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

doi:10.1083/jcb.140.6.1383

A correction to this article has been published: J. Cell Biol. 143 (1) 277

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© The Rockefeller University Press, 0021-9525/1998//1383 $5.00
The Journal of Cell Biology, Volume 140, Number 6, , 1998 1383-1393

Article

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 rolein cell motility and cancer invasion. We have produced a monoclonalantibody (NCC- Lu-632, IgM, k) reactive with an antigenic proteinthat is upregulated upon enhanced cell movement. The cDNA for the antigen molecule was found to encode a novel isoformof nonmuscle ${alpha}$ -actinin. This isoform (designated actinin-4) wasconcentrated in the cytoplasm where cells were sharply extendedand 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-4shifted steadily from the cytoplasm to the nucleus upon inhibitionof phosphatidylinositol 3 kinase or actin depolymerization.The cytoplasmic localization of actinin-4 was closely associatedwith an infiltrative histological phenotype and correlatedsignificantly with a poorer prognosis in 61 cases of breastcancer. These findings suggest that cytoplasmic actinin-4 regulatesthe actin cytoskeleton and increases cellular motility and that its inactivation by transfer to the nucleus abolishes the metastatic potential of human cancers.

Abbreviations used in this paper: GST, glutathione S-transferase; HFK, human foreskin keratinocyte(s); PH, pleckstrin homology; PI3, phosphatidylinositol 3; PIP2, phosphatidylinositol 4,5-biphosphate.

K. Honda is a recipient of a Research Resident Fellowship fromthe Foundation for Promotion of Cancer Research. This researchwas supported in part by a Grant-in-Aid for the Second TermComprehensive 10-Year Strategy for Cancer Control from theMinistry of Health and Welfare, Japan.

The nucleotide sequence data reported in this paper will appearin the GenBank/EMBL/DDBJ nucleotide sequence databases underaccession number D89980.

Address all correspondence to Setsuo Hirohashi, Pathology Division, National Cancer Center Research Institute, 1-1 Tsukiji 5-chome,Chuo-ku, Tokyo 104, Japan. Tel.: +81-3-3542-2511, ext. 4102.Fax: +81-3-3248-2737. E-mail: shirohas{at}gan2.ncc.go.jp

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