Nerve growth factor stimulates the hydrolysis of glycosylphosphatidylinositol in PC-12 cells: a mechanism of protein kinase C regulation.

Abstract

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 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.

Overexpression of atypical PKC in PC12 cells enhances NGF-responsiveness and survival through an NF-κB dependent pathway

“…Thus, PKC's position within neurotrophin signaling pathways has been understudied. Upon binding of NGF to PC12 cells, diacylglycerol is generated, 3 followed by PKC activation. 4,5 Phorbol esters are PKC activators and mimic certain biological activities of NGF in PC12 cells.…”

Both p140 and p75NGFR Nerve Growth Factor Receptors Mediate Nerve Growth Factor-stimulated Calcium Uptake

“…Although there is substantial information about the mechanism by which NGF causes profound and global changes in cell phenotypes, the identification of specific second messengers responsible for specific biological actions of NGF has proven difficult. NGF-induced changes in a number of these second messengers, such as cAMP (12), cGMP (13), calcium (14), phosphoinositides (15), arachidonic acid (16,17), and glycosylphosphatidylinositol metabolites (18), have been reported in PC12 cells and other NGF-responsive cells.…”

Does oligosaccharide‐phosphatidylinositol (glycosyl‐phosphatidylinositol) hydrolysis mediate prolactin signal transduction in granulosa cells?

“…Receptor-activated (Ose),PtdIns hydrolysis has been associated with hormones or growth factors that bind to receptors with tyrosine kinase activity (Chan et al, 1989;Saltiel, 1987;Farese et al, 1988a;Farese et al, 1988b;Gaulton et al, 1988;Eardley and Koshland, 1991) or receptors with seven transmembrane domains coupled to cAMP generation (Cozza et al, 1988;Martiny et al, 1992). The lactogenicreceptor family has recently been included in the haematopoietin-cytokine-receptor superfamily involved in the growth and differentiation of cells of the lymphohaematopoietic lineages (Bazan, 1989;Bazan, 1990).…”

“…Recently, a reduced number of observations have implicated diacylglycerol (DAG) and/or activation of protein kinase C (PKC) as intracellular mediators of PRL in liver (Buckley et al, 1986;Buckley et al, 1987;Buckley et al, 1988;Johnson et al, 1990;Crowe et al, 1991) and smooth-muscle cells (Sauro et al, 1989;Sauro and Zorn, 1991). Nevertheless, since PRL-receptor activation in these cells is not accompanied by inositol 1,4,5-trisphosphate generation and/or increases in intracellular calcium, it seems reasonable to conclude that the source of DAG generated in response to PRL may involve membrane phospholipids other than phosphatidylinositolbisphosphate (PtdInsP,;Farese et al, 1988a;Chan et al, 1989;Exton, 1990). Evaluation of this hypothesis led us to investigate the possibility that PRLreceptor activation stimulates the cleavage by phosphodiest-erase of hormone-sensitive (Ose),PtdIns lipids in ovarian granulosa cells.…”

“…Hormone-receptor activated (Ose),PtdIns hydrolysis elicited by insulin Saltiel and Sorbara-Cazan, 1987;Mato et al, 1987a) and other regulatory ligands (Cozza et al, 1988;Farese et al, 1988b;Chan et al, 1989;Eardley and Koshland, 1991) results in the generation of myristoyl-DAG species (Saltiel and Sorbara-Cazan, 1987;Eardley and Koshland, 1991) and a soluble phosphoinositol-oligosaccharide (Ose,InsP) moiety containing inositol, glucosamine, galactose and several phosphates (Saltie1 et al, 1986;Mato et al, 1987a;Mato et al, 1987b;Gaulton et al, 1988). Although a second-messenger function for DAG species generated after (Ose),PtdIns hydrolysis has not been clearly established, in intact cells the inositol-glycan moiety is endowed with effects which mimic those of insulin in widespread intracellular events including inhibition of lipolysis (Kelly et al, 1987) stimulation of lipogenesis (Saltiel and Sorbara-Cazan, 1987) inhibition of CAMP-dependent protein phosphorylation (Lamer et al, 1979), intracellular CAMP accumulation (Alvarez et al, 1987) and the phosphorylation/dephosphorylation of some of the proteins resembling insulin action (Larner et al, 1979;Alemany et al, 1987).…”