Cadherin-Cadherin Engagement Promotes Cell Survival via Rac1/Cdc42 and Signal Transducer and Activator of Transcription-3
Cadherin-Cadherin Engagement Promotes Cell Survival via Rac1/Cdc42 and Signal Transducer and Activator of Transcription-3
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DOI：
10.1158/1541-7786.mcr-08-0469
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发表时间：
2009-08-01
影响因子：
5.2
通讯作者：
Raptis, Leda
中科院分区：
文献类型：
--
作者：
Arulanandam, Rozanne;Vultur, Adina;Raptis, Leda
信号转导子和转录激活子-3（Stat 3）被许多受体和非受体酪氨酸激酶激活，而单独的Stat 3组成型活性形式足以诱导肿瘤转化。在本报告中，我们表明，Stat 3也可以通过嗜同性相互作用的上皮（E）-钙粘蛋白激活。事实上，通过将细胞接种到覆盖有包含该钙粘蛋白的两个最外层结构域的片段的表面上，我们清楚地表明，即使在没有直接细胞与细胞接触的情况下，钙粘蛋白接合也可以激活Stat 3。最重要的是，我们的研究结果还首次揭示了由钙粘蛋白参与引发的总Rac 1和Cdc 42蛋白水平的意外和戏剧性的激增以及Rac 1和Cdc 42活性的增加，这是观察到的Stat 3刺激的原因。使用肽、可溶性钙粘蛋白片段或基因消融诱导的细胞凋亡抑制钙粘蛋白相互作用，指出该途径在细胞存活信号传导中的重要作用，这一发现也可能具有重要的治疗意义。(Mol Cancer Res 2009;7（8）：1310-27）
Signal transducer and activator of transcription-3 (Stat3) is activated by a number of receptor and nonreceptor tyrosine kinases, whereas a constitutively active form of Stat3 alone is sufficient to induce neoplastic transformation. In the present report, we show that Stat3 can also be activated through homophilic interactions by the epithelial (E)-cadherin. Indeed, by plating cells onto surfaces coated with fragments encompassing the two outermost domains of this cadherin, we clearly show that cadherin engagement can activate Stat3, even in the absence of direct cell-to-cell contact. Most importantly, our results also reveal for the first time an unexpected and dramatic surge in total Rac1 and Cdc42 protein levels triggered by cadherin engagement and an increase in Rac1 and Cdc42 activity, which is responsible for the Stat3 stimulation observed. Inhibition of cadherin interactions using a peptide, a soluble cadherin fragment, or genetic ablation induced apoptosis, points to a significant role of this pathway in cell survival signaling, a finding that could also have important therapeutic implications. (Mol Cancer Res 2009;7(8):1310-27)