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.
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.
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DOI：
10.1152/ajpcell.00617.2005
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发表时间：
2006-12
期刊：
影响因子：
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通讯作者：
Michael D. Godeny;P. Sayeski
中科院分区：
文献类型：
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作者：
Michael D. Godeny;P. Sayeski
血管紧张素II（ANG II）与ANG II 1型受体（AT（1）R）的高亲和力结合导致ERK 1/2丝裂原活化蛋白激酶（MAPK）活化。然而，ANG II诱导的ERK 1/2激活的精确机制尚未完全确定。在此，我们使用AT（1）R稳定转染的c-Src/Yes/Fyn酪氨酸激酶缺陷小鼠胚胎成纤维细胞（MEF）细胞系（SYF/AT（1））研究了导致ANG II诱导的ERK 1/2激活的信号传导事件。与野生型对照组相比，这些细胞中ERK 1/2活化降低了约50%（WT/AT（1））。其余约50%的细胞内ERK 1/2激活依赖于异源三聚体G蛋白和蛋白激酶C ζ（PKCzeta）激活。因此，ANG II诱导的ERK 1/2激活通过两种独立的机制发生。接下来，我们研究了c-Src/Yes/Fyn或PKCzeta信号转导的缺失是否会影响ERK 1/2核转位和细胞增殖对ANG II的反应。ANG Ⅱ诱导的SYF/AT（1）细胞增殖明显低于WT/AT（1）细胞（P < 0.01），但ERK 2核转位正常。用PKCzeta假底物预处理WT/AT（1）细胞可阻断ANG II诱导的ERK 2核转位。ANG II诱导的细胞增殖在PKCzeta假底物处理的WT/AT（1）细胞中显著降低（P < 0.01），并且在用该相同化合物处理的SYF/AT（1）细胞中被完全阻断。因此，ANG II诱导的细胞增殖似乎受到ERK 1/2驱动的细胞核和细胞质事件的调节。响应ANG II，ERK 1/2保留在细胞质内或易位到细胞核中的能力分别由c-Src/Yes/Fyn或异源三聚体G蛋白/PKCzeta信号传导控制。
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.