Phospholipase activity of phospholipase C-gamma 1 is required for nerve growth factor-regulated MAP kinase signaling cascade in PC12 cells
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- Phospholipase activity of phospholipase C-gamma 1 is required for nerve growth factor-regulated MAP kinase signaling cascade in PC12 cells
- Rong, R; Ahn, JY; Chen, P; Suh, Pann-Ghill; Ye, KQ
- NUCLEOTIDE EXCHANGE FACTOR; SH3 DOMAIN; C-GAMMA; B-RAF; MEDIATED ACTIVATION; PROTEIN-KINASE; NUCLEAR GTPASE; DNA-SYNTHESIS; C-GAMMA-1; PLC-GAMMA-1
- Issue Date
- AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
- JOURNAL OF BIOLOGICAL CHEMISTRY, v.278, no.52, pp.52497 - 52503
- Phospholipase C-gamma1( PLC-gamma1) hydrolyzes phosphatidylinositol 4,5-bisphosphate to the second messengers inositol 1,4,5-trisphosphate and diacylglycerol (DAG). PLC-gamma1 is implicated in a variety of cellular signalings and processes including mitogenesis and calcium entry. However, numerous studies demonstrate that the lipase activity is not required for PLC-gamma1 to mediate these events. Here, we report that the phospholipase activity of PLC-gamma1 plays an essential role in nerve growth factor (NGF)-triggered Raf/MEK/MAPK pathway activation in PC12 cells. Employing PC12 cells stably transfected with an inducible form of wild-type PLC-gamma1 or lipase inactive PLC-gamma1 with histidine 335 mutated into glutamine in the catalytic domain, we show that NGF provokes robust activation of MAP kinase in wild-type but not in lipase inactive cells. Both Ras/C-Raf/MEK1 and Rap1/B-Raf/MEK1 pathways are intact in the wild-type cells. By contrast, these signaling cascades are diminished in the mutant cells. Pretreatment with cell permeable DAG analog 1-oleyl-2-acetylglycerol rescues the MAP kinase pathway activation in the mutant cells. These observations indicate that the lipase activity of PLC-gamma1 mediates NGF-regulated MAPK signaling upstream of Ras/Rap1 activation probably through second messenger DAG-activated Ras and Rap-GEFs.
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