Disheveled proteins promote cell growth and tumorigenicity in ALK-positive anaplastic large cell lymphoma
Disheveled proteins promote cell growth and tumorigenicity in ALK-positive anaplastic large cell lymphoma
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DOI：
10.1016/j.cellsig.2012.09.027
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发表时间：
2013-01-01
影响因子：
4.8
通讯作者：
Lai, Raymond
中科院分区：
文献类型：
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作者：
Hegazy, Samar A.;Alshareef, Abdulraheem;Lai, Raymond
我们先前的寡核苷酸阵列研究表明，ALK阳性间变性大细胞淋巴瘤(ALK(+)ALCL)高水平表达脱发蛋白(Dvls)，Dvl是Wnt信号通路中不可或缺的一族蛋白。在这项研究中，我们评估了Dvls是否在ALK(+)ALCL的发病机制中起重要作用。Western blotting发现DVL-2和DVL-3在ALK(+)ALCL细胞株和患者样本中高表达。在这些裂解物中观察到与磷酸化/活性DVL蛋白一致的较高分子量形式。通过β-连环素蛋白水平和核定位评估，Dvls的siRNA敲除不影响Wnt典型途径。相反，同样的处理导致NFAT的转录活性和Src的磷酸化状态发生变化，这两者在其他类型的细胞中都受到Wnt非典型信号通路的调节，伴随着这些生化变化，细胞生长和软琼脂集落形成显著减少。NPM-ALK是ALK(+)ALCL的致癌酪氨酸激酶，被发现能与DVL结合并增强其酪氨酸磷酸化。综上所述，我们的数据提示Dvls通过Wnt非典型通路中的信号参与了ALK(+)ALCL的发病。据我们所知，这是第一个展示DVLS和致癌酪氨酸激酶之间的物理和功能相互作用的报告。(C)2012 Elsevier Inc.保留所有权利。
Our previous oligonucleotide array studies revealed that ALK-positive anaplastic large cell lymphoma (ALK(+)ALCL) express high levels of the disheveled proteins (Dvls), a family of proteins that is integral to the Wnt signaling pathways. In this study, we assessed whether the Dvls are important in the pathogenesis of ALK(+)ALCL. By Western blotting, Dvl-2 and Dvl-3 were found to be highly expressed in ALK(+)ALCL cell lines and patient samples. The higher molecular weight forms, consistent with phosphorylated/active Dvl proteins, were observed in these lysates. siRNA knock-down of Dvls did not affect the Wnt canonical pathway, as assessed by the beta-catenin protein levels and nuclear localization. In contrast, the same treatment led to changes in the transcriptional activity of NFAT and the phosphorylation status of Src, both of which are known to be regulated by the Wnt non-canonical signaling pathways in other cell types.Coupled with these biochemical changes, there was a significant decrease in cell growth and soft agar colony formation. NPM-ALK the oncogenic tyrosine kinase characteristic of ALK(+)ALCL, was found to bind to the Dvls and enhance their tyrosine phosphorylation. In conclusion, our data suggest that the Dvls contribute to the pathogenesis of ALK(+)ALCL via signaling in the Wnt non-canonical pathways. To our knowledge, this is the first report demonstrating a physical and functional interaction between the Dvls and an oncogenic tyrosine kinase. (C) 2012 Elsevier Inc. All rights reserved.