Transactivation of the epidermal growth factor receptor in endothelin-1-induced mitogenic signaling in human ovarian carcinoma cells.
Transactivation of the epidermal growth factor receptor in endothelin-1-induced mitogenic signaling in human ovarian carcinoma cells.
复制标题
DOI：
--
复制
发表时间：
2000-09
期刊：
影响因子：
11.2
通讯作者：
F. Vacca;A. Bagnato;K. Catt;R. Tecce
中科院分区：
文献类型：
--
作者：
F. Vacca;A. Bagnato;K. Catt;R. Tecce
内皮素（ET）-1在卵巢癌细胞中产生，并且已知在体外和体内作为自分泌生长因子通过ET（A）受体起作用。在OVCA 433人卵巢癌细胞中，ET-1引起表皮生长因子受体（EGF-R）的磷酸化，伴随着Shc的磷酸化及其与Grb 2复合的募集。这些结果表明，EGF-R/ras依赖的途径可能有助于激活丝裂原活化蛋白激酶（MAPK）/细胞外信号调节激酶（Erk）2和有丝分裂信号诱导ET-1在这些细胞中。特异性抑制EGF-R激酶活性的tyrphostin AG 1478阻止ET-1诱导的EGF-R的反式激活，以及Shc磷酸化和招募Grb 2。Tyrphostin AG 1478可部分抑制ET-1诱导的Erk 2激活。与这一发现雅阁的是，ET-1在OVCA 433细胞中的促有丝分裂作用也被一定浓度的酪氨酸磷酸化抑制剂AG 1478显著降低，该浓度消除了EGF刺激的细胞的生长反应。蛋白激酶C活性的抑制，这有助于在OVCA 433细胞中的ET-1的增殖作用，没有影响Erk 2的激活ET-1，这表明蛋白激酶C的这种效果不涉及Ras独立的激活Erk 2。渥曼青霉素对ET-1和其他G蛋白偶联受体（GPCR）介导的信号通路中所涉及的PI 3激酶活性的抑制，减少了ET-1对Erk 2的激活，但对ET-1诱导的EGF-R和Shc磷酸化没有影响。这些发现表明，ET-1诱导的Erk 2磷酸化刺激，OVCA 433卵巢癌细胞中的促有丝分裂反应部分介导的信号转导途径，启动EGF-R的反式激活。
Endothelin (ET)-1 is produced in ovarian carcinoma cells and is known to act through ET(A) receptors as an autocrine growth factor in vitro and in vivo. In OVCA 433 human ovarian carcinoma cells, ET-1 caused phosphorylation of the epidermal growth factor receptor (EGF-R) that was accompanied by phosphorylation of Shc and its recruitment complexed with Grb2. These findings suggested that an EGF-R/ras-dependent pathway may contribute to the activation of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (Erk) 2 and mitogenic signaling induced by ET-1 in these cells. Specific inhibition of EGF-R kinase activity by tyrphostin AG1478 prevented ET-1-induced transactivation of the EGF-R, as well as Shc phosphorylation and recruitment with Grb2. Furthermore, ET-1-induced activation of Erk 2 was partially inhibited by tyrphostin AG1478. In accord with this finding, the mitogenic action of ET-1 in OVCA 433 cells was also significantly reduced by a concentration of tyrphostin AG1478 that abolished the growth response of EGF-stimulated cells. Inhibition of protein kinase C activity, which contributes to the proliferative action of ET-1 in OVCA 433 cells, had no effect on the activation of Erk 2 by ET-1, which suggests that this effect of protein kinase C does not involve ras-independent activation of Erk 2. Inhibition by wortmannin of PI3-kinase activity, which has been implicated in ET-1 and other G protein-coupled receptor (GPCR)-mediated signaling pathways, reduced Erk 2 activation by ET-1 but had no effect on ET-1-induced EGF-R and Shc phosphorylation. These findings indicate that ET-1-induced stimulation of Erk 2 phosphorylation, and mitogenic responses in OVCA 433 ovarian cancer cells are mediated in part by signaling pathways that are initiated by transactivation of the EGF-R.