E-cadherin regulates the association between β-catenin and actinin-4
E-cadherin regulates the association between β-catenin and actinin-4
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DOI：
10.1158/0008-5472.can-05-0718
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发表时间：
2005-10-01
期刊：
影响因子：
11.2
通讯作者：
Yamada, T
中科院分区：
文献类型：
--
作者：
Hayashida, Y;Honda, K;Yamada, T
E-钙粘蛋白/连环蛋白系统充当上皮恶性肿瘤的侵袭抑制剂。这种侵袭抑制活性似乎不仅由 E-钙粘蛋白的细胞粘附活性介导，而且还由 β-连环蛋白引发的其他未确定的信号通路介导。事实上，浸润基质的癌细胞会减少 E-钙粘蛋白的表达并积累 β-连环蛋白。我们试图鉴定在没有 E-钙粘蛋白的情况下与连环蛋白形成复合物的替代伙伴蛋白。一种类似于 100 kDa 的蛋白质与来自 SW480 结直肠癌细胞的 β-catenin 不断共免疫沉淀，该细胞缺乏 E-cadherin 的表达，并通过质谱鉴定为 actinin-4。 E-钙粘蛋白 cDNA 的转染抑制了 β-catenin 和 actinin-4 之间的关联。 RNA 干扰对 E-钙粘蛋白的抑制将 β-连环蛋白和肌动蛋白-4 蛋白转移到 DLD-1 细胞的膜突起中。临床结直肠癌标本的免疫荧光组织化学显示，β-catenin 和 actinin-4 蛋白共定位于浸润基质的结直肠癌细胞中。我们之前报道过actinin-4的过度表达会诱导细胞运动，并特异性促进结直肠癌的淋巴结转移。 β-catenin 和 actinin-4 之间的关联及其受 E-钙粘蛋白的调节可能代表了连接细胞粘附和运动的新分子联系。关闭介导这种关联的信号可能值得考虑作为癌症侵袭和转移的治疗方法。
The E-cadherin/catenin system acts as an invasion suppressor of epithelial malignancies. This invasion suppressive activity seems be mediated not only by the cell adhesive activity of E-cadherin but by other undetermined signaling pathways elicited by beta-catenin. In fact, cancer cells that have infiltrated the stroma reduce the expression of E-cadherin and accumulate beta-catenin. We attempted to identify the alternative partner proteins that make complexes with catenin in the absence of E-cadherin. An similar to 100-kDa protein was constantly coimmunoprecipitated with beta-catenin from SW480 colorectal cancer cells, which lack the expression of E-cadherin, and was identified as actinin-4 by mass spectrometry. Transfection of E-cadherin cDNA suppressed the association between beta-catenin and actinin-4. Inhibition of E-cadherin by RNA interference transferred the beta-catenin and actinin-4 proteins into the membrane protrusions of DLD-1 cells. Immunofluorescence histochemistry of clinical colorectal cancer specimens showed that the beta-catenin and actinin-4 proteins were colocalized in colorectal cancer cells infiltrating the stroma. We reported previously that overexpression of actinin-4 induces cell motility and specifically promotes lymph node metastasis by colorectal cancer. The association between beta-catenin and actinin-4 and its regulation by E-cadherin may represent a novel molecular link connecting cell adhesion and motility. Shutting down the signals mediating this association may be worth considering as a therapeutic approach to cancer invasion and metastasis.