The membrane cytoskeletal crosslinker ezrin is required for metastasis of breast carcinoma cells.
The membrane cytoskeletal crosslinker ezrin is required for metastasis of breast carcinoma cells.
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DOI：
10.1186/bcr1006
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发表时间：
2005
期刊：
影响因子：
--
通讯作者：
Arpin M
中科院分区：
文献类型：
--
作者：
Elliott BE;Meens JA;SenGupta SK;Louvard D;Arpin M
膜细胞骨架交联剂ezrin参与多种功能，包括细胞粘附、运动和细胞存活，并且越来越多的证据表明它调节肿瘤进展。然而，ezrin在乳腺癌转移中所起的作用还没有被清楚地描述。我们使用高转移性小鼠乳腺癌细胞系，即AC 2 M2，研究了ezrin在转移中的作用。选择过表达野生型埃兹蛋白或埃兹蛋白的显性负性氨基末端结构域的稳定细胞克隆。然后测试它们的细胞运动性和体外侵袭性，以及在小鼠体内肿瘤移植模型中的转移。将亲本AC 2 M2细胞和过表达野生型ezrin的细胞移植到同基因受体小鼠的乳腺脂肪垫中;这些动物随后发生肺转移。相反，显性负性氨基末端ezrin结构域的表达显著抑制肺转移。与这种效果相一致，我们观察到，氨基末端埃兹蛋白的表达引起了强烈的钙粘蛋白的膜定位，增加细胞-细胞接触和细胞运动性和侵袭的减少，而表达野生型埃兹蛋白的细胞表现出强烈的细胞质表达的钙粘蛋白和伪足的延伸。此外，磷脂酰肌醇3-激酶和c-Src的抑制剂显着阻断表达野生型埃兹蛋白的AC 2 M2细胞的细胞运动和侵袭。我们进一步发现氨基末端ezrin的过表达降低了AC 2 M2细胞中Akt pS473和细胞内相关c-Src pY 418的水平，这与表达野生型ezrin的细胞中这些蛋白的高水平磷酸化形成对比。磷酸化Erk 1/2也减少氨基末端ezrin表达细胞，虽然有丝分裂原活化蛋白激酶激酶（MEK）抑制剂在这个系统中细胞运动或入侵没有可检测的影响。我们的研究结果表明，ezrin是乳腺癌转移所需的，c-Src和磷脂酰肌醇3-激酶/Akt是ezrin在转移过程的细胞运动和侵袭阶段的效应物。总之，这些结果表明，阻断ezrin功能可能是预防乳腺癌转移的一种新的有效策略。
The membrane cytoskeletal crosslinker ezrin participates in several functions including cell adhesion, motility and cell survival, and there is increasing evidence that it regulates tumour progression. However, the role played by ezrin in breast cancer metastasis has not been clearly delineated. We examined the role of ezrin in metastasis using a highly metastatic murine mammary carcinoma cell line, namely AC2M2. Stable cell clones that overexpress wild-type ezrin or a dominant-negative amino-terminal domain of ezrin were selected. They were then tested for cell motility and invasion in vitro, and metastasis in a mouse in vivo tumour transplantation model. Parental AC2M2 cells and cells overexpressing wild-type ezrin were transplanted into the mammary fat pad of syngeneic recipient mice; these animals subsequently developed lung metastases. In contrast, expression of the dominant-negative amino-terminal ezrin domain markedly inhibited lung metastasis. Consistent with this effect, we observed that the expression of amino-terminal ezrin caused strong membrane localization of cadherin, with increased cell–cell contact and a decrease in cell motility and invasion, whereas cells expressing wild-type ezrin exhibited strong cytoplasmic expression of cadherins and pseudopodia extensions. In addition, inhibitors of phosphatidylinositol 3-kinase and c-Src significantly blocked cell motility and invasion of AC2M2 cells expressing wild-type ezrin. We further found that overexpression of amino-terminal ezrin reduced levels of Akt pS473 and cytoskeletal-associated c-Src pY418 in AC2M2 cells, which contrasts with the high levels of phosphorylation of these proteins in cells expressing wild-type ezrin. Phosphorylated Erk1/2 was also reduced in amino-terminal ezrin expressing cells, although a mitogen-activated protein kinase kinase (MEK) inhibitor had no detectable effect on cell motility or invasion in this system. Our findings indicate that ezrin is required for breast cancer metastasis, and that c-Src and phosphatidylinositol 3-kinase/Akt are effectors of ezrin in the cell motility and invasion stages of the metastatic process. Together, these results suggest that blocking ezrin function may represent a novel and effective strategy for preventing breast cancer metastasis.
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磷酸肌醇的结合和磷酸化在ezrin的激活机理中依次起作用。
影响因子：
7.8
作者：
Fievet, BT;Gautreau, A;Roy, C;Del Maestro, L;Mangeat, P;Louvard, D;Arpin, M
通讯作者：
Arpin, M
影响因子：
82.9
作者：
Yu, YL;Khan, J;Merlino, G
通讯作者：
Merlino, G
影响因子：
6.4
作者：
ELLIOTT, BE;TAM, SP;CHEN, ZQ
通讯作者：
CHEN, ZQ
影响因子：
3.3
作者：
Srivastava, J;Elliott, BE;Arpin, M
通讯作者：
Arpin, M
影响因子：
4
作者：
Elliott, BE;Qiao, H;Arpin, M
通讯作者：
Arpin, M