E-cadherin regulates the association between beta-catenin and actinin-4.
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 beta-catenin in the absence of E-cadherin. An approximately 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.
Hayashida
Yasuharu
Y
Chemotherapy Division and Cancer Proteomics Project, National Cancer Center Research Institute, Tokyo, Japan.
Honda
Kazufumi
K
Idogawa
Masashi
M
Ino
Yoshinori
Y
Ono
Masaya
M
Tsuchida
Akihiko
A
Aoki
Tatsuya
T
Hirohashi
Setsuo
S
Yamada
Tesshi
T
D000185:Actinin / Q000378:metabolism*; D000199:Actins / Q000378:metabolism; D000595:Amino Acid Sequence; D015820:Cadherins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007797:Laminin; D008840:Microfilament Proteins / Q000378:metabolism*; D008969:Molecular Sequence Data; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017154:Stromal Cells / Q000473:pathology; D014162:Transfection; D051176:beta Catenin / Q000096:biosynthesis / Q000378:metabolism*
C111453:ACTN4 protein, human; D000199:Actins; D015820:Cadherins; D007797:Laminin; D008840:Microfilament Proteins; D051176:beta Catenin; D000185:Actinin