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

Abstract

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 α-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.

Actinin-4 expression in ovarian cancer: a novel prognostic indicator independent of clinical stage and histological type

“…Actinin-4, another isoform of non-muscular a-actinin, was recently identified as an actin-bundling protein. 9 The actinin-4 protein is highly concentrated at the leading edge of the cytoplasm of motile cells or actively moving structures such as cell-surface ruffles. [9][10][11][12] The cytoplasmic expression levels of actinin-4 are significantly increased in cells exhibiting enhanced motility.…”

“…9 The actinin-4 protein is highly concentrated at the leading edge of the cytoplasm of motile cells or actively moving structures such as cell-surface ruffles. [9][10][11][12] The cytoplasmic expression levels of actinin-4 are significantly increased in cells exhibiting enhanced motility. 9,10 Increased cytoplasmic expression of actinin-4 is reportedly associated with histologically invasive phenotypes of breast cancer, poor prognosis of breast and non-small cell lung cancers, and lymph node metastasis of colorectal cancer.…”

“…[9][10][11][12] The cytoplasmic expression levels of actinin-4 are significantly increased in cells exhibiting enhanced motility. 9,10 Increased cytoplasmic expression of actinin-4 is reportedly associated with histologically invasive phenotypes of breast cancer, poor prognosis of breast and non-small cell lung cancers, and lymph node metastasis of colorectal cancer. 9,10,13 Notably, Honda et al 9 have also reported the expression of actinin-4 in the nucleus of several cancer cell lines and some low-infiltrative histological subtypes of breast cancer.…”

“…9,10 Increased cytoplasmic expression of actinin-4 is reportedly associated with histologically invasive phenotypes of breast cancer, poor prognosis of breast and non-small cell lung cancers, and lymph node metastasis of colorectal cancer. 9,10,13 Notably, Honda et al 9 have also reported the expression of actinin-4 in the nucleus of several cancer cell lines and some low-infiltrative histological subtypes of breast cancer. This nuclear expression was shown to result from translocation of actinin-4 induced by phosphatidylinositol 3-kinase (PI3-K) inhibitor or by cytochalasin D, which inhibits actin polymerization.…”

“…This nuclear expression was shown to result from translocation of actinin-4 induced by phosphatidylinositol 3-kinase (PI3-K) inhibitor or by cytochalasin D, which inhibits actin polymerization. 9 Therefore, it has been suggested that nuclear translocation of actinin-4 is caused by loss of its association with the cytoplasmic actin cytoskeleton.…”