Ezrin phosphorylation on tyrosine 477 regulates invasion and metastasis of breast cancer cells.
Ezrin phosphorylation on tyrosine 477 regulates invasion and metastasis of breast cancer cells.
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DOI：
10.1186/1471-2407-12-82
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发表时间：
2012-03-07
期刊：
影响因子：
3.8
通讯作者：
Elliott BE
中科院分区：
文献类型：
--
作者：
Mak H;Naba A;Varma S;Schick C;Day A;SenGupta SK;Arpin M;Elliott BE
膜细胞骨架交联剂ezrin是ERM蛋白家族的成员，在人乳腺癌中经常过表达，并且是上皮细胞运动和侵袭所需的。我们的小组先前表明，ezrin与非受体酪氨酸激酶Src合作，在细胞-细胞接触和上皮细胞分散的失调中起作用。特别是，ezrin磷酸化Y 477的Src是特定的ezrin在ERM家族，并需要HGF诱导的上皮细胞的散射。因此，我们试图研究Y 477磷酸化在ezrin中对肿瘤进展的作用。使用高转移性小鼠乳腺癌细胞系（AC 2 M2），我们测试了过表达非磷酸化形式的ezrin（Y 477 F）对三维基质胶培养物中的侵袭性集落生长以及原位移植模型中的局部侵袭和转移的影响。AC 2 M2细胞过度表达Y 477 F ezrin表现出延迟迁移在体外，和粘性的圆形集落在3维基质胶培养物，相比，对照细胞形成侵入性集落与细胞的分支链和许多肌动蛋白丰富的突起。此外，Y 477 F ezrin的过表达抑制体内局部肿瘤侵袭。而原位注射的野生型AC 2 M2肿瘤细胞被发现在三周内浸润到腹壁和内脏器官中，表达Y 477 F ezrin的肿瘤保持局限性，几乎没有侵入周围基质和腹壁。此外，Y 477 F ezrin减少肺转移病灶的数量。我们的研究暗示Y 477 ezrin，这是由Src磷酸化，在调节乳腺癌细胞的局部侵袭和转移的作用，并提供了一个临床相关的模型，用于评估Src/ezrin通路作为一个潜在的预后/预测标记物或治疗靶点的浸润性人乳腺癌。
The membrane cytoskeletal crosslinker, ezrin, a member of the ERM family of proteins, is frequently over-expressed in human breast cancers, and is required for motility and invasion of epithelial cells. Our group previously showed that ezrin acts co-operatively with the non-receptor tyrosine kinase, Src, in deregulation of cell-cell contacts and scattering of epithelial cells. In particular, ezrin phosphorylation on Y477 by Src is specific to ezrin within the ERM family, and is required for HGF-induced scattering of epithelial cells. We therefore sought to examine the role of Y477 phosphorylation in ezrin on tumor progression. Using a highly metastatic mouse mammary carcinoma cell line (AC2M2), we tested the effect of over-expressing a non-phosphorylatable form of ezrin (Y477F) on invasive colony growth in 3-dimensional Matrigel cultures, and on local invasion and metastasis in an orthotopic engraftment model. AC2M2 cells over-expressing Y477F ezrin exhibited delayed migration in vitro, and cohesive round colonies in 3-dimensional Matrigel cultures, compared to control cells that formed invasive colonies with branching chains of cells and numerous actin-rich protrusions. Moreover, over-expression of Y477F ezrin inhibits local tumor invasion in vivo. Whereas orthotopically injected wild type AC2M2 tumor cells were found to infiltrate into the abdominal wall and visceral organs within three weeks, tumors expressing Y477F ezrin remained circumscribed, with little invasion into the surrounding stroma and abdominal wall. Additionally, Y477F ezrin reduces the number of lung metastatic lesions. Our study implicates a role of Y477 ezrin, which is phosphorylated by Src, in regulating local invasion and metastasis of breast carcinoma cells, and provides a clinically relevant model for assessing the Src/ezrin pathway as a potential prognostic/predictive marker or treatment target for invasive human breast cancer.
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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
DOI：
10.1186/bcr1006
发表时间：
2005
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Elliott BE;Meens JA;SenGupta SK;Louvard D;Arpin M
通讯作者：
Arpin M
影响因子：
3.6
作者：
Ling, Li-Jun;Lu, Chao;Wang, Shui
通讯作者：
Wang, Shui
影响因子：
2.7
作者：
Avizienyte, E;Brunton, VG;Frame, MC
通讯作者：
Frame, MC
影响因子：
6.4
作者：
ELLIOTT, BE;TAM, SP;CHEN, ZQ
通讯作者：
CHEN, ZQ