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E-Cadherin Regulates the Association between ß-Catenin and Actinin-4

¹ Chemotherapy Division and Cancer Proteomics Project, National Cancer Center Research Institute and ² Third Department of Surgery, Tokyo Medical University, Tokyo, Japan

Requests for reprints: Tesshi Yamada, Chemotherapy Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. Phone: 81-3-3542-2511; Fax: 81-3-3547-6045; E-mail: tyamada{at}ncc.go.jp.

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 ß-catenin. In fact, cancer cells that have infiltrated the stroma reduce the expression of E-cadherin and accumulate ß-catenin. We attempted to identify the alternative partner proteins that make complexes with ß-catenin in the absence of E-cadherin. An 100-kDa protein was constantly coimmunoprecipitated with ß-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 ß-catenin and actinin-4. Inhibition of E-cadherin by RNA interference transferred the ß-catenin and actinin-4 proteins into the membrane protrusions of DLD-1 cells. Immunofluorescence histochemistry of clinical colorectal cancer specimens showed that the ß-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 ß-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.

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