Lysophosphatidylcholine activates mesangial cell PKC and MAP kinase by PLCgamma-1 and tyrosine kinase-Ras pathways

Although lysophosphatidylcholine (LPC)-mediated cellular responses are attr ibuted to the activation of protein kinase C (PKC), relatively little is kn own about the upstream signaling mechanisms that regulate the activation of PKC and downstream mitogen-activated protein (MAP) kinase, LPC activated p 42 MAP kinase and PKC in mesangial cells. LPC-mediated MAP kinase activatio n was inhibited (but not completely) by PKC inhibition, suggesting addition al signaling events. LPC stimulated protein tyrosine kinase (PTK) activity and induced Ras-GTP binding. LPC-induced MAP kinase activity was blocked by the PTK inhibitor genistein. Because LPC increased PTK activity, we examin ed the involvement of phospholipase C gamma-1 (PLC gamma-1) as a key partic ipant in LPC-induced PKC activation. LPC stimulated the phosphorylation of PLC gamma-1. PTK inhibitors suppressed LPC-induced PKC activity, whereas th e same had no effect on phorbol 12-myristate 13-acetate-mediated PKC activi ty. Other lysophospholipids [e.g., lysophosphatidylinositol and lysophospha tidic acid (LPA)] also induced MAP kinase activity, and only LPA-induced MA P kinase activation was sensitive to pertussis toxin. These results indicat e that LPC-mediated PKC activation may be regulated by PTK-dependent activa tion of PLC gamma-1, and both PKC and PTK-Ras pathways are involved in LPC- mediated downstream MAP kinase activation.