In a concurrently submitted article, we show that Ang II-induced ERK1/2 activation is mediated by both c-Src/Yes/Fyn and heterotrimeric G protein/PKC-dependent signaling. Furthermore, we show that heterotrimeric G protein/PKC-activated ERK1/2 is destined for the nucleus while ERK1/2 activated by c-Src/Yes/Fyn-dependent signaling remains in the cytoplasm. Interestingly, both mechanisms of activation are required for maximum Ang II-induced cell proliferation. Here, we sought to determine the mechanisms by which ERK1/2 facilitate cell proliferation via these distinct nuclear and cytoplasmic events, using cells that were lacking either c-Src/Yes/Fyn or heterotrimeric G protein/PKC-dependent ERK1/2 activation. A loss of c-Src/Yes/Fyn blocked Ang II-dependent RSK2 activation, RSK2 nuclear translocation, serum-response factor (SRF) phosphorylation, a portion of c-fos transcriptional activity and c-fos phosphorylation. Blocking Ang II-induced heterotrimeric G protein/PKC activity resulted in a loss of ERK1/2 nuclear translocation, elk1 phosphorylation, and the remaining portion of c-fos transcriptional activity not dependent on c-Src/Yes/Fyn. Inhibition of RSK with the potent and selective inhibitor, SL0101, attenuated Ang II-induced cell proliferation, and, in combination with a PKC pseudosubstrate, completely attenuated cell proliferation. Thus, we conclude that ERK1/2 mediate Ang II-dependent cell proliferation via distinct cytoplasmic and nuclear signaling events, which are in turn governed by c-Src/Yes/Fyn and heterotrimeric G protein/PKC-dependent signaling, respectively.