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J Biol Chem, Vol. 273, Issue 32, 20517-20524, August 7, 1998

Analysis of Platelet-derived Growth Factor-induced Phospholipase D Activation in Mouse Embryo Fibroblasts Lacking Phospholipase C-1

Jean A. Hess, Qun-sheng Ji^§, Graham Carpenter^§¶, and John H. Exton

From the  Department of Molecular Physiology and Biophysics, the  Howard Hughes Medical Institute, and the Departments of ^§ Biochemistry and ^¶ Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0295

Platelet-derived growth factor (PDGF) activates phospholipase D (PLD) in mouse embryo fibroblasts (MEFs). In order to investigate a role for phospholipase C-1 (PLC-1), we used targeted disruption of the Plcg1 gene in the mouse to develop Plcg1^+/+ and Plcg1^/ cell lines. Plcg1^+/+ MEFs treated with PDGF showed a time- and dose-dependent increase in the production of total inositol phosphates that was substantially reduced in Plcg1^/ cells. Plcg1^+/+ cells also showed a PDGF-induced increase in PLD activity that had a similar dose dependence to the PLC response but was down-regulated after 15 min. Phospholipase D activity, however, was markedly reduced in Plcg1^/ cells. The PDGF-induced inositol phosphate formation and the PLD activity that remained in the Plcg1^/ cells could be attributed to the presence of phospholipase C-2 (PLC-2) in the Plcg1^/ cells. The PLC-2 expressed in the Plcg1^/ cells was phosphorylated on tyrosine in response to PDGF treatment, and a small but significant fraction of the Plcg1^/ cells showed Ca²⁺ mobilization in response to PDGF, suggesting that the PLC-2 expressed in the Plcg1^/ cells was activated in response to PDGF. The inhibition of PDGF-induced phospholipid hydrolysis in Plcg1^/ cells was not due to differences in the level of PDGF receptor or in the ability of PDGF to cause autophosphorylation of the receptor. Upon treatment of the Plcg1^/ cells with oleoylacetylglycerol and the Ca²⁺ ionophore ionomycin to mimic the effect of PLC-1, PLD activity was restored. The targeted disruption of Plcg1 did not result in universal changes in the cell signaling pathways of Plcg1^/ cells, because the phosphorylation of mitogen-activated protein kinase was similar in Plcg1^+/+ and Plcg1^/ cells. Because increased plasma membrane ruffles occurred in both Plcg1^+/+ and Plcg1^/ cells following PDGF treatment, it is possible neither PLC nor PLD are necessary for this growth factor response. In summary, these data indicate that PLC- is required for growth factor-induced activation of PLD in MEFs.

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