Overexpression of RhoA-GTP induces activation of the Epidermal Growth Factor Receptor, dephosphorylation of focal adhesion kinase and increased motility in breast cancer cells
Overexpression of RhoA-GTP induces activation of the Epidermal Growth Factor Receptor, dephosphorylation of focal adhesion kinase and increased motility in breast cancer cells
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DOI：
10.1016/j.yexcr.2005.05.020
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发表时间：
2005-09-10
影响因子：
3.7
通讯作者：
Martínez, J
中科院分区：
文献类型：
--
作者：
Cáceres, M;Guerrero, J;Martínez, J
Rho GTP酶在人类肿瘤中高表达，参与多种细胞过程，如肌动蛋白细胞骨架的组织、细胞与细胞的接触和恶性转化。EGFR的激活在癌细胞运动特性的获得中起着关键作用，已有研究认为FAK活性的下调是其最相关的结果之一。在本研究中，我们利用乳腺MCF-7细胞，证明了小GTP酶活性形式RhoA的过表达诱导了EGFR的激活，这一现象依赖于一种金属蛋白酶(MMP)的活性，该酶可能会裂解与膜结合的EGFR配体。EGFR酪氨酸磷酸化与ERK1，2的激活以及对尿激酶产生的刺激有关。同时过度表达RhoA和EGFR活性形式的侵袭性乳腺细胞系(MDA-MB-231)也表现出依赖于基质金属蛋白酶的EGFR激活机制。RhoA-GTP转染的细胞显示出皮质排列的F-肌动蛋白，形态圆整，铺展能力降低，FAK去磷酸化，FAK通过整合素依赖的纤维连接蛋白黏附和特异性的EGFR酪氨酸激酶抑制剂释放。我们的结果表明，在V14 RhoA细胞中观察到的依赖于基质金属蛋白酶的EGFR激活代表了一条信号通路的起点，该信号通路通过激活ERK1，2并进一步增强蛋白水解酶的产生来促进细胞的运动。(C)2005 Elsevier Inc.保留所有权利。
Rho GTPases are overexpressed in human tumors and are involved in a variety of cellular processes such as organization of the actin cytoskeleton, cell-cell contact and malignant transformation. EGFR activation plays a key role in the acquisition of motile properties in carcinoma cells, and it has been proposed that downregulation of FAK activity is one of its most relevant consequences. In the present study, using mammary MCF-7 cells, we demonstrated that overexpression of the active form of the small GTPase RhoA induced the activation of EGFR by a phenomenon that depends on the activity of a metalloproteinase (MMP), which presumably cleaves a membrane-bound EGFR ligand. The EGFR tyrosine phosphorylation correlates with ERK1,2 activation and the stimulation of urokinase production. An aggressive mammary cell line (MDA-MB-231) that overexpresses both RhoA and EGFR in their active forms also displayed an MMP-dependent activation mechanism of EGFR. RhoA-GTP-transfected cells showed a cortical array of F-actin, rounded morphology, reduced spreading potential and a dephosphorylation of FAK that was released by integrin-dependent fibronectin adhesion and a specific EGFR tyrosine kinase inhibitor. Our results suggest that the MMP-dependent EGFR activation observed in V14 RhoA cells represents the starting point of a signaling route that promotes cell motility by activation of ERK1,2 and further enhancement of proteases production. (c) 2005 Elsevier Inc. All rights reserved.