Stimulation of the platelet-derived growth factor beta receptor (betaPDGFR) activates enzymes such as phosphatidylinositol 3-kinase (PI3K) and phospholipase Cgamma1 (PLCgamma), which ultimately initiate nuclear responses such as enhanced expression of immediate early genes. In an attempt to compare the signaling cascades initiated by PI3K and PLCgamma, we examined the activation of a panel of immediate early genes by betaPDGFR mutants, which preferentially engage PI3K or PLCgamma. When expressed in A431 cells, the wild type receptor and to a lesser extent the mutant receptor that associates with PLCgamma (Y1021) was able to up-regulate c-fos, junB, and KC mRNA expression. In contrast, the receptor mutant that engages PI3K (Y740/51) poorly stimulated c-fos mRNA expression and did not significantly stimulate expression of either JunB or KC. Receptor mutants that did not associate with either PI3K or PLCgamma were dramatically compromised or unable to increase expression of any of these immediate early genes. The differential ability of the Y1021 and Y740/51 receptors to activate c-fos correlated well with an apparent difference in their ability to engage distinct protein kinase C family members. However there did appear to be a degree of redundancy in the cytoplasmic signaling pathways initiated by PI3K and PLCgamma, since both the Y1021 and Y740/51 receptors were able to activate an AP-1-responsive element. We conclude that recruitment of signal relay enzymes to the betaPDGFR is necessary for PDGF-dependent activation of at least some immediate early genes. In addition, whereas the betaPDGFR activates multiple signaling enzymes capable of activating the same nuclear response (activation of c-fos), these signaling cascades do not appear to converge in the cytoplasm but arrive at the nucleus as distinguishable inputs.