Cross-linking of membrane Ig (mIg) on B lymphocytes induces protein tyrosine phosphorylation and phosphoinositide hydrolysis, events that are thought to mediate the diverse biologic responses of B cells to Ag binding. mIg stimulation also induces the expression of the putative transcriptional regulators c-myc, c-fos, egr-1, and jun-B. In this report, normal murine B cells and two murine B lymphoma cell lines were examined for the induction of mRNA expression of seven early response genes first identified in fibroblasts. Expression of four of the seven genes (nur77, nup475, pip92, and 3CH134), encoding two putative transcriptional regulators, a protein of unknown function, and a putative protein phosphatase, was induced after cross-linking of mIg in resting B cells isolated from mouse spleen. In the 2PK-3 and WEHI-231 B lymphoma cell lines three and two, respectively, of these four genes were induced. Expression of these genes could be induced in 2PK-3 cells by activating the phosphoinositide-signaling pathway independently of the tyrosine phosphorylation pathway by signaling through an M1 muscarinic acetylcholine receptor introduced by transfection. Additionally, in all but one case, these early response genes could be induced by directly activating protein kinase C with phorbol esters. In the cell line 2PK-3, the gene 3CH134 was not induced by phorbol ester treatment, but was induced by elevation of intracellular calcium. Thus, a subset of the early response genes identified in serum-stimulated fibroblasts is also induced by Ag-receptor stimulation in B lymphocytes, and this induction appears to be mediated by the phosphoinositide signaling pathway and, for the most part, protein kinase C.