J. Cell Biol., Volume 140, Number 6, March 23, 1998 1383-1393

Actinin-4, a Novel Actin-bundling Protein Associated with Cell Motility and Cancer Invasion

Kazufumi Honda,^* Tesshi Yamada,^* Ritsuko Endo,^* Yoshinori Ino,^* Masahiro Gotoh,^* Hitoshi Tsuda,^* Yozo Yamada, Hiroshige Chiba, and Setsuo Hirohashi^*§

^* Pathology Division, National Cancer Center Research Institute, Tokyo 104, Japan;  Department of Oral and Maxillofacial Surgery, Tokyo Medical College, Tokyo 160, Japan; and ^§ Hirohashi Cell Configuration Project, ERATO, Japan Scientific and Technology Corporation (JST), Tsukuba 300-26, Japan

Regulation of the actin cytoskeleton may play a crucial role in cell motility and cancer invasion. We have produced a monoclonal antibody (NCC- Lu-632, IgM, k) reactive with an antigenic protein that is upregulated upon enhanced cell movement. The cDNA for the antigen molecule was found to encode a novel isoform of nonmuscle -actinin. This isoform (designated actinin-4) was concentrated in the cytoplasm where cells were sharply extended and in cells migrating and located at the edge of cell clusters, but was absent from focal adhesion plaques or adherens junctions, where the classic isoform (actinin-1) was concentrated. Actinin-4 shifted steadily from the cytoplasm to the nucleus upon inhibition of phosphatidylinositol 3 kinase or actin depolymerization. The cytoplasmic localization of actinin-4 was closely associated with an infiltrative histological phenotype and correlated significantly with a poorer prognosis in 61 cases of breast cancer. These findings suggest that cytoplasmic actinin-4 regulates the actin cytoskeleton and increases cellular motility and that its inactivation by transfer to the nucleus abolishes the metastatic potential of human cancers.

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