ANG II-induced cell proliferation is dually mediated by c-Src/Yes/Fyn-regulated ERK1/2 activation in the cytoplasm and PKCzeta-controlled ERK1/2 activity within the nucleus

Michael D Godeny, Peter P Sayeski
American Journal of Physiology. Cell Physiology 2006, 291 (6): C1297-307
High-affinity binding of angiotensin II (ANG II) to the ANG II type 1 receptor (AT(1)R) results in the activation of ERK1/2 mitogen-activated protein kinases (MAPK). However, the precise mechanism of ANG II-induced ERK1/2 activation has not been fully characterized. Here, we investigated the signaling events leading to ANG II-induced ERK1/2 activation using a c-Src/Yes/Fyn tyrosine kinase-deficient mouse embryonic fibroblast (MEF) cell line stably transfected with the AT(1)R (SYF/AT(1)). ERK1/2 activation was reduced by approximately 50% within these cells compared with wild-type controls (WT/AT(1)). The remaining approximately 50% of intracellular ERK1/2 activation was dependent upon heterotrimeric G protein and protein kinase C zeta (PKCzeta) activation. Therefore, ANG II-induced ERK1/2 activation occurs via two independent mechanisms. We next investigated whether a loss of either c-Src/Yes/Fyn or PKCzeta signaling affected ERK1/2 nuclear translocation and cell proliferation in response to ANG II. ANG II-induced cell proliferation was markedly reduced in SYF/AT(1) cells compared with WT/AT(1) cells (P < 0.01), but interestingly, ERK2 nuclear translocation was normal. ANG II-induced nuclear translocation of ERK2 was blocked via pretreatment of WT/AT(1) cells with a PKCzeta pseudosubstrate. ANG II-induced cell proliferation was significantly reduced in PKCzeta pseudosubstrate-treated WT/AT(1) cells (P < 0.01) and was completely blocked in SYF/AT(1) cells treated with this same compound. Thus ANG II-induced cell proliferation appears to be regulated by both ERK1/2-driven nuclear and cytoplasmic events. In response to ANG II, the ability of ERK1/2 to remain within the cytoplasm or translocate into the nucleus is controlled by c-Src/Yes/Fyn or heterotrimeric G protein/PKCzeta signaling, respectively.

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