We previously demonstrated that secretory phospholipase A 2 (sPLA 2 ) and lysophosphatidylcholine (LPC) exhibit neurotrophin-like neuritogenic activity in the rat pheochromocytoma cell line PC12. In this study, we further analyzed the mechanism whereby sPLA 2 displays neurite-inducing activity. Exogenously added mammalian group X sPLA 2 (sPLA 2 -X), but not group IB and IIA sPLA 2 s, induced neuritogenesis, which correlated with the ability of sPLA 2 -X to liberate LPC into the culture media. In accordance, blocking the effect of LPC by supplementation of bovine serum albumin or phospholipase B attenuated neuritogenesis by sPLA 2 or LPC. Overproduction or suppression of G2A, a G-protein-coupled receptor involved in LPC signaling, resulted in the enhancement or reduction of neuritogenesis induced by sPLA 2 treatment. These results indicate that the neuritogenic effect of sPLA 2 is mediated by generation of LPC and subsequent activation of G2A.