ANG II-induced cell proliferation is dually mediated by c-Src/Yes/Fyn-regulated ERK1/2 activation in the cytoplasm and PKCζ-controlled ERK1/2 activity within the nucleus
- 1 December 2006
- journal article
- Published by American Physiological Society in American Journal of Physiology-Cell Physiology
- Vol. 291 (6), C1297-C1307
- https://doi.org/10.1152/ajpcell.00617.2005
Abstract
High-affinity binding of angiotensin II (ANG II) to the ANG II type 1 receptor (AT1R) 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 AT1R (SYF/AT1). ERK1/2 activation was reduced by ∼50% within these cells compared with wild-type controls (WT/AT1). The remaining ∼50% of intracellular ERK1/2 activation was dependent upon heterotrimeric G protein and protein kinase C zeta (PKCζ) 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 PKCζ signaling affected ERK1/2 nuclear translocation and cell proliferation in response to ANG II. ANG II-induced cell proliferation was markedly reduced in SYF/AT1cells compared with WT/AT1cells ( P < 0.01), but interestingly, ERK2 nuclear translocation was normal. ANG II-induced nuclear translocation of ERK2 was blocked via pretreatment of WT/AT1cells with a PKCζ pseudosubstrate. ANG II-induced cell proliferation was significantly reduced in PKCζ pseudosubstrate-treated WT/AT1cells ( P < 0.01) and was completely blocked in SYF/AT1cells 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/PKCζ signaling, respectively.Keywords
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