α-Catenin overrides Src-dependent activation of β-catenin oncogenic signaling
α-Catenin overrides Src-dependent activation of β-catenin oncogenic signaling
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DOI：
10.1158/1535-7163.mct-07-2029
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发表时间：
2008-06-01
影响因子：
5.7
通讯作者：
Rajasekaran, Ayyappan K.
中科院分区：
文献类型：
--
作者：
Inge, Landon J.;Rajasekaran, Sigrid A.;Rajasekaran, Ayyappan K.
α-连环蛋白的丢失是前列腺癌的特征之一。与 E-钙粘蛋白相关的连环蛋白（α 和 β）在细胞粘附的调节中发挥着关键作用。 β-连环蛋白的酪氨酸磷酸化使其与 E-钙粘蛋白分离并促进其进入细胞核，其中 β-连环蛋白充当转录激活剂，诱导参与细胞增殖的基因。因此，β-连环蛋白调节细胞间粘附和细胞增殖。控制 β-连环蛋白这些功能之间平衡的机制在癌症中总是会发生改变。尽管有大量关于肿瘤发生过程中 β-连环蛋白失调的信息，但关于 α-连环蛋白如何或是否调节 β-连环蛋白功能知之甚少。在这项研究中，我们证明α-连环蛋白充当调节β-连环蛋白的细胞-细胞粘附和增殖功能的开关。在α-连环蛋白缺失的前列腺癌细胞中，α-连环蛋白的重新表达增加了细胞间粘附，并降低了β-连环蛋白转录活性、细胞周期蛋白D1水平和细胞增殖。此外，Src 介导的 β-catenin 酪氨酸磷酸化是 α-catenin-nuil 细胞中 β-catenin 与 E-cadherin 相互作用减少的主要机制。 α-连环蛋白通过增加 β-连环蛋白与 E-钙粘蛋白的结合来减弱 Src 磷酸化的影响。我们还表明，α-连环蛋白可增加前列腺癌细胞对 Src 抑制剂抑制细胞增殖的敏感性。该研究首次揭示α-catenin是β-catenin转录活性的关键调节因子，肿瘤组织中α-catenin的表达状态可能对Src靶向治疗具有预后价值。
Loss of alpha-catenin is one of the characteristics of prostate cancer. The catenins (alpha and beta) associated with E-cadherin play a critical role in the regulation of cellcell adhesion. Tyrosine phosphorylation of beta-catenin dissociates it from E-cadherin and facilitates its entry into the nucleus, where beta-catenin acts as a transcriptional activator inducing genes involved in cell proliferation. Thus, beta-catenin regulates cell-cell adhesion and cell proliferation. Mechanisms controlling the balance between these functions of beta-catenin invariably are altered in cancer. Although a wealth of information is available about beta-catenin deregulation during oncogenesis, much less is known about how or whether alpha-catenin regulates beta-catenin functions. In this study, we show that alpha-catenin acts as a switch regulating the cell-cell adhesion and proliferation functions of beta-catenin. In alpha-catenin-nuil prostate cancer cells, reexpression of alpha-catenin increased cell-cell adhesion and decreased beta-catenin transcriptional activity, cyclin D1 levels, and cell proliferation. Further, Src-mediated tyrosine phosphorylation of beta-catenin is a major mechanism for decreased beta-catenin interaction with E-cadherin in alpha-catenin-nuil cells. alpha-Catenin attenuated the effect of Src phosphorylation by increasing beta-catenin association with E-cadherin. We also show that alpha-catenin increases the sensitivity of prostate cancer cells to a Src inhibitor in suppressing cell proliferation. This study reveals for the first time that alpha-catenin is a key regulator of beta-catenin transcriptional activity and that the status of alpha-catenin expression in tumor tissues might have prognostic value for Src targeted therapy.