Autophosphorylation of the platelet-derived growth factor (PDGF) receptor on tyrosine, which is dependent upon and occurs immediately after ligand binding, has been linked to the activation of second messenger pathways thought to be necessary for the induction of gene expression, DNA synthesis, and mitogenesis. We have investigated PDGF signal transduction in Balb/c3T3 and NIH-3T3 cells at the level of immediate-early gene induction under three conditions in which PDGF receptor autophosphorylation in response to PDGF binding is blocked: cells transformed by v-rasKi, cells transformed by v-mos, and cells treated with genistein, a specific inhibitor of tyrosine kinases. PDGF induction of immediate-early genes c-myc, c-fos, and JE is blocked in these systems. Induction of another immediate-early gene, egr-1, occurs normally despite the absence of measurable tyrosine kinase activity. The same results were obtained when cells were stimulated with PDGF-AA or PDGF-BB. It is not yet clear if this receptor tyrosine kinase-independent signal utilizes known PDGF second messengers, but these results demonstrate a new arm of the PDGF signal transduction pathway which operates in the absence of, and independently from, autophosphorylation of the receptor on tyrosine.