; D001095:Arachidonic Acids; D004075:Diglycerides; D006017:Glycolipids; D017261:Glycosylphosphatidylinositols; D009227:Myristic Acids; D009414:Nerve Growth Factors; D010710:Phosphates; D010712:Phosphatidic Acids; D010716:Phosphatidylinositols; D011134:Polysaccharides; D011518:Proto-Oncogene Proteins; D016760:Proto-Oncogene Proteins c-fos; D011956:Receptors, Cell Surface; D017475:Receptors, Nerve Growth Factor; D019814:Myristic Acid; D016718:Arachidonic Acid; D011493:Protein Kinase C; D019311:Staurosporine