Activation of B cells through their Ag receptor is known to be negatively regulated by Fc gamma RII engagement. To explore the molecular and biochemical mechanisms of Fc gamma RII-mediated inhibition, we investigated the effect of Fc gamma RII engagement on the expression of two immediate-early genes, egr-1 and egr-2, and tyrosine phosphorylation events following the activation of the murine B cell line, BCL1. Egr-1 and egr-2 were expressed in BCL1 after slg cross-linking. The induction of egr-1 and egr-2 expression was prevented when the Fc gamma RII was co-cross-linked with slg in BCL1, but not in WEHI-231. The inhibitory effects of Fc gamma RII engagement on egr-1 and egr-2 expression occurred when the Fc gamma RII was cross-linked with either slgM or slgD. Treatment with cyclosporin A prevented the expression of egr-2 induced by slg cross-linking, but did not inhibit egr-1 expression. In addition, cyclosporin A did not prevent the negative-regulatory effects of Fc gamma RII engagement on egr-1 expression, suggesting that the Fc gamma RII works upstream from the site of action of cyclosporin A. To investigate activation signals more proximal to the plasma membrane, we compared tyrosine phosphorylation patterns of several effector molecules known to play a role in B cell activation. Cross-linking of slg induced tyrosine phosphorylation of the p62 GAP-associated protein. The p62 protein became hyperphosphorylated in response to co-cross-linking of slg with Fc gamma RII. Our results identify egr-1 and egr-2 as targets of Fc gamma RII-mediated inhibition of anti-Ig-induced B cell activation. In addition, they show that negative regulation by Fc gamma RII is effective in both cyclosporin A-sensitive and insensitive pathways. Further, we suggest a possible Fc gamma RII signaling pathway leading to the inhibition of egr-1 and egr-2 expression.